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M2M > Unit 2 > Flashcards

Unit 2 Flashcards

1
Q

Genotype

A

Refers to the DNA sequence

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2
Q

Phenotype

A

Refers to the observed traits

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3
Q

Dominant trait

A

A phenotype that is expressed in heterozygotes

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4
Q

Recessive trait

A

A phenotype that is expressed only in homozygotes or hemizygotes

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5
Q

Semi-dominant trait

A

When the hetrozygous phenotype is intermediate between the two homozygous phenotypes

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6
Q

Penetrance

A

The fraction of individuals with a trait genotype who show manifestations of the disease

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7
Q

Expressivity

A

The degree to which a trait is expressed in an individual (~severity)

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8
Q

Pleitropy

A

Some mutations have multiple and different phenotypes

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9
Q

Law of segregation

A

At meiosis, each allele of a single gene separate into different gametes

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10
Q

Law of independent assortment

A

At meiosis, the segregation of each pair of alleles in multiple genes is independent. Each allele has a 50% chance of gong either way

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11
Q

Autosomal trait

A

Classic Mendelian gene - on autosomal chromosomes (1-22)

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12
Q

Sex-linked trait

A

Usually linked to x-chromosome and usuall manifests in males

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13
Q

Mitochondrial trait

A

Passed on from mother to all offspring

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14
Q

Homozygous

A

2 identical alleles

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15
Q

Heterozygous

A

2 different alleles

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16
Q

Hemizygous

A

Refers mostly to males - single copy of gene

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17
Q

How many nuclear chromosomes?

A

46 (23 pairs - 22 autosomes, 1 sex)

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18
Q

What contributes to phenotype?

A

Genotype + Environment

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19
Q

What three chromosomes are most viable in trisomy cases?

A

13, 18, 21

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20
Q

Tandem Repeats

A

Salellite DNAs - alpha-satellite repeats (171bp repeats) near centromeric regions

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21
Q

What is Non-Allelic Homologous Recombination (NAHR)?

A

Between blocks of segmental duplication during meiosis leads to microdeletion and microduplication. May lead to under/over expression of dosage-sensitive genes.

Predisposed to further rounds of NAHR

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22
Q

Gene family

A

Composed of genes with high sequence similarity (>85%) that may carry out similar but distinct functions

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23
Q

DUF1220

A

Gene expressed more and more closer to human. Signs of positive selection in primates. Associated with brain size.

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24
Q

ISCN Nomenclature for individual chromosome

A

Chromosome #; arm (p or q); band number; .sub section

e.x. 1q21.1 (chromosome 1, long arm, 21st band from centromere, 1st sub section).

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25
Q

When should cytogenic studies be ordered?

A
  • Multiple congenital abnormalities
  • Developmental delay + minor abnormalities
  • History of a familial chromosomal abnormality
  • Intrauterine growth reduction or failure to thrive
  • History of multiple spontaneous abortions
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26
Q

Mosaicism

A

Two or more different karyotypes from same individual. Most commonly caused by nondisjunction in early embryonic development.

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27
Q

Hardy-Weinberg Equilibrium

A

allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences.
p + q = 1
p2 + 2pq + q2 = 1

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28
Q

Dispersed repetitive elements

A
  • Alu family (Short INterspersed repetitive Elements - SINE) ~300bp; 500k copies in genome
  • L1 family (Long INterspersed repetitive Elements - LINE) ~6kbp; 100k copies in genome
  • Facilitate aberrant recombination (non-allelic homologous recombination)
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29
Q

Insertion-Deletion Polymorphisms (indels)

A

Minisatellites
- Tandem repeated 10-100bp blocks of DNA (VNTR)
Microsatellites
- di-, tri-, tetra-nucleotide repeats ~5 x 10^4 per genome

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30
Q

Prevalence of Single Nucleotide Polymorphisms (SNPs)

A

1/1,000 bps

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31
Q

Copy number variations (CNVs)

A

Variation in segments of genome from 200bp - 2Mb
Can range from one additional copy to many
Array comparative genomic hybridization (array CGH)

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32
Q

How are gene families created

A

Gene’s duplicated and modified to prevent loss of function of essential genes.

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33
Q

Interhominoid cDNA Array-Based Comparative Genomic Hybridization (arrayCGH)

A

Microarray for cDNA - Fluorescence ratios are dependent on the prevalence of comparable genes. One color means unique gene - hybrid color means shared gene.

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34
Q

Mechanism of DUF1220 proliferation

A

-> Evolutionary advantage -> Increased 1q21.1 instability -> Increased DUF1220 copy number ->

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35
Q

1q21.1 duplications/deletions

A

Duplications -> Macrocephaly; autism

Deletion -> Microcephaly; Schizophrenia

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36
Q

Constitutional Karyotype

A

Congenital aberrations. Can be de novo or familial

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37
Q

Acquired Karyotype

A

Developed after conception

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38
Q

Metacentric Chromosome

A

Centromere is in center of chromosome

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39
Q

Submetacentric Chromosome

A

Centromere is asymmetric along chromosome

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40
Q

Acrocentric Chromosome

A

Centromere is on one side of centromere with a small nub on otherside

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41
Q

ISCN Nomenclature for chromosome counting

A

of individual chromosomes, sex chromosomes, abnormalities.
46,XY - normal male
47,XY,+21 - Trisomy 21 male
45,X - Turner syndrome

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42
Q

Ploidy

A

of homologous chromosome sets

  • Diploid: having two sets (46 chromosomes)
  • Haploid: having one set (23 chromosomes)
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43
Q

Euploidy

A

Full set of chromosomes (46)

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44
Q

Polyploidy

A

Chromosome number more than double

  • Triploidy: having three sets (69 chromosomes)
  • Tetraploidy: having four sets (92 chromosomes)
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45
Q

Aneuploidy

A

Incomplete sets
- Trisomy: 47
- Monosomy: 45
Arises during meiosis

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46
Q

Chiasmata

A

the point where two homologous non-sister chromatids exchange genetic material during chromosomal crossover during meiosis

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47
Q

How many cross-over events/pair of homologous chromosomes?

A

2-3: reason for genetic variability

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48
Q

Incidence issue of aneuploidy

A

Spontaneous Abortions: 50-60%
Stillbirth: 4-6%
Newborns: 0.6%

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49
Q

gene-rich area of chromosome

A

Area where the density of genes is high

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50
Q

gene-poor area of chromosome

A

Area where the density of genes is low

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51
Q

stable area of chromosome

A

Majority of chromosome where genomic variation is depressed

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52
Q

unstable area of chromosome

A

Disease associated regions of chromosome where mutations are more frequent

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53
Q

GC-rich area of chromosome

AT-rich area of chromosome

A

38% of genome

54% of genome

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54
Q

what is euchromatin

A

Looser bound parts of DNA containing transcribed genes

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55
Q

what is heterochromatin

A

Tighter bound parts of DNA containing telomeres and centromeres

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56
Q

Missing Heritability Problem

A

The “missing heritability” problem can be defined as the fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person’s susceptibility to disease may depend more on “the combined effect of all the genes in the background than on the disease genes in the foreground”.

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57
Q

How big are visible Structural Abnormalities?

What do they require?

A

5mb of DNA

Required Double Strand Breaks

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58
Q

What are the two major classes of structural abnormalities?

A

Balanced: Normal complement of chromosomal material
Unbalanced: Abnormal complement of chromosomal material

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59
Q

What is a translocation?

A

A reciprocal, interchromosomal exchange. A break in an arm of each of two chromosomes and an exchange of material.

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60
Q

What is a balanced translocation?

A

No apparent gain or loss of genetic material

No phenotypic effect (exception when the breakpoint is in a gene)

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61
Q

What type of splicing is conducive to balanced translocations? Unbalanced?

A

Balanced: Alternate splicing
Unbalanced: Adjacent splicing

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62
Q

How are reciprocal translocations formed at Meiosis I?

A

In a reciprocal translocation, two non-homologous chromosomes break and exchange fragments.

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63
Q

What happens during reciprocal translocations?

A

Centromeres of homologues go to opposite poles

Only mode of segregation that leads to gamete with full and balanced chromosome complement

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64
Q

What happens during adjacent translocations?

A

Adjacent centromeres go to same pole

Results in trisomy and monosomy for translocated segments

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65
Q

Relationship between size of translocation and possibility of additional translocation? Why?

A

The larger the translocation the greater the chance of additional translocations. This is because there are additional sequences that can bind to homologue chromosome in incorrect spot.

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66
Q

What are the risks of translocation carriers having unbalanced offspring?

A

0-30%. Maternal carriers have a greater chance than paternal.

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67
Q

What is a Robertsonian Translocation?

A

Structural chromosomal rearrangement between acrocentric chromosomes at the centromere.

Short arm lost.

Risks to having offspring with unbalanced karyotypes

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68
Q

What elements of the chromosome are lost in Robertsonian Translocations?

A

α (centromeric area – some, not all)
β
satelites I-IV
rRNA encoding genes

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69
Q

What are the most common Robertsonian Translocations?

A

13;14 - 75%
14;21
21;21

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70
Q

Characteristics of balanced Robertson Translocations?

A

Usually no phenotype

Risk to having offspring with unbalanced karyotype

Increased infertility in balanced RT men

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71
Q

Characteristics of unbalanced Robertson Translocations?

A

46 chromosomes

Normal homologue PLUS RT homologue - usually leads to trisomy 21 (or 13)

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72
Q

What are chromosomal inversions?

A

Inverted segment in chromosome

Normal phenotype (usually)

Familial

~1% of population

Can be pericentric or paracentric

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73
Q

What are pericentric inversions?

A

Inverted segment including centromere

Break in both p and q arm

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74
Q

What are the most common benign pericentric inversions?

A

9 qh, 16qh, 1qh, Yqh

Not associated with SAB, infertility or recombinant offspring

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75
Q

How do pericentric inversions behave during meiosis?

A

Form loops to maximize pairing

Potential to form recombinant chromosomes which result in deletions and duplications (~50%) (can result in trisomy phenotype)

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76
Q

What is the rec(8) phenotype?

A

Normal fetal development
VSD (Ventricular Septal Defect)
Hypertelorism, thin upper lip, wide face
Recurrent risk of 6.7% in families

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77
Q

What are paracentric inversions?

A

Inversions NOT including centromere

Two breaks within the same arm

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78
Q

What can paracentric inversions lead to?

