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Clinical Cytogenetics and Molecular Genetics > Human Disease Genes > Flashcards

Human Disease Genes Flashcards

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1
Q

Define pleiotropy

A

mutations in a single gene can cause multiple disorders (distinct phenotypes)

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2
Q

Define genetic heterogeneity

A

A single phenotype can be caused by variants in multiple gene
e.g. hypercholesterolemia (APOA2, GHR, GSBS, EPHX2 and LDLR)

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3
Q

Define allelic heterogeneity

A

A single disorder caused by multiple mutations within the same gene

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4
Q

Define incomplete penetrance

A

Same variant allele but only some individuals express the associated phenotype
e.g. RB1, HTT -high, BRCA1 moderate, HFE hemochromatosis low

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5
Q

Define variable expressivity

A

The same genotype causes a wide range of clinical symptoms across a spectrum.
e.g. Two people have the same diagnosis and variant in NF1 but only one has all the features
*can be due to allelic heterogeneity

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6
Q

Give examples of TBX5 (T-box 5) pleiotropy

A

Holt-Oram syndrome (heart-hand) syndrome
Cardiac abnormalities
Limb anomalies

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7
Q

Give examples of NBN (nibrin) pleiotropy

A

Microcephaly
Immunodeficiency
Nigmegen breakage syndrome (cancer predisposition)

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8
Q

Give examples of PAH (F hydroxylase) pleiotropy

A

Phenylketonuria
Intellectual disability
Eczema
Pigment defects

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9
Q

Define missense variant

A

Causes substitution of one amino acid for another

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10
Q

Define nonsense variant

A

Causes premature stop codon

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11
Q

Define synonymous variant

A

Changes DNA and RNA, but not amino acid

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12
Q

Define splice-site variant

A

Causes exon skipping or read-through into intron

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13
Q

Define in-frame deletion/insertion

A

Deletes or inserts one or more amino acids

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14
Q

Define frameshift variant

A

Changes the reading frame (can result in premature stop)

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15
Q

Define indel

A

Small insertion and deletion of up to ~50 bp

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16
Q

Define stop loss

A

Normal termination is lost
p.Ter1481TyrextTer4

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17
Q

Define microsatellite polymorphisms

A

short tandem repeats
Dynamic variants in neurological disorders

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18
Q

Define copy number variants (CNVs)

A

Dosage imbalance of one or more genes

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19
Q

Approximately ___% of the genome is composed of single copy DNA sequences and ____% of the genome is composed of repetitive DNA

A

50%, 50%

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20
Q

The genome consists of _____% of coding sequences (exome) and ________ monogenic diseases

A

1-2%
6000

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21
Q

The human genome is composed of _______ base pairs

A

6 billion

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22
Q

The average genome contains around _____ very rare (<0.1%) coding variants and ____ variants previously reported as disease causing

A

200
54

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23
Q

The ____ and ____ polymerases are high fidelity and replicated the 6x10^9 bases in the human genome

A

delta and epsilon

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24
Q

____ other polymerases can carry out lower fidelity DNA synthesis during DNA replication or repair (99.9% of errors are repaired)

A

15
(alpha, beta, sigma, gamma, lambda, REV1, zeta, eta, iota, kappa, theta, nu, mu, Tdt and PrimPol)

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24
Q

On average there is less than ___ mutation per genome/cell division

A

one
1x10^-10

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25
Q

On average between _____ and ____ nucleotides are damaged per human cell per day

A

10,000 and 1 million

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26
Q

1 in ____ persons likely to receive a new mutation in a known disease gene from one or the other parent

A

200

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27
Q

What are the two types of nucleotide substitutions?

A

transition, transversion

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28
Q

A ______ is a pyrimidine to pyrimidine or purine to purine substitution

A

transition

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29
Q

A ______ is a pyrimidine to purine or purine to pyrimidine substitution

A

transversion

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30
Q

Although there are 2x more possibilities for transversions, what is the transition:transversion ratio?

A

60%:40%

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31
Q

A ____ to ____ transition is the most common point mutation. Mechanism?