A

Aniridia
Turner Syndrome

Chromosomes with either two or zero centromeres which are highly unstable

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79
Q

Deletion or Duplication 22q11.2 syndrome

A

Critical protein TBX-1 involved in neural crest cells into pharyngeal arches and pouches resulting in cleft lip/palate and heart defects.

Thymus defects: T cell dysfunction
Parathyroid defects: hypocalcemia

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80
Q

What is an epigenetic effect?

A

Mitotic and meiotically heritable variations in gene expressions that are not caused by changes in DNA.

They are reversible, post-translatable modifications of histones and DNA methylation.

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81
Q

Describe the mechanism by which genes are regulated epigenetically.

A

DNA gets methylated in CpG islands

MeCP2 recognizes methylated regions and deacetylates histones which causes them to tighten their binding with DNA.

This silences the genes… except when it doesn’t…

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82
Q

Describe sex-dependent epigenetic modulation:

A

Genes are methylated depending on if they are paternal or maternal. This ensures the proper modulation of genetic material so the proper number of proteins are produced.

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83
Q

Where are DNA methylation marks established?

A

In the gamete

It is reversible and reestablished during gametogenesis to transmit the appropriate sex-specific imprint to progeny

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84
Q

How is methylation altered after fertilization

A

It isn’t. It is stable once the embryo is fertilized.

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85
Q

What are two examples of genetic imprinting (methylation) disorders?

A

Prader-Willi Syndrome: Deletion of paternal 15q11-13

Angelman Syndrome: Deletion of maternal 15q11-13

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86
Q

What is the imprinting center on a gene?

A

The region on a chromosome proximal to the genes which determine what genes will be expressed.

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87
Q

What is trisomy rescue?

A

Mitotic disjunction early in gestation which kicks out an extra chromosome, rescuing it from lethality.

Can lead to Prader-Willi or Angelman syndromes

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88
Q

What are the prognoses for Acute Lymphocytic Leukemia?

A

Hypodiploid: Poor
Hyperdiploid: Favorable

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89
Q

3yo female presenting: 2wks intermittent extremity pain; 102deg; Abdomen distention; Irritable; Liver down 7cm; Scattered bruises on shins; high blast count. What’s up?

A

B-lymphoblastic leukemia

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90
Q

What is FISH?

A

Fluorescence In Situ Hybridization: Used to identify specific chromosomal abnormalities by annealing fluorescent probes to known sequences.

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91
Q

What are FISH dual fusion probes used for?

A

Translocations
Determining products of gene fusion (BCR/ABL)
Marking chromosomes and then marking specific genes

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92
Q

What causes Acute Myelogenous Leukemia (AML)

A

PML-PAR(alpha)

ABL1-BCR

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93
Q

11yo presents with ++ bleeding; Blasts: 15% ++; Bone marrow: (Blasts:81%++), Auer rods. Sup?

A

Acute Promyelocytic Leukemia 46, XY,t(15;17)

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94
Q

30yo Night sweats; fatigue, weight loss, anemia. Peripheral blood smear shows lobulated large cell. Ugly spleen. What’s going on?

A

Chronic Myeloid Leukemia 46, XY, t(9;22)

Treat with Gleevec

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95
Q

Chromosomal MicroArray

A

Targets DNA on a slide

Detects gains and losses

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96
Q

Characteristics of cytogenetic testing

A 
Genome Screen
Mitotic Cells
Selected Cells
Gain/Loss
Balanced Rearrangements
Technologist Expertise
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97
Q

Characteristics of CMA

A 
Genome Screen
Interphase DNA
Analyze all cells
Gain/Loss only
Technology-dependent
Detects runs of homozygosity
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98
Q

Advantages of CMA

A

Detects chromosomal gains/losses of tiny mutations.
Detects abnormalities in known hot spots
Detects abnormalities in backbone

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99
Q

6yo female w/ global development delay, ADHD, lack of coordination and congenital anomaly of aortic arch. Receiving OT. CMA and FISH indicate loss in 22q11.21. What does this chromosomal abnormality indicate?

A

DiGeorge Syndrome

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100
Q

3yo female w/ hx of failure to thrive, short stature and dysmorphic facies. Admitted to ED w/ cough, vomiting. CMA and FISH indicate loss in 16p11.2 What does the chromosomal malformation indicate?

A

Autism

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101
Q

Laboratory reporting thresholds of Chromosomal MicroArray

  • Deletions
  • Duplications
  • Runs of Homozygosity (ROH)
A
  • Deletions: >200kb
  • Duplications: > 400kb
  • ROH: > 5Mb - 10Mb
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102
Q

What are FISH centromere probes used for?

A

enumeration - ALL panel; prenatal dx

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103
Q

What are the chromosomal abnormalities associated with Down Syndrome?

A

Trisomy 21: 95%
Unbalanced Translocation involving chromosome 21: 3-4%
Mosaic trisomy 21: 1-2%

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104
Q

What are the phenotypes associated with Down Syndrome?

A
  • Normal growth
  • Midfacial hypoplasia
  • Upslantng palpebral fissures
  • Small Ears
  • Protruding tongue
  • Low muscle tone, increased joint mobility
  • Short fingers, transverse palmar crease, 5th finger incurving, increased space between 1st and 2nd toes
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105
Q

What are the medical problems associated with Down Syndrome?

A
  • Cardiac (50%): Atrioventricular Canal is most common to DS.
  • Gastrointestinal (10-15%): Esophageal atresia, duodenal atresia, Hirschprung’s (missing ganglion cells in colon)
  • Functional GI issues: Feeding problems, constipation, GERD, Celiac Dz
  • Ophthalmologic: Blocked tear ducts, myopia, lazy eye, nystagmus, cataracts
  • ENT: Chronic ear infections, deafness, chronic nasal congestion, enlarged tonsils and adenoids
  • Endocrine: Thyroid Dz, insulin dependent diabetes, alopecia areata, reduced fertility
  • Orthopedic: hips, joint subluxation, atlantoaxial subluxation
  • Hematologic Issues: Myeloproliferative disorder, increased risk of leukemia, iron deficiency anemia
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106
Q

What is the developmental and behavioral phenotype of Down Syndrome?

A
  • Hypotonia effects gross motor development
  • Spectrum of intellectual disability - average is mild-moderate disabilities
  • Speech problems
  • Neurologic problems: hypotonia, seizures
  • Psychiatric issues: depression, early onset Alzheimer’s, Autism
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107
Q

What prenatal screening is done for Trisomy 21?

A

1st Trimester

  • Ultrasound measurements of nuchal folds
  • β-hCG
  • PAPP-A

2nd Trimester

  • αFP
  • Unconjugated estriol and inhibin levels
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108
Q

Describe the chromosomal 15 abnormalities associated with Prader-Willi Syndrome (PWS) and how to test for them.

A

Genetic information missing from paternal allele of 15q11-q13. Can occur by uniparental disomy or imprinting error. Tested by using FISH or microarray

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109
Q

Describe the role of imprinting in disorders involving chromosome 15.

A

Prader-Willi Syndrome - errors or deletions in paternal imprinted regions of chromosome 15.
Angelman Syndrome - errors or deletions in maternal imprinted regions of chromosome 15.

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110
Q

Describe the physical features (Phenotype) seen in a patient with Prader-Willi Syndrome.

A

Infancy: hypotonic, almond shaped eyes, undescended testicles (males), feeding problems, lighter pigmentation

Toddler/Preschooler: feeding problems reverse - overeat

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111
Q

Describe the medical problems seen in patients with Prader-Willi Syndrome.

A

Eyes: Strabismus
Orthopedics: scoliosis
Respiratory: Obstructive sleep apnea

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112
Q

Recognize and describe the developmental and behavioral phenotypes of a patient with Prader-Willi Syndrome.

A

Developmentally: Mild-moderate cognitive disabilities, and behavioral issues are common

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113
Q

Describe Inverted Duplicated Isodicentric 15q (IDIC 15)

A

Autism

Polymorphisms is GABA locus (important neurotransmitter)

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114
Q

Describe Angelman Syndrome

A

Mildly dismorphic facial features which evolve with age. Hypotonia in infancy which leads to spasticity. Intellectual disability, seizures, Autism

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115
Q

Describe Maternally Derived Interstitial 15q duplications

A

Phenotypical only from mom.

Autism. NOT dysmorphic, seizures, hypotonia during infancy

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116
Q

Define and distinguish between pharmacogenetics and pharmacogenomics.

A

Pharmacogenetics: Study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity (variable response due to individual genes)

Pharmacogenomics: Genomic approach to pharmacogenetics, concerned with the assessment of common genetic variants in the aggregate (variable response due to multiple loci across the genome)

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117
Q

Explain the two major physiologic response to drugs, pharmacokinetics and pharmacodynamics, and briefly contrast Phase I and Phase II drug metabolism steps.

A

Pharmacokinetics: describes Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs.

Pharmacodynamics: describes the relationship between the concentration of a drug at its site of action and the observed biological effects.

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118
Q

Explain the central role of the CYP450 enzyme system in drug metabolism.

A

CYP450 complex are detoxifying proteins active in liver and intestinal epithelium. Most CYPs function to inactivate drugs but rarely are needed for activation (CYP2D6: codeine -> morphine)

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119
Q

What does CYP3A do?

A

Metabolizes cyclosporine, ketoconazole, rifampin,

grapefruit juice inhibits

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120
Q

What does CYP2D6 do?

A

Metabolizes codeine (activation into morphine)

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121
Q

What do CYP2C9 + VKORC1 do?

A

Metabolizes Warfarin

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122
Q

What does NAT (N-Acetyltransferase) do?

A

Metablozies Isoniazid

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123
Q

What does TPMT (Thiopurine Methyltransferase) do?

A

Metabolizes 6-mercaptopurine/ 6-thiguanine

prescribed for childhood ALL

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124
Q

What does G6PD do?

A

Deficiency causes hemolytic anemia

Given after sulfa drugs

125
Q

Define the field of population genetics and explain why “population-field” has relevance to doctors who often treat just “one patient” at a time.

A

The study of allele frequencies and changes in allele frequencies in populations

126
Q

Explain the assumptions required for Hardy-Weinberg principle to apply.

A
  • Population is large
  • Matings are random
  • Allele frequencies remain constant over time
    . no appreciable rate of mutation
    . all genotypes are equally fit
    . no significant immigration/ emigration
127
Q

Describe the biological advantages of sexual reproduction.