A

C>T
Deamination of cytosine (through 5-methylcytosine and deamination or uracil methylation to T)

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32
Q

The _____ is a ribonucleoprotein (RNP) complex responsible for excision of intragenic regions from eukaryotic RNA polymerase II transcripts (precursors to mRNA)

A

spliceosome

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33
Q

The spliceosome utilizes ___ unique snRNAs and over _____ different proteins

A

9
300

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34
Q

The 5 prime splice donor is a ______ pair in the intron while the 3 prime acceptor is a ______ pair in the intron

A

5 prime: GT
3 prime: AG

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35
Q

Aberrant splicing and sequence variants that insert premature termination codons can lead to ______ _______ _______

A

nonsense-mediated decay (NMD)

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36
Q

Nonsense-mediated decay is an mRNA surveillance pathway that degrades mRNA that harbor ______ mutations and helps prevent production of _____ proteins that could result in disease

A

nonsense
truncated

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37
Q

Nonsense mediated decay will not occur if the premature stop codon is in the _______ exon or within ______ base pairs of the end of the ______ exon

A

last exon
50 bp of the end of the penultimate exon

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38
Q

Nonsense mediated decay will not occur for _______ exon genes

A

single

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39
Q

The premature stop codon is recognized by the ribosome and detaches from the mRNA but the _____ ____ ____ remain bound and signals remain bound and signal mRNA for destruction

A

exon-junction complexes

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40
Q

Two gene examples and the severity of phenotype based on the location of premature stop codons

A

SOX10: PCWH (peripheral demyelinating neuropathy central dysmyelination Waardenburg syndrome and Hirschsprung disease) vs Waardenburg syndrome 4 (haplonisufficiency)
SFTPB - neonatal to infant death (complete loss) whereas partial loss leads to later onset and longer survival

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41
Q

Four Consequences of Variants on Protein function and most common?

A

LOF (most common)
GOF (FGFR3 achondroplasia, BetaAPP, PMP22 - CMT, Hb Kempsey)
Novel property (IDH, HbS)
Dominant negative variants (collagen - multimer)

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42
Q

What are the 3 factors that affect expressivity and penetrance?

A

Global modifiers (threshold, polygenic, genetic compensation, NMD, FHx, age, sex, environment)
Gene expression (allelic expression, isoforms, cis/trans, somatic mosaicism, epigenetics)
Causal Variants (location, consequence and repeat expansion)

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43
Q

Genetic testing is performed to determine __________ to particular health condition in a ________ individual or to confirm a _________ of genetic disease in a __________ individual

A

predisposition (asymptomatic)
diagnosis (symptomatic)

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44
Q

_____ testing determine likely disease course/severity/response to treatment

A

Prognostic

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45
Q

________ testing is in an asymptomatic patient to determine risk of affected offpsring

A

Carrier

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46
Q

COL1A1 and Ehlers-Danlos syndrome is an example of pleiotropy: Give two examples of disease

A

Infantile cortical hyperostosis (Caffey disease)
osteogenesis imperfecta

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47
Q

________ genetics is a subdivision of genetics concerned with the structure and function of genes at the molecular level

A

Molecular

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48
Q

_________ genetics is the study of inheritance in relation to the structure and function of chromosomes

A

cyto

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49
Q

_________ is characterized by relative macrocephaly, short limbs and trident hand

A

Achondroplasia
*short-limbed dwarfism
1in 25,000 births worldwide

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50
Q

99% of achondroplasia is caused by a single mutation in the _______ gene

A

FGFR3

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51
Q

______% of achondroplasia is caused by de novo mutations

A

80%

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52
Q

Most common (99%) mutation in FGFR3 that causes achondroplasia

A

c.1138G>A, p.Gly380Arg

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53
Q

A newer version of gel electrophoresis, restriction digest, sequencing that uses FRET/quencher

A

Taqman PCR

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54
Q

Lynch syndrome is an autosomal ______________ cancer predisposition syndrome

A

(autosomal) dominant

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55
Q

What 4 cancers are associated with Lynch syndrome?

A
  1. Colorectal
  2. Endometrial
  3. Ovarian
  4. Gastric
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56
Q

Lynch syndrome is also known as __________ ___________ _________ syndrome

A

hereditary nonpolyposis coli syndrome (HNPCC)

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57
Q

What are the 4 Amsterdam II criteria for Lynch syndrome?