A

Introduction of genetic variation to propagate fitness and new genetic traits

128
Q

Describe X chromosomal inactivation and its implications.

A

No matter how many X chromosomes there are, there is still only one that is fully active. The remainders probably have little function which leads to genetic disorder when there is aneuploidy

129
Q

Describe the genetic regulation of sexual differentiation.

A

Generally the presence of a normal Y chromosome results in a male individual.

Presence of a normal X chromosome and absence of a Y chromosome results in a female individual

130
Q

Describe the basic embryology of dimorphic human reproductive organs.

A

7th wk: Male
genital ridge Sertoli ; Leydig Cells
8th wk:
Male –> Leydig produce testosterone; Sertoli produce Anti Mullerian Hormone; primitive sex cords –> testis cords; rete testis
Female –> Primitive sex cords dissociate. cortical cords are formed

Genital ducts:
Mesonephric (Wolffian) duct: Male (under influence of testosterone)
Paramesonephric (Mullerian) duct: Female

131
Q

Describe the clinical characteristics of disorders of sex chromosomes.

A

Based on Prader Scale from “no virilization” to stage 5 “full virilization”

132
Q

Describe the clinical approach to disorders of sexual differentiation.

A 
Day 1: FISH studies for sex chromosomes and karyotype
Hormone studies
Ultrasound study (evaluate for gonads; uterus)
Surgical consult with urology, endocrinology, genetics, psychology
133
Q

Turner Syndrome

A 
45, XO
- Signs at birth
  . prenatal cystic hygroma
  . webbed neck
  . puffy hands and feet
  . heart defects
- Short stature
- Normal intelligence
- Infertility
- Hormone dysfunction
- low set ears and broad chest
- 1/2500 newborn girls
134
Q

Kleinfelter Syndrome

A 
47, XXY
- Can be seen in childhood
  . learning disabilities
  . Delayed speech
  . tendency toward being quiet
- Tall stature
- Small testes
- Reduced facial and body hair
- Infertility
- Hypospadias
- Gynecomastia
- 1/500 - 1/1000 newborn boys
135
Q

Jacobs Syndrome

A

47, XYY

  • Learning disabilities
  • Speech delays
  • Developmental delays
  • Behavioral and emotional difficulties
  • Autism spectrum disorders
  • Tall stature
  • 1/1000 newborn boys
136
Q

Triple X Syndrome

A 
47, XXX
- Tall stature
- Increased risk of 
  . Learning disabilities
  . Delayed speech
  . delayed motor milestones
  . Seizures
  . Kidney abnormalities
- 1/1000 newborn girls
137
Q

Androgen Insensitivity Syndrome

A

46, XY
Causes abnormality of androgen receptor
Phenotypes range from mild under-virilization to full sex reversal

138
Q

5-Alpha Reductase Deficiency

A

46, XY
Causes decreased ability of the body to convert testosterone to dihydrotestosterone
Phenotype: undervirilized male with increased virilization at puberty

139
Q

Describe development of external genitalia

A 
Both originate from urogenital sinus
Male structures: Androgen exposure leads to 
- penis
- scrotum
- urethral opening at tip of penis
Female structure: Estrogen exposure leads to
- clitoris
- labia majora and minora
- lower 2/3 of vagina
140
Q

A young child presents to your office with a genotype of 46XY del(15)(q11q13) on the maternal chromosome. Which of the following clinical features would be most consistent with the patient’s genotype?

hypotonia
seizures
transverse palmar creases
obesity

A

seizures

141
Q

How are imprinting patterns maintained in offspring?

maintenance demethylation
maintenance methylation
methylation patterns coded by sex chromosomes
no maintenance is necessary

A

maintenance methylation

142
Q

Methyl CpG binding proteins are the proteins that bind to the methylated portion of the chromosome and affect gene expression. In a patient with Prader-Willi Syndrome, where would you expect these proteins to bind?

Paternal chromosome 15, enhancing transcription
Paternal chromosome 15, silencing transcription
Maternal chromosome 15, enhancing transcription
Maternal chromosome 15, silencing transcription

A

Maternal chromosome 15, silencing transcription

143
Q

Prader-Willi and Angelman’s syndromes result from genetic aberrations to the same region of chromosome 15. Which of the following correctly explains why the resulting phenotypes differ from each other?

Phenotype depends on whether the mutation is maternal or paternal in origin
Severity of disease worsens with succeeding generations
Variable expressivity effects
One allele exerts dominant negative effects over the other

A

Phenotype depends on whether the mutation is maternal or paternal in origin

144
Q

Which of the following correctly describes the mechanism for an epigenetic modification?

reversible modification to chromatin structure
irreversible modification to chromatin structure
post-transcriptional modification to DNA sequence
post-translational modification to DNA sequence

A

reversible modification to chromatin structure

145
Q

Which of the following is an essential characteristic for normal epigenetic marking to be successful?

Modification must be established in the developing embryo
Differential modification must occur when alleles are in the same compartment
Modification must remain stable after fertilization
Modification must be permanent

A

Modification must remain stable after fertilization

146
Q

After ordering a Chromosomal Microarray report on a patient, how many oligomers should be present before pursuing further investigation?

3
13
30
300

A

3

147
Q

An 11-year-old female presents to your office with excessive bleeding after a tooth extraction. Upon microscopy you find 15% blasts. You decide to examine a bone marrow sample, which shows Auer Rods and 81% blasts. A FISH analysis using a fusion probe detects a PML/RARA translocation. What is your diagnosis?

CML - chronic myelogenous leukemia
AML - acute myelogenous leukemia
ALL - acute lymphoblastic leukemia
APL - acute promyelocytic leukemia

A

AML - acute myelogenous leukemia

148
Q

Hyperdiploidy revealed by chromosome and FISH analysis is diagnostic for which type of leukemia?

acute lymphoblastic (ALL) 
chronic myelogenous (CML) 
acute myelogenous (AML) 
chronic lymphoblastic (CLL)
A

acute lymphoblastic (ALL)

149
Q

In which of the following cases would you use a centromeric probe during FISH analysis?

enumeration leukemias (ALL) 
deletion leukemias 
translocation leukemias (CML, AML) 
locus specific leukemias
A

enumeration leukemias (ALL)

150
Q

The bcr-abl oncogene is detected by FISH using which type of probe?

locus-specific
fusion
whole chromosome
centromeric

A

fusion

151
Q

The genotype t(15;17) is diagnostic for which type of leukemia?

acute lymphoblastic (ALL) 
chronic myelogenous (CML) 
acute promyelocytic (APL) 
chronic lymphoblastic (CLL)
A

acute promyelocytic (APL)

152
Q

What is the purpose of a whole chromosome paint using FISH?

identification of markers and translocations
identification of parent of origin imprints
identification of microdeletions
identification of copy number variations

A

identification of markers and translocations

153
Q

A female baby is born to a 38-year-old mother. The baby is moderately floppy, with transverse palmar creases. There is a large gap between her first two toes, and her occipital bone is flatter than normal. You are worried about all of the following potential medical complications EXCEPT:

frequent ear infections
GERD
indiscriminate eating and obesity
Alzheimer’s

A

indiscriminate eating and obesity

154
Q

About 95% of Down syndrome is due to true trisomy 21. Which of the following karyotypes could also be Down syndrome?

47, XX, +21 / 46, XX
46, XX, del(21)(p16.3)
46, XX, dup(21)(q22q25
46, XX, ins(21)(p13q21q31)

A

47, XX, +21 / 46, XX

155
Q

If a pregnant 40-year-old woman presents to your office at 16 weeks of gestation, what standard test are you likely to perform to rule out Down syndrome?

amniocentesis followed by FISH
amniocentesis followed by restriction digest assay
amniocentesis followed by Southern blot analysis
ultrasound

A

amniocentesis followed by FISH

156
Q

What percentage of babies with Down syndrome also have congenital heart defects?

10%-20%
30%-50%
50%-75%
almost 100%

A

30%-50%

157
Q

All of the following pertain to retrotransposons EXCEPT:

SINEs, LINEs and NAHR
Alpha satellites
insertional inactivation
Mobility to any position on genome

A

Alpha satellites

158
Q

Which of the following best describes pseudogenes?

They are functional, exon containing regions that are sometimes inactivated by methylation
They are functional exon containing regions that are only expressed in hemizygotes
They are non-functional genes that can be synthesized through reverse transcription
They are non-function genes that always contain introns and are retrotransposive

A

They are non-functional genes that can be synthesized through reverse transcription

159
Q

Which of the following is correct regarding the distribution of A-T and C-G rich regions in DNA?

38% AT, 54% CG may occur in clusters or be distributive
54% AT, 38% CG may occur in clusters or be distributive
54% AT, 38% CG only occur in banding patterns
38% AT, 54% CG only occur in banding patterns

A

54% AT, 38% CG may occur in clusters or be distributive

160
Q

Which of the following is true regarding copy number variations?

They cover 50% of the genome
They are highly conserved genetic sequences
They are enriched with non-specific duplications
They are often enriched with sequence gaps

A

They are often enriched with sequence gaps

Copy number variations are often enriched with specific duplications, sequence gaps and are associated with recurrent disease. CNV’s are a primary structural variation in DNA. CNV’s are not highly conserved, rather they have been associated with rapid evolutionary and genetic change. CNV’s cover 12% of the genome, and can range from one additional copy to many.

161
Q

Which of the following is true regarding gene families?

They share 8.5-9% common sequences
They arise through genomic deletions
Duplication rich regions are associated with non-allelic homologous recombination
Members always have identical functions

A

Duplication rich regions are associated with non-allelic homologous recombination

162
Q

Joe has a disease called awesomitis, he is married to Jane and they have 4 children. Neither of his sons are affected but both of his daughters, Janet and Jenny are. His daughter Janet married Jed and they have identical twin boys who both have awesomitis and one son who is unaffected. One of the twins, Justin, marries Bieber, who is unaffected. They have 3 sons who do not have awesomitis. What is the inheritance pattern?

X-linked recessive
X-linked dominant
Y-linked
Autosomal recessive

A

X-linked dominant

163
Q

Sally has 4 siblings and is married to Joe. They have 7 children and 6 grandchildren and her parents are still living. Sally has 2 nieces and 4 nephews. How many 1st degree relatives does she have?

6
7
11
13

A

13

4 siblings 2 parents 7 children

164
Q

Which of the following is a characteristic of autosomal recessive traits?

Vertical inheritance pattern
Consanguinity decreases the number of homozygotes
Carriers do not have the phenotype
100% of daughters will be affected if their dad is.

A

Carriers do not have the phenotype

165
Q

Which of the following is an example of variable expressivity?

10 homozygotes with the same recessive alleles show manifestations of disease in skin, liver and reproductive systems
Two heterozygotes for CF mate and have a 25% chance of having a child with CF.
Two 30 year old individuals have the same single-gene disease that affects muscle tone. One must use a wheelchair and the other is able to walk
A single-gene recessive disease has been shown to onset in both childhood and adulthood

A

Two 30 year old individuals have the same single-gene disease that affects muscle tone. One must use a wheelchair and the other is able to walk

166
Q

Which of the following is true of Y-linked pedigrees?

If an affected dad has four daughters, their children have a 25% chance of getting the allele
Only males are affected and all sons must have an affected father
They are the pattern of inheritance for mitochondrial DNA
Women are typically carriers

A

Only males are affected and all sons must have an affected father

167
Q

Your patient reports that his nephew has dystrophic epidermolysis bullosa, a rare autosomal recessive skin condition (~1:1,000,000 live births) where Affected infants are typically born with widespread blistering and areas of missing skin, often caused by trauma during birth. You want to use the Hardy-Weinberg principle to estimate the likelihood that your patient’s spouse is a carrier of dystrophic epidermolysis bullosa. Which of the following can you assume?

p2 is the population risk
2q estimates 2pq
2pq is the risk of being an affected heterozygote
our patient’s risk is equal to the population risk

A

2q estimates 2pq

168
Q

A baby is born to a 40-year-old mother. The baby weighs 2lbs 7 oz. even though the pregnancy was carried to full term. You notice a cleft palate as well as two extra digits on the baby’s left hand. You do a transverse CT of the baby’s brain and see that there is no division between right and left lobes. You diagnose the baby with Patau syndrome. A karyotype of the baby’s chromosomes will show:

trisomy 13
trisomy 18
trisomy 21
47 XXY

A

trisomy 13 (Patau Syndrome)

169
Q

A female baby is born to a 25-year-old mother. The baby weighs only 3 lbs. but was carried to full term. The baby’s hands remain clenched and her hips are very narrow. A valvular heart defect was identified before she was born. Shortly after her birth, the baby experiences a number of seizures. What is the baby’s most likely genotype?

47, XX + 18
47, XX + 13
46, XX der(14;18)(p12;p12)+18
46, XX der(14;13)(p12;p12)+13

A

46, XX der(14;18)(p12;p12)+18 (Edwards Syndrome)

Usually due to translocation not UPD (also, mother is young so UPD not likely) so A and B are incorrect. D would be the phenotype for a Patau syndrome caused by translocation.

170
Q

During mitosis, centromeres on paired sister chromatids segregate from each other during which phase?

prophase
metaphase
anaphase
telophase

A

anaphase

During mitosis, sister chromatids segregate from each other during anaphase. Mitosis = one round of DNA replication + one round of chromosome segregation. Daughter cells are identical to the parent cells.

171
Q

Paternally and maternally derived homologous chromosomes synapse along their entire length to form bivalent structures during which phase of meiosis?

prophase I
prophase II
anaphase I
anaphase II

A

prophase I

172
Q

Recombination is required for which of the following to be successful?

mitosis
meiosis
both
neither

A

meiosis

173
Q

Which of the following is a feature of BOTH mitosis and meiosis?

euploid number of chromosomes
homologous chromosome pairing
recombination via chiasmata
DNA replication during prophase

A

DNA replication during prophase

174
Q

Which of the following is correct regarding DNA structure?

AATTCCUUU represents an STRP microsatellite
ATCATCATC represents a VNTP minisatellite
46XY, del (4)(p13.3) represents a terminal deletion
46XX, dup (1)(q22q25) represents mosaicism

A

46XY, del (4)(p13.3) represents a terminal deletion

175
Q

A 4-year-old boy comes to your clinic for an obesity evaluation. He was born at term but his mom noticed minimal movements during pregnancy. He was very floppy when he was born, had undescended testicles and mildly unusual facial features. He had difficulty feeding as an infant but now eats anything and everything in sight without satiety. What do you suspect is his genotype?

trisomy 21
15q11-q13 paternal deletion (detected by FISH), normal karyotype
15q11-q13 maternal deletion (detected by FISH), normal karyotype
22q11.3 deletion (detected by FISH), normal karyotype

A

15q11-q13 paternal deletion (detected by FISH), normal karyotype

176
Q

An interstitial 15q duplication is found in a FISH study. Without knowing the patient’s symptoms, what can you conclude based on the fact that the methylation tests show the duplication to be paternally derived?

the patient will have have autism
the patient will have Prader-Willi
the patient will have Angelman’s
the patient will be phenotypically normal

A

the patient will be phenotypically normal

15q duplications that are paternally derived will show a normal phenotype. 15q duplications that are maternally derived will have partial trisomy as the phenotype and increased likelihood of autism It must be a paternal DELETION to be Prader-Willi; Angelman’s is associated with a maternal deletion.

177
Q

Sleep apnea is a contraindication to the use of growth hormone in PWS patients. For this reason, treatment with growth hormone should begin:

at onset of excessive eating symptoms onset
as soon as the patient reaches an obese BMI
in utero
as soon as a patient is diagnosed with sleep apnea

A

at onset of excessive eating symptoms onset

178
Q

What effect will supplemental growth hormone have on a child with Prader-Willi Syndrome?

decrease weight but will not change height
increase height, alleviate excessive eating
increase height but may cause excessive eating
decrease weight and arrest growth

A

increase height, alleviate excessive eating.

179
Q

Besides PWS and Angelman’s, 15q deletions have been associated with what disorder?

Down Syndrome
Charcot Marie Tooth
Autism
DiGeorge

A

Autism

180
Q

You do a FISH study on a child who presents with severe developmental delays and seizures. He is otherwise phenotypically normal, with normal facial features and no obvious anatomic defects. What is the most likely finding?

IDIC 15 (Supernumerary marker chromosome) 
Paternal deletion of 15q11q13 
Maternal deletion of 15q11q13 
Robertsonian translocation at 21p33
A

IDIC 15 (Supernumerary marker chromosome)

IDIC is the most common marker for autism. These patients are hypotonic but not dysmorphic, seizures common (Supernumerary marker chromosome)

181
Q

A normal healthy parent has a baby with the genotype 47XXY i(Xq). What is the likelihood that a second child will also have an abnormal genotype?

A

100%

Since the first baby has a normal Y you can assume that the mom is the carrier of iXq. Though her phenotype is normal, this is the only X she can pass on. All offspring will have the isochromosome for X.

182
Q

In the ‘two-hit’ model of maternal age effect what are considered to be the first and second hits?

diminished recombination cause by a lack of chiasmata or mislocated chiasmata, faulty segregation of chromosomes by oocytes
too much recombination too close to the centromere, faulty alpha satellites
maternal DNA gets shorter due to age and degeneration of telomerases
diminished recombination due to chiasmata that can no longer attach to spindle fibers.

A

diminished recombination cause by a lack of chiasmata or mislocated chiasmata, faulty segregation of chromosomes by oocytes

183
Q

Two cells derived from two different male patients are cultured in lab and stimulated to undergo meiosis. The first cell, undergoes an error during meiosis 1, the second undergoes an error during meiosis 2. If these cells were used to fertilize genotypically normal female eggs in-vitro, what will be the possible genotypes and phenotypes of their offspring?

Cell 1: 47, XYY fertile, Cell 2: 47, XXY infertile
Cell 1: 47, XYY infertile, Cell 2: 47, XXY fertile
Cell 1: 47, XXY fertile, Cell 2: 47, XYY infertile
Cell 1: 47, XXY infertile, Cell 2: 47, XYY fertile

A

Cell 1: 47, XXY infertile, Cell 2: 47, XYY fertile

Paternal error in meiosis 1 results in 47XXY, Klinefelter. Patients are usually infertile with tall stature, hypogonadism, gynecomastia and language impairment. Paternal error in meiosis 2 results in XYY (XYY syndrome). Patients are phenotypically normal and usually fertile. Increased risk of behavior and educational/speech problems, but not associated with criminality. Both are 1/1000 live births

184
Q

What is indicated by a genotype of 46, X i(Xq)?

an inversion of the long arm of X
A patient with mosaic Turner syndrome
an ideogram showing only the long arm of X
a female with isochromosome for the long arm of X

A

a female with isochromosome for the long arm of X

185
Q

What is the genotype of a male with fragile X?

45, X
46, XX
46, Y fra(X)(q27.3)
46, XY fra(Xp)(p22p25)

A

46, Y fra(X)(q27.3)

186
Q

What type of inversion in this? 46, XX inv(9)(p13q13)

unbalanced acentric
balanced dicentric
balanced paracentric
balanced pericentric

A

balanced pericentric

187
Q

Which of the following is the correct pair of normal genetic variation steps that occur in meiosis?

nondisjunction during prophase 1, recombination during prophase 1
disjunction during anaphase, recombination during prophase
non-disjunction during anaphase, recombination during prophase
crossover during metaphase, disjunction during telophase

A

disjunction during anaphase, recombination during prophase

disjunction (segregation) during anaphases 1 and 2, recombination (crossover) during prophase 1 Nondisjunction most frequently occurs during anaphase 1 but can happen during anaphase 2.