A
  1. Three affected first degree relatives
  2. Two successive generations affected
  3. One or more HNPCC cancers before 50
  4. Negative of APC mutation or familial adenomatous polyposis (FAP)
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58
Q

In HNPCC the _________/________ heterodimer recognizes the defect

A

MSH2/MSH6

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59
Q

In HNPCC the _________/________ heterodimer repairs the defect

A

MLH1/PMS2

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60
Q

90% of HNPCC is caused by mutations in ________ and ________

A

MLH1 and MSH2

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61
Q

7-10% of HNPCC is caused by mutations in _________ and <5% is caused by mutations in ________

A

MSH6
<5% in PMS2

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62
Q

Microsatellite instability is caused by defective ______ _______ ________

A

mismatch repair (dMMR)

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63
Q

MSI is caused by _________ mutations in MSH2, MLH1, MSH6 and PMS2

A

germline

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64
Q

PCR product sizing is done by ______________ ______________ and ___________ ________ (old school)

A

capillary and gel electrophoresis

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65
Q

Risk of HNPCC in nonpolyposis CRC a priori and with MSI-H?

A

2-5% (a priori)
20% (MSI-H)

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66
Q

Lynch syndrome risk by age 70
1. CRC
2. Endometrial
3. Ovarian

A
  1. 50%
  2. 20%
  3. 25%
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67
Q

The third step of MPS is sequencing by _________

A

synthesis

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68
Q

The first step of MPS is ___________ preparation

A

library

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69
Q

The second step of MPS is _________ ___________

A

bridge amplification

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70
Q

The fourth step of MPS is ________________

A

alignment and mapping

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71
Q

The fifth step of MPS is _________________

A

annotation

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72
Q

_________ and ____________ files hold sequencing information and/or quality scores

A

FASTA
FASTQ (quality)

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73
Q

__________ files have alignment information

A

SAM
sequence alignment map

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74
Q

3 things that MPS does well

A

mutations and short deletions or insertions

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75
Q

4 things done poorly by MPS

A
  1. Large dels/ins
  2. Structural rearrangements
  3. Repeat tracks
  4. Pseudogenes
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76
Q

The average fragment length of MPS is < ____________ bp

A

< 200 BP

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77
Q

Most common shearing techniques for MPS are _________ and _________

A

physical
enzymatic
**focused acoustic shearing

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78
Q

Gene responsible for dopa responsive dystonia

A

GCH1
guanine triphosphate cyclohydrolase I

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79
Q

Abbreviation for coding sequence change

A

c.

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80
Q

Abbreviation for protein sequence change

A

p.

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81
Q

The ______________ has guidelines for interpretation of variants

A

ACMG
American College for Genetics and Genomics

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82
Q

The _____________ has guidelines for naming variants

A

HGVS
Human Genome Variation Society

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83
Q

What is the nomenclature for a frameshift ending in 4 codons

A

fs*4

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84
Q

The 5 prime splice donor is an _________

A

GT

85
Q

The 3 prime splice acceptor is an __________AG

A

AG

86
Q

Coding and Protein variants are ascribed to the farthest _______ prime position as possible

A

3 prime

87
Q

Cystic fibrosis is an autosomal _____________ disease with a carrier rate of 1 in 25 and a prevalence of 40,000 in the US

A

recessive

88
Q

Cystic fibrosis is caused by mutation in ______________ on chromosome __________

A

cystic fibrosis transmembrane conductance regulator
chromosome 7

89
Q

CF can cause __________ and thus infertility in 95% men (infertile, not sterile)

A

CBAVD
Congenital bilateral absence of the vas deferens

90
Q

CF can cause neonatal ________ ___________ (obstruction) and prenatal ___________ obstruction

A

meconium ileus
prenatal bowel obstruction

91
Q

CF can cause ____________ pancreatic insufficiency (88%) and CF-related _______________ (18%)

A

exocrine
diabetes (endocrine)

92
Q

CF causes lung disease in ________% of patients and chronic sinus disease in _____% of patient

A

100%
38%

93
Q

CF can cause growth failure from malabsorption of vitamins __________________

A

D,E,A and K

94
Q

CF patients have a __-___x higher risk of colon cancer and ____-______x higher risk after transplantation

A

5-10x higher CRC
25-30x after transplant

95
Q

The median survival for CF is now ________ years whereas it used to be less than 20 years

A

61

96
Q

Newborn test for CF due to partial pancreatic blockage

A

immunoreactive trypsinogen

97
Q

Besides trypsinogen, what are the two other tests for CF?