188
Q

47XXY individuals

develop as females but have male gonads
develop as males but have gonadal dysgenesis
have 2 active X chromosomes
experience a lack of estrogen production

A

develop as males but have gonadal dysgenesis

189
Q

A 46XY individual with androgen insensitivity will have:

external male genitalia with female gonads
external female genitalia with male gonads
duplication of DAX1
duplication of SF1

A

external female genitalia with male gonads

190
Q

What are the 3 steps of sexual determination?

genetic presence or absence of Y, development of gonads, development of internal and external organs
genetic presence or absence of Y, establishment of imprinting patterns, gonad development
genetic presence or absence of X, gonad development, imprinting
genetic presence or absence of X, gonad development, sexual organ development

A

genetic presence or absence of Y, development of gonads, development of internal and external organs

191
Q

X-inactivation:
depends on XIST expression on the active X
inhibits Xp activation in males
involves cis formation of XIST RNA/Barr body complex
will occur so that the same X is expressed in all female cells

A

involves cis formation of XIST RNA/Barr body complex

192
Q

Which of the following best describes the study of differences in drug resistance due to allelic variation in discrete genes affecting drug metabolism, efficacy and toxicity?

pharmacogenetics
pharmacogenomics
pharmacokinetics
pharmacodynamics

A

pharmacogenetics

193
Q

You want to prescribe rifampicin to a renal transplant patient. Why will you also need to increase his dose of cyclosporin?

cyclosporin induces CYP3A to metabolize rifampin more quickly
he has an infection so immunosuppressants + antibiotic will have the most efficacy
rifampicin induces CYP3A to metabolize cyclosporin more quickly

A

rifampicin induces CYP3A to metabolize cyclosporin more quickly

rifampicin induces CYP3A to metabolize cyclosporin so the patient will need more cyclosporin so that he will not reject his new kidney

194
Q

Which of the following correctly defines pharmacogenetics?

how much of a drug reaches its target
what happens once the drug reaches its target
the examination of polymorphic loci in a population
the examination of individual alleles and their differences

A

the examination of individual alleles and their differences

Pharmacokinetics = how much/if a drug reaches its target Pharmacogenetics = examines a few genes/individual allele differences Pharmacogenomics = examines polymorphic loci at large Pharmacodynamics = what happens once the drug reaches its target

195
Q

Which of the following is most correct regarding CYP2D6?
it is involved in phase 2 metabolism
it is involved in the metabolism of 40% of clinical drugs
it is involved in the conversion of codeine into morphine
it is involved in the metabolism of mercaptopurines in the treatment of childhood leukemia

A

it is involved in the conversion of codeine into morphine

196
Q

Which of the following mutations to a CYP gene is most likely to result in DECREASED levels of free drug in a patient’s plasma?

frameshift
increased copy number
nonsense
splicing

A

increased copy number

197
Q

Which of the following patients will need a genetic screening before being put on mercaptopurine-based chemotherapy?

acute lymphoblastic leukemia patients
renal transplant patients
patients also taking rifampicin
patients on warfarin

A

acute lymphoblastic leukemia patients

Mercaptopurines will cure ALL in patients who have a normal active TMPT gene to break it down. If they don’t, it will put them at risk for myelosuppression because they will break down ~0.5% of the drug and end up with no bone marrow and most likely die of immunosuppression. In patients with minimal TMPT activity, use 10% of normal dose

198
Q

Why is personalized dosing so important when prescribing warfarin?

narrow therapeutic window in populations with wide therapeutic window in individual patients
narrow therapeutic window in individual patients with wide therapeutic window in populations
the drug is rarely prescribed so little is known about its affects
too much will cause clotting, too little will cause bleeds

A

narrow therapeutic window in populations with wide therapeutic window in individual patients

199
Q

You are studying pharmacogenetics and have a patient that presents to you with disabling back pain. You know from your research that the patient has increased CPY3A4 levels. Which dosage of an active drug metabolized by CYP3A4 is most appropriate for treating her pain?

standard dose
a lower than standard dose
a higher than standard dose
high CYP3A4 is contraindicated to analgesics - prescribe nothing

A

a higher than standard dose

a higher than standard dose is necessary because the patient will metabolize the drug more rapidly than patients with normal CYP3A4 levels

200
Q

You know that a patient has decreased levels of CYP2D6. Which of the following drugs is primarily metabolized through different pathways and will be least influenced by the reduced CYP2D6 metabolism?

codeine
flecainide
metoprolol
warfarin

A

warfarin

warfarin is metabolized by CYP2C9 and VKORC1 CYP2D6 metabolized: beta blockers, tricyclic antidepressants, opioids (codeine)

201
Q

You prescribe felodipine to a hypertensive patient. A few weeks later, the patient develops a sinus infection and drinks a glass of grapefruit juice each morning with the medication you prescribed. What is the most likely outcome regarding the drug’s action?

deactivation by the grapefruit juice making the patient hypertensive
deactivation by the grapefruit juice making the patient hypotensive
inhibition of CYP3A metabolism making the patient hypertensive
inhibition of CYP3A metabolism making the patient hypotensive

A

inhibition of CYP3A metabolism making the patient hypotensive

the patient will be hypotensive because CYP3A metabolism is inhibited by grapefruit juice. The drug will have amplified effects because it will not get broken down.

202
Q

Identify and describe the characteristics of diseases and other traits that demonstrate multifactorial inheritance.

A

Complex traits aggregate in families
Do not follow simple Mendelian modes of inheritance
Need to be teased out from environmental factors

203
Q

Give specific examples of diseases and other traits that demonstrate multifactorial inheritance.

A 
Some cancers
Type 1 diabetes
Type 2 diabetes
Alzheimer disease
Inflammatory bowel disease
Schizophrenia
Cleft lip/palate
Hypertension
Rheumatoid arthritis
Asthma
204
Q

Describe the strategies used to determine the relative importance of genetic vs. non-genetic factors in contributing to the variation in a complex trait.

A

Twin studies using monozygotic and dizygotic twins are the favored designs for teasing out whether a disease is genetic or environmental.

205
Q

Recognize the potential difficulties associated with quantifying the role of genetic factors in contributing to risk of disease at both the population level and the individual level.

A

Overlap in disease prevalence between target and control groups makes it difficult to determine the contribution of factors leading to disease.

206
Q

What is concordance rate?

A

the presence of the same trait in both members of a pair of twins.

207
Q

If twins raised together in a similar environment then differences in concordance rate between mono- and dizygotic twins is likely due to what?

A

Genetic Factors

208
Q

Monozygotic twins raised apart in different environments who had high concordance rate would be likely due to what?

A

Genetic Factors

209
Q

What is the relative risk of disease in relatives?

A

λs = (risk of disease in siblings of affected)/(risk of disease in general population)

210
Q

What is heritabilitiy?

A

The proportion of variance in a trait that is due to genetic variation.

211
Q

What are characteristics of complex traits?

A 
Incomplete penetrance (not all will show signs of disease)
Variable expressivity (not all will have same effect of disease)
Allelic Heterogenteity (different alleles may express as same disease or different diseases)
Presence of phenocopies (environment may cause phenotype that mimics genetic version of trait)
212
Q

Describe the rationale for finding disease genes.

A

Genes play a major role in disease.
Genes can be systematically discovered
Gene discovery provides clues to disease pathogenesis which may lead to new treatments/prevention
May lead to testing of high risk individuals

213
Q

Differentiate the difference between genetic association study (candidate gene and genome-wide), genetic linkage study, and exome/genome sequencing study.

A

Association studies occur where the disease allele frequency is relatively high but the effect size (odds ratio) is relatively small

Genetic linkage studies occur with rarer allele frequency but high effect size (think Mendelian single-gene diseases).

214
Q

Recall the three most commonly used types of DNA polymorphisms as tools for finding genes.

A

Microsatellites
Single nucleotide polymorphisms
Copy number variants

215
Q

Discuss the emerging use of genome/exome sequencing in genetic analysis and genetic testing.

A

Exome sequencing good for use in Mendelian diseases .

Exome is only approximately ~1% of genome so cheaper to sequence only a portion that is necessary for identifying disease.

This doesn’t help for more complex diseases that are diseases of regulation segments of DNA.

216
Q

Describe gene-to-function disease gene mapping

A

Requires polymorphic DNA markers
Genotype polymorphic DNA markers at known positions
Sometimes they are surrogates for gene mutations (i.e. they don’t necessarily cause disease but they indicate a gene that does). This occurs due to linkage disequilibrium.
Identified using microsatellites, SNPs, CNVs, physical/genetic maps

217
Q

What are the clinical presentation of patients with Turner Syndrome.

(This list is ridiculously long)

A 
Karyotype of 45, XO
Abnormalities of CVS
 - Bicuspid Aortic Valve
 - Coarctation of aorta
 - Hypertension
 - Prolonged QTc Syndrome
 - Partial anomalous pulmonary venous connection
 - Persistant left SVC
Abnormalities of the eye
 - inner canthal folds
 - Ptosis
 - Blue Sclera
Skeletal System
 - Cubitus Valgus
 - Short 4th metacarpal
 - Short Stature
218
Q

Enumerate the challenges across the lifespan in patients with Turner Syndrome.

A

Infertility
Stature
Sexual development
Concerns regarding health and aging

219
Q

Identify pitfalls of the medical culture in dealing with patients with Turner Syndrome.

A

Secret keeping
Difficulty in communicating the infertility diagnosis
Perceived negative experiences with physicians

220
Q

Describe the common characteristics of disorders that are of autosomal recessive inheritance.

A

Phenotype expressed only in homozygotes
Males and females affected equally
Horizontal inheritance pattern
Parents of affected children are obligate carriers
The recurrence risk for each child is 1/4
Chance an unaffected child is a carrier is 2/3

221
Q

Describe the following concepts:

1) Allelic heterogeneity
2) Compound heterozygote
3) Parental consanguinity
4) High-risk groups

A

Allelic heterogeneity: The presence of multiple common mutant alleles of the same gene in a population

Compound heterozygote: An individual who carries two different mutant alleles of the same gene

Parental consanguinity: Blood related parents

High-risk groups: Small populations with higher than expected mutant allele prevalence.

222
Q

Describe Phenylketonuria (PKU).

A

High levels of phenylalanine in blood
High levels of phenylalanine metabolite in urine
Hyperactivity and epilepsy
Mental retardation and microcephaly

223
Q

Discuss biochemical deficiencies in PKU patients and the appropriate treatments.

A

Defects either in PAH (phenylalanine hydroxylase >98%) or its cofactor, BH4 (tetrahydrobiopterin Tyr requires PAH

The pathways to convert Tyr -> dopamine and Trp -> serotonin require BH4

224
Q

Explain maternal PKU and its treatment.

A

PKU women need to maintain low-Phe diet. If they stray, you increase the risk of miscarriage and congenital malformations.

225
Q

Describe newborn screening procedures for PKU and importance of the timing of the test.

A

Tandem Mass Spectrometry sorts molecules by size and charge. Needs to occur soon (but not right after) birth to determine the phenylalanine concentrations of the child once they are on their own.

226
Q

Describe alpha 1-Antitrypsin Deficiency (ATD).

A 
Deficiency in α1-antitrypsin
Northern European disease
1/2500 (1/25 carrier)
Increased risk of developing emphysema 
Increased risk of cirrhosis and liver cancer
Increased symptom severity in smokers
227
Q

Identify which enzyme is the primary target of alpha 1-antitrypsin.