A

sweat chloride
sequencing - biallelic pathogenic CFTR mutations

98
Q

CF requires an elevated sweat chloride test of > _____ mmol/L

A

60
0-29/39 unlikely

99
Q

CF mutation analysis is usually a ______ variant screen

A

39 variant

100
Q

__________ testing is the gold standard for CF

A

sweat

101
Q

_________ is utilized to stimulate localized sweating for CF sweat test

A

pilocarpine

102
Q

CF-related metabolic syndrome/ CF screen positive indeterminate diagnosis (CRMS/CFSPID) with IRT and nl/int sweat chloride and heterozygous/negative CFTR mutants should be monitored until age ___________

A

8

103
Q

CFTR is a _________ regulated ____________ channel

A

cAMP
chloride

103
Q

CFTR stands for ______ __________ _________ __________ __________

A

cystic fibrosis transmembrane conductance regulator

103
Q

CFTR-related disorders (CFTR-RD) have _________ CF mutations + CF features in at least one organ system (CBAVD, disseminated bronchiectasis, pancreatitis) + normal/borderline sweat chloride and milder phenotype and unknown spectrum of risk

A

biallelic

104
Q

CFTR maintains hydration of secretions within airways and ducts through the release of cellular ______ and the inhibition of _________ uptake

A

chloride
sodium

105
Q

In CFTR ____________ or compound _________ mutations cause disease

A

homozygous
compound heterozygous

106
Q

Over 70% of all CF patients have at least one _________ mutation

A

ΔF508
p.Phe508del
c.1521_1523delCTT
38% homozygous

107
Q

The ΔF508 CFTR mutation is most common in the _____________ population

A

white

108
Q

Class III CFTR defects are ____________ defects or _________ opening defects

A

regulatory
channel opening

108
Q

The CFTR ΔF508 mutation is a class __________ CFTR and results in ________________

A

class II
protein misfolding

109
Q

Class IV CFTR defects are _____ ____________ defects

A

ion transport
R117H

109
Q

Class I CFTR defects are a result of ________________

A

lack of CFTR protein synthesis
nonsense mutations
splice site

110
Q

Class V CFTR defects are ____________ ____________ defects

A

protein synthesis
5T
splice sites
promoters

111
Q

Class VI CFTR defects are protein ______ _______ defects

A

half life

112
Q

Class ____ to _____ CFTR defects have classic CF phenotype

A

I to III

113
Q

Class _______ to _______ CFTR defects have late-onset or mild phenotype (CFTR-RD) or pancreatic insufficiency

A

IV to VI

114
Q

In 2023 ACMG expands min. CF variant set to ______ to achieve 95% carrier detection rate across 6 ancestral populations

A

100

115
Q

R117H can cause an ion transport or class ______ CF defect with the ____T tract in cis

A

IV, 5T

116
Q

R117H can cause CFTR-RD with the ______T tract

A

7T
Longer polyT = more normal function

117
Q

R117H may or may not be associated with the lung disease of cystic fibrosis
Phenotypic expression depends on the presence of a polyT tract and poly TG tract in intron ____

A

intron 8

118
Q

The penetrance of the 5T poly T tract (and thus R117H phenotype) is determined by a 5 prime uptream _______ _____ sequence where the ________ the repeats the more penetrance of disease

A

poly TG
longer (13 > 12 > 11)

119
Q

Determining whether the R117H and 5T occur in cis is called _________ and should prompt testing of family members

A

phasing

120
Q

______/____ w/o R117H can behave as CF-causing and in trans with severe CF mutation or homozygous 5T can cause CBAVD, CFTR-RD, or CF

A

5T/TG13

121
Q

___________(ivacaftor, elexacaftor) help open channel and increase ion transport
Class III-V CFTR mutations (G551D)

A

potentiators

122
Q

____________________ (elexacaftor, tezacaftor, lumacaftor) help with protein folding and transport to cell surface
Class II (ΔF508)