A

α1-antitrypsin (or SERPINA1) inhibits elastase. Elastase is released by activated neutrophils, destroying elastin in the connective tissues. A deficiency allows elastin to breakdown the elastin at a higher rate, leading to lung disease.

228
Q

Identify the two most common mutant alleles that cause ATD and the severity of different allelic combinations, and describe why some ATD patients have liver failure.

A

Z-allele is the most common allele. Individuals with the Z/Z genotype have 15% normal SERPINA1 protein. This misfolding of the protein leads to it building up in the liver causing liver damage.

S allele is less common. Individuals with the S/S genotype have about 50-60% normal SERPINA1 protein.

229
Q

Describe Tay-Sach Disease (T-S).

A

A fatal genetic disorder in children that leads to rapid degeneration of the central nervous system. Death usually in 2-4 years.

230
Q

Explain biochemical defects in Tay-Sachs disease and why the brain is the major target.

A

T-S is a lysosomal storage disorder of the GM2 ganglioside in the lysosome. GM2 ganglioside is primarily synthesized in neurons of the brain. T-S patients are unable to degrade the GM2 ganglioside because of a defective hexosaminidase A gene (HEX A)

231
Q

Compare similarities and differences between Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease.

A

All lead to accumulated glycolipids. They differ in what part of the chain they affect.

T-S affects the α subunit of the hexosaminidase protein (HEX A)
Sandhoff disease affects the β subunit
T-S AB variant affects the GM2AP gene which is an activator of the hexosamidase protein.

232
Q

Describe the high-risk group for Tay-Sachs disease and the available methods for carrier screening and prenatal screening in the high-risk population.

A

Ashkenazi jews are the high-risk population. DNA testing can detect ~95% of carriers.

233
Q

Describe the layout of the α- and β-globin gene clusters and the switch between different forms of hemoglobin (Hb) during development. Explain the function of the locus control region (LCR).

A

α-like genes: ζ in embryonic stage, α2 and α1 from fetal to adult stage
β-like genes: ε in embryonic stage, γ in fetal stage, δ then β in adult.

LCR regulates globin transcription

234
Q

Describe the mutations that cause sickle cell anemia and hemoglobin C disease and their consequences.

A

Sickle cell anemia is caused by a mutation in the β6 Glu codon which changes to the code to a Val. This causes Hb S fibers in low-O2 states which leads to vaso-occlusion

Hemoglobin C disease changes the Glu to a Lys causing similar but milder symptoms

235
Q

Describe the DNA diagnosis method of the sickle cell disease mutant allele.

A

Using Mst II cleaves the β RNA at three sites creating a distinct Southern blot. In sickle cell disease, the enzyme only cuts in two places causing a different Southern blot profile.

236
Q

Describe the six possible genotypes of α-globin locus, their clinical phenotypes.

A 
αα/αα: Normal
αα/α-: Silent Carrier
αα/--: α-thalasemia 1 trait (mild)
α-/α-: α-thalasemia 2 trait (mild)
α-/--: severe anemia (HbH)
--/--: hydrops fetalis
237
Q

Describe the following concepts about β-thalassemias:

(a) thalassemia major
(b) thalassemia minor
(c) β0-thalassemia
(d) β+-thalassemia
(e) β0-thal allele
(f) β+-thal allele
(g) simple β-thalassemias
(h) complex thalassemias

A

Thalassemia Major: Severe decrease in β-globin production “Cooley’s anemia”
Thalassemia Minor: Decreased but sustainable production in β-globin production
β0-thalassemia: Complete loss of β-globin production
β+-thalassemia: Almost total loss of β-globin production
β0-thal allele: Complete loss of β-globin production on an allele.
β+-thal allele: Reduced production of β-globin production on an allele.
simple β-thalassemias: single mutation variation
complex thalassemias: multiple mutation variation

238
Q

Explain hereditary persistence of fetal hemoglobin (HPFH) and its clinical implications.

A

HPFH is a disorder in which fetal hemoglobin persists into adulthood. It usually is asymptomatic and may have potential treatment affect in sickle cell disease and β-thalassemias.

239
Q

What are the geographical distributions of α-thal-1 (–) and α-thal-2 (α -) alleles.

A 
α-thal-1 (--): SE Asia
  --/--: hydrops fetalis
  α-/--: HbH disease
  αα/--: mild anemia
α-thal-2 (α -): Africa, Mediterranean, Asia
  α-/α-: mild anemia
  αα/α-: silent carrier
240
Q

Recognize quantitative and qualitative changes in globin chains.

A 
Qualitative:
  - Hb S (Sickle Cell Disease)
  - Hb C (Hemoglobin C Disease)
  - Hb E (SE Asian β-Thalassemia)
Quantitative:
  - α-thalassemia
  - β-thalassemia
  - γ-thalassemia
  - δ-thallassemia
241
Q

Describe the geographic distribution of the common hemoglobin variants.

A

269mm worldwide carriers

  • 15% of Africans are S carriers
  • 7% of SE Asians are E carriers
  • 4-5% of SE Asians and Mediterraneans are β-thal carriers
242
Q

What diseases are associated with Hb S?

A 
Homozygous SS disease: Sickle Cell Anemia
S Heterozygous: AS: Sickle Cell Trait
Sickle Syndromes:
1) Hemoglobin SC hemoglobinopathy
2) SB° thalassemia
3) SB+ thalassemia
243
Q

What diseases are associated with Hb C?

A

Homozygous CC hemoglobinopathy
Heterozygous C
C-β-thalassemia

244
Q

What diseases are associated with Hb E?

A

Homozygous EE
Heterozygous AE
E-β-thalassemia

245
Q

How to treat thalassemia?

A 
Red cell transfusion
Iron chelators
Vitamin C
Splenectomy/cholecystectomy
Bone marrow transplant
246
Q

Recognize the characteristic pattern in a pedigree showing autosomal dominant inheritance.

A

Passed by either parent
One allele is sufficient to transmit trait
Rare homozygous when mutation causes disease

247
Q

Describe features that may complicate the assessment of an autosomal dominant pedigree.

A

Reduced penetrance

Variable expresivity

248
Q

Describe unique features of Trinucleotide-Repeat disorders.

A 
Expansion of DNA consisting of three nucleotides.
Slipped mispairing
Anticipation
Parental transmission bias
AD, AR and X-linked transmission
249
Q

Recognize and describe clinical features and the molecular basis of Huntington Disease.

A

Autosomal dominant
CAG repeat disorder
Anticipation
- Paternal - earlier onset

Progressive neuronal degeneration
Onset 35-44, death 15years later

Mutation in HTT gene - expansion of Glu may cause altered structure of protein

250
Q

Recognize and describe the clinical features and molecular basis of Achodroplasia.

A 
Autosomal dominant
Small stature
Rhizomelic limb shortening
short fingers
Genu varum
Trident hands
Large head/frontal bossing
Mid facial retrusion
Small foramen magnum

Mutation in Fibroblast Growth Factor Receptor 3 (FGBR3)

  • Regulates bone growth by limiting cartilage > bone formation
  • Missense mutation increasing the activity of the protein interfering with skeletal development
251
Q

Recognize and describe the clinical features and molecular basis of Neurofibromatosis Type 1

A

2 or more of the following

  • 6 or more cafe-au-lait spots
  • 2 or more neurofibromas
  • 1 plexiform neurofibroma
  • Freckling in axillary or inguinal area
  • Optic glioma
  • 2 or more Lisch Nodules
  • Distinctive osseous lesions
  • Affected first degree relative

Mutation in NF1 gene - tumor suppressor
Loss of function mutation
Dominant but requires second NF1 mutation

252
Q

Recognize and describe the clinical features and molecular basis of Marfan Syndrome

A

Systemic disorder of connective tissue

  • Ocular
  • Skeletal
  • Cardiovascular
Diagnosis:
- Aortic root enlargement
- +1 of the following
  . Ectopia lentis
  . FBN1 mutation
  . Systemic score >7
253
Q

Distinguish the differences between X-linked dominant and X-linked recessive inheritance.

A

X-linked recessive: phenotype in all males and homozygous females.
Heterozygote females are carriers

X-linked dominant: phenotype expressed in homozygote females and all males.

254
Q

Describe the unique features of mitochondrial inheritance and the clinical manifestations of these mutations.

A

Always from maternal side
mitochondrial DNA sorts randomly so depending on the amount of mtDNA in each egg, disease could be more severe.

Group of diseases center around tissues that require heavy oxidative phosphorylation: brain, retina, skeletal muscle and heart.

255
Q

Explain functional mosaicism in female X-chromosomes

A

Half of female cells express the maternally-inherited X and half express the paternal-inherited X.

256
Q

What is the mechanism of X chromosome inactivation?

Nonrandom X-chromosome inactivation
Skewed X-chromosome inactivation

A

XIST - gene located on X chromosome expressed only from the inactivated X. Majority of genes on inactive X chromosomes are methylated, inactivating them.

Nonrandom X chromosome inactivation occurs when there are structural abnormalities.

Skewed X inactivation observed when a female shows signs of symptoms of an X-linked recessive condition such as Duchene Muscular Dystrophy

257
Q

Describe Hypophosphatemic Rickets

A

X-linked dominant

  • Hypophosphatemia
  • Short stature
  • Bone deformity

Gene: PHEX

  • Regulates fibroblast growth factor
  • Inhibits kidneys ability to reabsorb phosphate
258
Q

Describe Fragile X Syndrome

A 
X-linked dominant
Gene: FMR1
Trinucleotide repeat: CGG
Most common inherited cause of inherited development delay
Anticipation
Maternal transmission bias (transmitte on X-chromosome)
 - Intellectual diabilities
 - Dysmorphic features (large ears, long face, macroorchidism)
 - Autistic behavior
 - Social anxiety
 - Hand flapping/biting
 - Aggression
259
Q

What are dystrophinopathies

A 
X-linked recessive disorders
Spectrum of muscle diseases
 - Duchenne Muscular Dystrophy
 - Becker Muscular Dystrophy
 - DMD-associated dilated cardiomyopathy
Mutation in DMD gene (largest human gene)
260
Q

Describe Duchenne Muscular Dystrophy

A

Progressive muscular weakness: proximal > distal
Calf hypertrophy
Dilated cardiomyopathy
Elevated creatine kinase levels
Onset prior to 5yo, wheelchair bound before 13, death by 30

261
Q

Describe Hemophilia A

A

X-linked recessive
- Blood disorder where blood fails to clot (deficiency in Factor VIII)
- Spontaneous bleeds into joints, muscles, intracranial
- Excessive bruising
- Prolonged bleeding after injury
Mutation in F8 gene

262
Q

Describe the four main characteristics of epigenetic phenomena.

A

1) Different gene expression pattern/phenotype, identical genome
2) Inheritance through cell division, even through generations
3) Like a switch: on/off
4) Erase-able (inter-convertible)

263
Q

Explain the basic principle of Waddington’s epigenetic landscape.

A

Cell states start as pluripotent cells but finally rest in a “lower energy state” of differntiation

264
Q

List three specific examples of epigenetic phenomena.

A

Cells differentiating into discrete organs
Ancestral behavior affects methylation
Disease can occur from methylation reversing and having the cell turn into an undifferentiated cell (cancer)

265
Q

Describe how DNA methylation can be inherited through cell division.

A

Methylation occurs on CpG islands.
When cells reproduce the reciprocal strand will have the same sequence. New strand is methylated based on parental strand

266
Q

Name three chemical modifications to DNA or histones that can potentially be inherited.

A

DNA Methylation
Histone Modification
Chromatin State

267
Q

Describe how epigenetic mechanisms and inheritance can occur both inside and outside the nucleus.

A

Protein structures that can form (prion disease)

Cytoplasmic epigenetic cycle

268
Q

Name a specific type of gene that, when aberrantly methylated with 5meC, can lead to cancer and an approach to therapeutic intervention in this case.

A

Silencing of a tumor suppressor gene can lead to cancer. Treatment can include using a DNA methyltransferase and histone deacetylase to “open up” the tumor suppressor.

269
Q

Describe and give examples of loss of function of the protein (most common) that leads to disease

A

Caused by genetic mutations (deletions, insertions or rearrangements) that eliminate or reduce the function of a protein.

Duchenne Muscular Dystophy
Alpha-thalassemia
Turner Syndrome
Hereditary neuropathy w/ liability to pressure palsies
Osteogenesis Imperfecta Type I (trimer collagen disease)

270
Q

Describe and give examples of gain of function of the protein that leads to disease

A

Caused by genetic mutations that increase the function (or quantity) of a protein.

Hemoglobin Kempsey
Charcot Marie Tooth

271
Q

Describe and give examples of acquisition of a novel property by the mutant protein that leads to disease

A

Caused by a genetic mutation that alters the behavior of a protein

Sickle cell anemia
Osteogenesis Imperfecta Types II, III, IV

272
Q

Describe and give examples of perturbed expression of a gene at the wrong time (heterochronic expression) or in the wrong place (ectopic expression), or both that leads to disease

A

Caused by altered promotors/silencer mechanism which fails to alter gene expression

Hereditary Persistence of Fetal Hemoglobin

273
Q

Discuss and cite examples* of the eight steps at which mutations can disrupt the production of a normal protein.

A

Transcription: Thalassemias, Hereditary Persistence of Fetal Hemoglobin

Translation: Thalassemias

Polypeptide folding: More than 70 hemoglobinopathies

Post-translational Modification: I-cell disease

Assembly of monomers into a holomeric protein: Osteogenesis imperfecta

Subcellular localization of the polypeptide or the holomer: Familial hypercholesterolemia

Cofactor or prosthetic group binding to the polypeptide: homocystinuria

Function of a correctly folded, assembled, and localized protein produced in normal amounts: Hb Kempsey

274
Q

Explain the mechanism of genetic anticipation in tri/tetra-nucleotide repeat disorder and recognize the phenotypes of these disorders.

A

Disease severity worsening in subsequent generations. Genetic anticipation is explained by the mechanism of tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster.

275
Q

What are Allelic Disorders?

A

Diseases that are genetically related (due to the same gene)

ex: Duchenne, Becker 1 and Becker 2 Muscular Dystophy (Dystrophin Gene)
ex2: CMT1A and HNPP (PMP22 Gene)

276
Q

Define what constitutes a “genetic test.”

A

Examining biochemical or genetic material that indicate the presence or absence of genetic disease.

277
Q

Explain how allelic heterogeneity and genetic heterogeneity can affect the performance of genetic tests.

A

Allelic heterogeneity refers to multiple mutations of the same allele, each able to contribute to a disease.

Genetic heterogeneity refers to multiple genes, each able to contribute to a disease.

Negative genetic results don’t always mean the patient doesn’t carry the disorder. Will need to be confirmed by testing affected individuals in same family.

278
Q

What are the basic approaches, advantages, limitations, and interpretation of Chromosomal Analysis

A

Observing the visual characteristics of a chromosome.

Can diagnose aneuploidy, duplications, rearrangements, insertions and deletions great in size that 5Mb

Cannot diagnose single gene deletions, point mutations, small deletions, duplications, and insertions, methylation defects, trinucleotide repeat abnormalities.

279
Q

What are the basic approaches, advantages, limitations, and interpretation of FISH

A

Observing specific alterations of the chromosome (need a hybridized marker) usually beyond the resolution of chromosomal analysis. Best during interphase.

Used to observe deletions, translocations and abnormal copy numbers in chromosomes,

Cannot diagnos any diseases not specifically known (need a fluorescent hybridized marker that is known. Not good for point mutations.

280
Q

What are the basic approaches, advantages, limitations, and interpretation of Micro Array Analysis

A

Expression Arrays generally used to test the presence of RNA (expression). These test the activity of genes rather than just the presence or absence of them.

Chromosomal Micro Arrays look for chromosomal deletion/duplications.

Used as a higher resolution version of chromosomal analysis as you can observe changes in chromosomes with a resolution of ~200kb (del) ~400kb (dup) vs 5Mb. Used for aneuploidies, unbalanced chromosomal rearrangements, chromosome deletions and duplications

Can’t diagnose abnormalities less than resolution

281
Q

What are the basic approaches, advantages, limitations, and interpretation of DNA sequencing

A

When mutations in certain genes are known, can be used to identify small DNA level mutations.

Advantages - very sensitive 1-100bp detection. Can detect known or novel mutations.

Disadvantages - might miss whole gene deletions.

282
Q

Identify genetic conditions that currently can be treated and those for which treatment may soon be available.

A

Trisomy 21 - Supportive care and cardiac surgery
Multiple Endocrine Neoplasia - prophylactic surgery
Metabolic Diseases - Enzyme Replacement Therapy

283
Q

Discuss examples of genetic disorders that are treated on the basis of protein/enzyme replacement therapy.

A

Alpha-1 AT (Antitrypsin) - elastases unchecked: recombinant AT1 therapy

Fabry Disease - Deficiency of alpha-galactosidase A: Recombinant Alpha-Galactose therapy

284
Q

Identify the principles and theoretical risks of gene therapy.

A

Gene Therapy: Introduction of genetic material into human cells to treat an acquired or inherited disease

Principle: Introduction of a disease should cure or slow down the progression of the disease

Approaches: Non-viral, viral, in/ex vivo

285
Q

What are treatment strategies for metabolic diseases?

A 
Avoidance
Dietary Restriction
Replacement
Diversion
Inhibition
Depletion
286
Q

Explain and contrast the molecular genetic features and mechanisms of three key genetic diseases: Achondroplasia, Nonsyndromic deafness, and Fragile X syndrome.

A

Achondroplasia

  • GOF mutation
  • Advanced paternal age (de novo)
  • Autosomal dominant
  • FGFR3 transmembrane TKR - inhibits bone growth

Nonsyndromic Deafness

  • LOF mutation
  • Congenital deafness (recessive), Progressive deafness (dominant)
  • 3/4 nonsyndromic
  • GJB2 mutation

Fragile X Syndrome

  • FMR1 gene
  • Triplet repeat expansion
  • LOF/GOF
287
Q

Recognize clinical signs and symptoms of Achondroplasia, Nonsyndromic deafness, and Fragile X syndrome.

A

Achondroplasia

  • Prenatal onset
  • Rhizomelic short stature
  • Megalencephaly
  • Spinal cord compression

Nonsyndromic Deafness

  • Congenital deafness (recessive)
  • Progressive deafness (dominant)

Fragile X Syndrome

  • Age at onset: childhood
  • Mental deficiency
  • Dysmorphic facies
  • Male postpubertal macroorchidism
288
Q

Correctly recommend and interpret genetic testing for Achondroplasia, Nonsyndromic deafness, and Fragile X syndrome.

A

Achondroplasia
- FGFR3 mutation: PCR genetic sequencing

Nonsyndromic Deafness
- GJB2 mutation: PCR genetic sequencing

Fragile X Syndrome
- Southern Blot

289
Q

A patient presents to your clinic with multiple neurofibromas due to a disease that is common in her family. Physical exam reveals Lisch nodules (pigmented iris hamartomas), numerous café au lait spots, and axillary and inguinal freckling. Which of the following is a feature of the disease that is most likely responsible for this patient’s phenotype?

autosomal recessive inheritance pattern
x-linked recessive inheritance pattern
incomplete penetrance
variable expressivity

A

variable expressivity

Neurofibromatosis Type 1 presents with autosomal dominance, 100% penetrance, and variable expressivity. The clinical presentation includes cafe au lait spots, Lisch nodules, neurofibromas, pheochromocytomas and scoliosis. The mutation is of the NF-1 gene on chromosome 17.

290
Q

A patient with end-stage renal disease presents to your clinic with elevated blood pressure and bilateral flank pain. The patient tells you that her mother and sister both died of the same kidney problem but that she cannot remember its name. She recalls being told that her condition may also lead to intracranial aneurysms and liver disease. Which of the following is a feature of the disease that is most likely responsible for this patient’s phenotype?

locus heterogeneity
x-linked recessive inheritance
variable expressivity
incomplete penetrance

A

locus heterogeneity

This patient has autosomal dominant polycystic kidney disease, a genetic disorder with locus heterogeneity. Locus heterogeneity means that mutations to different genes can produce the same phenotype. PKD1 = 85% PKD2 = 14.5% Clinical features include bilateral enlarged kidneys with multiple cysts, end-stage renal disease, extrarenal cysts, intracranial aneurysms, hypertens

291
Q

A six month old baby comes to your office for a routine checkup. During the head and neck exam, you notice a cherry-red spot in the baby’s eye. You suspect which of the following genetic disorders?

alpha1-antitrypsin deficiency
phenylketonuria
sickle cell anemia
Tay-Sachs disease

A

Tay-Sachs disease

a cherry red spot on the eye is a characteristic feature of lipid storage disorders, such as Tay-Sachs, and in central retinal artery occlusion

292
Q

In an attempt to diagnose a patient, you run HexA and HexB enzyme assays. You observe that both HexA and HexB activity is reduced. Which diagnosis is most consistent with this finding?