A

correctors

123
Q

____________ are the most common monogenic disease in the world, 5% of world are carriers

A

hemoglobinopathies

124
Q

_______ _______ _______ was the first disease to be characterized at the molecular level and remains among the best characterized of all inherited disorders

A

sickle cell disease

125
Q

~______ million molecules in each RBC

A

270

126
Q

Alpha globin is on chromosome ______ and regulated by ____________

A

chromosome 16
HS-40

126
Q

Beta globin is on chromosome ______ and regulated by the __________

A

chromosome 11
LCR - locus control region

127
Q

3 hemoglobins of embryonic life and their chains

A

Gower 1 - ζ2ε2
Gower 2 - α2ε2
Portland - ζ2γ2

127
Q

Fetal hemoglobin chains

A

α2γ2

128
Q

Hemoglobin A and A2 chains

A

HbA alpha2beta2
HbA2 alpha2delta2

129
Q

____________ are quantitative reduction of globin chain production

A

thalassemias

129
Q

Hemoglobinopathies are detected using ________ ____________ and ________

A

Gel electrophoresis
HPLC

129
Q

alpha2gamma2 persistence after birth — called?

A

Hereditary Persistence of Fetal Hemoglobin (HPFH)
clinically benign

129
Q

There are over _____________ structural Hb variants

A

1000

130
Q

What are the HbS, HbC and HbE mutations?

A

HbS - Glu6Val
HbC - Glu6Lys
HbE - Glu26Lys

131
Q

HbS in low oxygen state sickles and causes ______________ anemia and can cause vaso-occlusion and ___________

A

hemolytic
ischemia

132
Q

______ ______ ________ is the major cause of morbidity and mortality in SCD

A

Acute chest syndrome

133
Q

Prophylactic ____________ in children with SCD significantly reduces infection

A

penicillin

134
Q

SCD reduces life expectancy to ____________ years and is a major cause of death in kids under _______________

A

53
5

135
Q

Hydroxyurea reduces ACS through increased expression of _______________ which reduces HbS polymerization and sickling

A

HbF (alpha2gamma2)

136
Q

Treatment for HbS transfusion iron overload

A

Chelation therapy

137
Q

Curative treatment (1 old and 2 new) for HbS

A

bone marrow transplant
Lyfgenia (lentiviral gene therapy) - HBB gene
Casgevy (CRISPR-Cas9) - BCL11 disruption

138
Q

Casgevy (CRISPR-Cas9) works by inhibiting _____________ which serves to inhibit ____________ production

A

BCL11
HbF (a2g2)

139
Q

Sickle cell trait in HbS/HbA has higher risk for _________ infarction and renal ____________ carcinoma

A

splenic infarction
renal medullary carcinoma

140
Q

Ethnicities most at risk for HbS?

A

African and mediterranean

141
Q

Ethnicities at risk for alpha thalassemia?

A

Asians and mediterranean

142
Q

Ethnicities at risk for beta thalassemia?

A

All other than N. European

143
Q

HbS/HbA shows improved fitness over HbA/HbA for which parasite infection?

A

plasmodium/malaria

144
Q

HbS (Glu6Val), HbC (Glu6Lys) and HbE (Glu26Lys) have autosomal _________ inheritance?

A

recessive

145
Q

In thalassemias, whatever globin chain is in ___________ leads to precipitation

A

excess

146
Q

Do beta globins have any prenatal consequences?

A

No
HbF is a2g2

147
Q

The most common mutations in alpha thalassemia are ____________?

A

Deletions

148
Q

Most common alpha thalassemia is called hemoglobin ___________ ______________?