Tay-Sachs
AB-variant of Tay-Sachs
Sandhoff Disease
Tay-Sandhoff

A

Sandhoff Disease

In Tay-Sachs, only HexA activity is affected. In AB variant, neither HexA nor HexB activity is affected in this test. In Sandhoff disease, both HexA and HexB activity are affected.

293
Q

Which of the following genotypes with alpha1 anti-trypsin deficiency will have the highest levels of elastase?

M/M
M/S
S/Z
Z/Z

A

Z/Z

Patients with this genotype produce only 10%-15% of normal levels of alpha1-antitrypsin, whose role is to inhibit elastase. Z/Z accounts for most cases of disease. M/M is normal. S/S genotypes have 50%-60% of normal levels and do not express disease symptoms S/Z are compound heterozygotes that produce 30%-35% of normal levels. These patients may develop emphysema. The Z allele makes a misfolded protein that aggregates in the ER of the liver, leading to damage to liver and lung. The S allele makes an unstable protein that is less effective in inhibiting elastase.

294
Q

You screen a baby for phenylketonuria (PKU) 48 hours after birth using the Guthrie test. The lab reports no growth of Bacillus subtilis. What is the best conclusion about the baby’s PKU status?

The baby has high levels of phenylalanine, and therefore does not have PKU
The baby has low levels of phenylalanine, and therefore does not have PKU
The baby has high levels of phenylalanine, and therefore does have PKU
The baby has low levels of phenylalanine, and therefore does have PKU

A

The baby has low levels of phenylalanine, and therefore does not have PKU

PKU is caused by a defect in the phenylalanine hydroxylase (PAH) enzyme causing phenylalanine to accumulate in the blood. In the Guthrie bacterial inhibition assay, the infant’s blood is added to an agar plate containing Bacillus subtilis and thienylalanine. Thienylalanine normally inhibits B. subtilis but high levels of phenylalanine; however, block inhibition by thienylalanine. B. subtilis growth suggests PKU but does not specify the cause; i.e., the problem could be in the PAH cofactor tetrahydrobiopterin (BH4).

295
Q

Which of the following is a characteristic of Myotonic Dystrophy type 1?

expanded CTG repeats at the intron
expanded CTG repeats at the 3’ UTR
paternal anticipation
maternal inheritance pattern

A

expanded CTG repeats at the 3’ UTR

The novel function of DM1 is due to expanded CTG repeats at the 3’UTR. The disease is inherited in an autosomal dominant. DM1 has two variants: congenital, which is more severe, and mild. The congenital form demonstrates maternal anticipation (associated with increased maternal age); can be lethal and results in severe intellectual disability. Females can pass on thousands of repeats, dads can only pass on about 1,000.

296
Q

Which of the following trinucleotide repeat disorders has an autosomal recessive inheritance pattern?

Huntington disease
Fragile X/FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome)
Friedreich’s Ataxia
myotonic dystrophy

A

Friedreich’s Ataxia

Friedreich’s Ataxia is caused by a loss-of-function mutation. Fragile X/FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome) are X-linked. Huntington is autosomal dominant. Myotonic dystrophy is autosomal dominant.

297
Q

Genetic linkage studies assume that:

families share common phenocopies
multiplex families (families with multiple cases of a disease) share genome segments that are disproportionately co-inherited
affected relatives are genetically dissimilar to their unaffected siblings
complex traits can be mapped through families with a history of disease

A

multiplex families (families with multiple cases of a disease) share genome segments that are disproportionately co-inherited

Affected relatives share disease susceptibility genes (not phenocopies) Genetic linkage studies are best for Mendelian traits (rare alleles with strong effects); less powerful for complex traits.

298
Q

Which markers are typically used in genetic linkage studies?

microsatellites
recombination blocks
single nucleotide polymorphisms (SNPs)
copy number variations (CNVs)

A

microsatellites

Microsatelites are a common way to track haplotypes and do genetic linkage analysis. Recombination blocks are used for genetic association studies. SNPs are commonly used for Genome-Wide Association Studies (GWAS). CNVs are less useful for genetic studies

299
Q

Which of the following is correct regarding candidate association studies?

require a very large sample size (>1,000)
require complex statistical regression models
multiple variants can be tested without additional testing correction
association suggests linkage disequilibrium with a causal mutation

A

association suggests linkage disequilibrium with a causal mutation

Real association doesn’t imply causation but you can identify linkage disequilibrium that is linked to causal mutation. Simple studies with simple stats (chi square, Fisher) and small sample size (100s) must apply multiple test correction if testing multiple variants. Must match cases and controls ethnically.

300
Q

Why does population stratification often lead to false positive findings in genetic association studies?

misclassification of ethnicity impairs researchers ability to match cases and controls
ethnic categories are often the product of two more ancient populations so controls may have 2 different allele frequencies but are counted as genetically similar
ethnic categories are often the product of a more ancient populations but evolutionary changes are not accounted for
ethnic groups are not always similar in their allele frequency

A

ethnic categories are often the product of two more ancient populations so controls may have 2 different allele frequencies but are counted as genetically similar

2 populations may have mixed so 2 separate allele patterns are considered one ethnic category example would be if ‘African American’ were an ethnicity. If African American = African + European + Spanish + Italian + Native American then a single ethnic group will have a lot of variation.

301
Q

You are studying a new genetic disease that has been shown to have 100% penetrance among allele carriers. When you calculate the odds ratio of having the allele, you get an estimate of 1.0015. What can you conclude about the population attributable risk of getting this disease for those who have the genetic variant?

high, because penetrance is 100%
low, because penetrance is 100%
high, because the Odds Ratio is approaching 1
low, because the Odds Ratio is approaching 1

A

high, because penetrance is 100%

The Population Attributable Risk (PAR) is high for diseases that are 100% penetrant even if the odds ratio is low because the odds ratio only calculates the risk of having/not having the variant, not the chance of disease if you have it.

302
Q

HbA is the major form of hemoglobin (97% of total). What combination of tetramers makes up the minor form of adult hemoglobin?

two alphas, two betas
two alphas, two gammas
two betas, two deltas
two alphas, two deltas

A

two alphas, two deltas

There are two forms of adult hemoglobin. The major form (97%) is HbA and is comprised of two alphas and two betas, the minor form is HbA2 and is comprised of two alphas and two deltas.

303
Q

Throughout embryogenesis, expression of hemoglobin varies. Choose the correct group of hemoglobins that are expressed at the time of birth.

zeta, epsilon, and alpha
epsilon, alpha, delta
alpha, beta, gamma, and delta
zeta, alpha, gamma, and delta

A

alpha, beta, gamma, and delta

alpha and gamma are turned on in early embryogenesis 1. Zeta and Epsilon turned off, alpha and gamma turned on early in embryogenesis 2. Gamma turned off eventually, beta and delta turned on at birth. The switch from gamma to beta is gradual, taking ~120 days. At birth there is still gamma.

304
Q

You suspect a hemoglobinopathy in a patient of yours. You decide to run the diagnostic test by performing PCR of the genomic DNA surrounding exon 1 of the beta globin gene and digesting the PCR product with the restriction enzyme Mst II. Upon gel electrophoresis, you notice that the patient’s DNA sample has a 1.35 kb fragment instead of the 1.15 kb fragment in the control. What diagnosis is most likely based on this observation?

Hemoglobin C disease
Hereditary Persistence of Fetal Hemoglobin
Alpha Thalassemia
Sickle Cell Anemia

A

Sickle Cell Anemia

The diagnostic test for sickle cell anemia is a restriction digest test. A restriction site is deleted in SSA, so that the fragment is actually longer. Longer fragments do not move as far in a gel electrophoresis. Hemoglobin C disease is not distinguishable from sickle cell anemia based on this test. This would not be an appropriate test to diagnose HPFH or Alpha thalassemia.

305
Q

A young mother brings her child in for an evaluation because she suspects the baby, who is learning to walk, may have a fracture. Upon physical examination you notice that he has bluish sclera, but is otherwise normal. After discussing other possible causes of the child’s fracture, you confirm that he has several broken bones and decreased bone mineral density. A genetic test comes back positive for an inherited disorder in collagen formation. Which mutational mechanism has resulted in this child’s phenotype?

Loss of function
Gain of function
Novel properties
Nucleotide repeats

A

Loss of function

Osteogenesis imperfecta type 1 is the diagnosis. The mechanism is loss of function of the COL1A1 protein. The inheritance pattern is autosomal dominant.

306
Q

Cooley’s anemia can be detected by the absence of which of the following?

HbA
HbF
Alpha-globin chains
All of the above

A

HbA

Cooley’s anemia = no good copies of the beta-globin gene. Patients cannot make HbA and are severely anemic, have low MCV (small RBCs) and will be transfusion dependent. Physical findings of Cooley’s: Osteopenia Dense skull, marrow expansion Iron overload and endocrine failure Enlarged spleen Treatment: Vitamin C, RBC infusions, iron chelation, splenectomy, bone marrow transplant.

307
Q

Which of the following would NOT be of concern in a patient with Beta-thalassemia major?

osteopenia
splenomegaly
HbA2 production
iron overload

A

HbA2 production

HbA2 would not make much of a difference because they produce normal amount (it’s made from alpha and delta) Osteopenia, splenomegaly, iron overload Treat with: blood transfusion, iron chelation therapy, bone marrow transplant, vitamin C You will not know a child has beta-thalassemia major until after birth

308
Q

Individuals with a G6PD deficiency should particularly avoid:

anti-malarial drugs
barbiturates
galactose
statin drugs

A

anti-malarial drugs

G6PD is a metabolic disease, treatment = avoid anti-malarial drugs because you can’t break them down

309
Q

When should patient’s with Turner’s syndrome be transitioned to an adult primary care doctor and adult specialists?

at age 10
during adolescence
after puberty
whenever they want

A

during adolescence

As girls affected with Turner’s syndrome progress through adolescence, the process of transitioning to adult PCP’s and specialists becomes paramount.

M2M (4 decks)

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