A

Constant Spring

149
Q

______________ is used to detect alpha thalassemia deletions

A

Multiplex ligation-dependent probe amplification (MLPA)

150
Q

Hemoglobin disease with 2 alpha deletions and mild microcytic anemia

A

alpha thalassemia minor

151
Q

Hemoglobin disease with 1 alpha deletion

A

carrier - asymptomatic

152
Q

Hemoglobin disease with 3 alpha deletions, splenomegaly, hemolytic and microcytic anemia

A

HbH

153
Q

Fetal condition with 4 alpha deletions

A

Hydrops fetalis
from heart failure
in utero death

154
Q

Mechanism of 95% of alpha thalassemia or alpha deletions

A

Homologous recombination with unequal crossovers

155
Q

HbH ________ ___________ is a more severe form of HbH

A

Constant Spring

156
Q

The most common non-deletional hemoglobin alpha deletion

A

Hemoglobin Constant Spring (HbCS)

157
Q

Hemoglobin Constant Spring (HbCS) is caused by what mutation

A

stop codon mutation
results in abnormally long hemoglobin alpha

158
Q

HbH Constant Spring requires regular ______________________ and has a higher risk of _____________

A

transfusion
thrombosis

159
Q

HbH can have hepatosplenomegaly, require __________ in asplastic crises and have _________ changes

A

transfusion
bony (maxillary hypertrophy, skull bossing)

159
Q

Beta thalassemia is a result of ___________ mutations

A

point
β0 = little to no β synthesis
β+ = some β produced

160
Q

Hgb Barts has four ___________ chains as a results of deletion of 4 alpha chains

A

gamma4

161
Q

β-thal shows relative increased levels of Hb______ even after birth

A

HbF

162
Q

Categorization of beta thalassemia?

A

minor, intermedia, major

163
Q

Beta thalassemia may have mild ____________ and _________

A

mild microcytosis
mild anemia

164
Q

Beta thalassemia _____________ likely has a moderate anemia and may become transfusion dependent and be treated with _____________ for HbF

A

intermedia
hydroxyurea
Small amounts of normal beta globin (HbA) produced (β0/ β+)

165
Q

Untreated beta-thalassemia major has a _____% mortality by 5 years

A

80%

166
Q

Beta-thalassemia major has hepatosplenomegaly, _________ expansion from ineffective hematopoiesis, cardiomegaly/HF and ____________ overload

A

marrow expansion
iron overload (GI absorption, independent of transfusion)

167
Q

Two old treatments for beta-thalassemia major and two new treatments

A

Transfusion
BM transplant
Zynteglo (HBB)
Casgevy (CRSPR-Cas9) - BCL11 inhibition of inhibition of HbF production

168
Q

With a fully _____________ condition, every affected individual will have inherited the condition from an affected individual

A

penetrant

169
Q

Rare mutations include ______-_________ regulatory mutations, insertion of a ___________or __________ element (disrupting transcription or interrupting the coding sequence and _________ ______mutations (repeat sequences)

A

long-range
LINE or Alu (SINE)
tandem repeat (disorders)

170
Q

50% of all human genetic mutations are _______ mutations while 25% are _____________

A

50% missense (aa substitution)
25% additions/deletions

171
Q

Approximately 10% of all human genetic mutations are _________ mutations, another 10% are ___________ processing mutations and another 10% are _________-site mutations

A

10% nonsense
10% RNA processing mutations
10% splice-site

172
Q

Only 5% of human genetic mutations are larger gene deletions, inversions, fusions, and duplications and this may be mediated by DNA sequence _______ either within or between strands

A

homology

173
Q

Lynch syndrome (MMR) and LDLR are examples of genes with ________ inheritance paterns

A

two

174
Q

____________ is when 50% protein function causes the phenotype

A

haploinsufficiency
ex. WAGR -PAX6 and WT1
-microdel syndromes

175
Q

What does LOEUF stand for? What is it used for?

A

loss-of-function observed/expected upper bound fraction (LOEUF)
Genes with a high probability assignment (≥0.9) to the haploinsufficient class are classified as ‘extremely loss-of-function intolerant.

176
Q

WAGR haploinsufficiency genes and phenotypes?

A

PAX6 - aniridia
WT1 - tumor suppressor - Wilms tumor

177
Q

_______________ is a genetic condition that occurs when an extra copy of a gene is present, resulting in a phenotype. It’s the opposite of haploinsufficiency, which is when one copy of a gene is lost.

A

Triplosensitivity

177
Q

50% of CMT patients have a duplication at 17p11.2 where the ______ gene is located and this results in triplosensitivity

A

PMP22

178
Q

Tumor suppressor genes have autosomal __________ inheritance at the level of the organism and autosomal __________ inheritance at the level of the tumor

A

AD - organism
AR - tumor (double hit)

179
Q

The classic double hit hypothesis tumor is ___________________

A

retinoblastoma

180
Q

A __________ _________ mutation occurs when a single mutation eliminates the function of the protein encoded by one allele and also impairs the function of the normal protein

A

dominant negative

181
Q

What at are the genes for dominant negative mutations which cause osteogenesis imperfecta and Marfan syndrome?

A

OI - COLA1 (Chr17) and COLA2 (Chr7)
Marfan - FBN1 (Chr 15)

182
Q

Gain of function mutations are also called ___________ and are usually involved in __________ _____________

A

hypermorphs
intracellular signaling

183
Q

MEN1 (parathyroid, pancreatic and pituitary) is caused by a loss of tumor suppressor gene ________ on chromosome 11q13 while MEN 2A (pheochromocytoma, parathyroid adenoma, medullar thyroid ca) and 2B (pheochromocytoma, marfanoid habitus and mucosal neuromas) are caused by gains of function of the ________ gene on chromosome 10

A

MEN1 (menin) Chr 11q13
RET Chr 10

184
Q

_______ gain of function variants are autosomal dominant and result in excessive degradation of LDLR causing hypercholesterolemia and vascular disease

A

Proprotein convertase subtilisin/kexin type 9 (PCSK9)
*protease

185
Q

A ____________ is when the protein encoded by the mutated gene has a new effect that is not related to its typical function (IDH1/2, HDD)

A

neomorph

186
Q

There is a roughly 1 in a ________chance per gene per generation of a de novo mutation

A

million
*some higher

187
Q

________ 1138G is one of the most mutable positions in any gene and accounts for 99% of achondroplasia cases

A

FGFR3

188
Q

____% of achondroplasia mutations have a de novo mutation and the incidence increase with _______ age

A

80%
paternal age

189
Q

Somatic _____________ variants are dominant variants that would not be compatible with life if they were present in all tissues

A

mosaic

190
Q

Sturge Weber is caused by somatic autosomal dominant mutations in the ____________ gene on chromosome 9 and results in somatic mosaic variants

A

GNAQ

191
Q

Blood groups are an example of __________________ inheritance

A

codominance

192
Q

_______________ diseases are rare and do not show strict Mendelian inheritance with variable penetrance but possibly multiple rare variants in the same pathway

A

Oligogenic

193
Q

An example of oligogenic disease includes ___________ syndrome which is characterized by Idiopathic/Congenital hypogonadotropic hypogonadism (CHH) with anosmia

A

Kallmann Syndrome
FGF17, IL17RD, DUSP6, SPRY4 and FLRT3

194
Q

Kallmann syndrome inheritance

A

partially sex-limited phenotype
males:females 4:1

195
Q

Kallmann syndrome X-linked gene is ____________

A

KAL1 (anosmin) - axonal migration of GnRH and olfactory neurons
3-6% of patient
*females may express and secrete more anosmin than males - more toleratnt to dirsuptions of FGF8/FGFR1 signaling

196
Q

The following disease are examples of ___________ inheritance: Long QT, hearing loss, Usher, Bardet Biedl (ciliopathies), Hirschsprung and retinitis pigmentosa

A

Digenic
Long QT (KCNH2 and SCN5A)
Usher syndrome (MY07A and CDH23 but 6)
Bardet Biedl (BBS1 and BBS10)
Hirschsprung (RET, EDNRB, ,EDN3, SOX10)
RP (RDS and ROM1 gene)

197
Q

A ___________ effect in polygenic diseases is a phenomenon where a phenotype develops when a critical factor’s level or activity falls below a certain

A

threshold

198
Q

In Hirschsprung threshold effect a _____________ proband with long-segment HSCR increases the risk for a male sibling

A

Female
*also 1% vs 3% for female sibling with short-segment

199
Q

In Hirschsprung threshold effect a male proband with long-segment HSCR increases the risk for a male and female sibling by how much?

A

Male proband
Male sibling 5% SS HSCR to 17% LS HSCR (3x)
Female sibling SS HSCR 1% to 13% LS HSCR (13x)

Clinical Cytogenetics and Molecular Genetics (20 decks)

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