GENETICS: BOARDS AND BEYOND Flashcards
A second-semester quadruple screening test reveals decreased levels of all biomarkers, a finding most concerning for
Edwards syndrome (trisomy 18).
Edwards syndrome is most often caused by ?. Less common etiologies include mosaic trisomy 18 and partial trisomy 18.
Maternal nondisjunction during meiosis II
While only associated with the nondisjunction-derived variation of the disease, is the most significant risk factor for autosomal trisomies.
Advanced maternal age
Edwards syndrome: First-trimester biomarkers will likely show decreased β-hCG and pregnancy-associated plasma protein-A (PAPP-A), while a second-trimester quadruple screen will show
Decreased β-hCG, alpha-fetoprotein (AFP), estriol (uE3), and inhibin A (note: inhibin A may also be within normal limits).
Edwards syndrome: Additional screenings for definitive diagnosis include
- Ultrasound imaging
- Chorionic villi sampling
- Amniocentesis
- Cell-free fetal DNA
Edwards syndrome: Characteristic features include
low-set ears, a small jaw (micrognathia), cleft lip and palate, clenched hands with overriding fingers, flexed feet (rocker-bottom feet), and congenital heart defects (e.g., ventricular septal defect). Microcephaly, omphalocele, and neural tube defects (e.g., myelomeningocele) can also be seen.
Edward syndrome carries an extremely poor prognosis, with the median survival ranging from ?
3 days to 2 weeks of age
Aplasia cutis, holoprosencephaly, microphthalmia, and polydactyly are clinical features consistent with
Patau syndrome (trisomy 13)
Patau syndrome is also most commonly caused by maternal nondisjunction and is associated with advanced maternal age; however, mothers typically have
A quadruple screen with normal levels of all biomarkers.
A broad chest with widely spaced nipples, cystic hygroma, low-set ears, and a weblike neck are consistent with
Turner syndrome (TS)
Brushfield spots, epicanthal folds, flat facies, and a single palmar crease are consistent with
Down syndrome (trisomy 21)
Down syndrome is the most common autosomal trisomy and is associated with a longer life expectancy than Edward syndrome and Patau syndrome. A quadruple screen showing
Elevated β-hCG and inhibin A
Decreased AFP and estriol
A high-pitched cry, microcephaly, moon facies, and widely spaced eyes are consistent with
Cri-du-chat syndrome
This condition is caused by a congenital deletion in the short arm of chromosome 5 and is associated with severe intellectual disability and cardiac abnormalities.
Cri-du-chat syndrome
First-trimester maternal serum markers will likely show decreased β-hCG and PAPP-A; a second-trimester quadruple screen will likely show decreased β-hCG, AFP, estriol, and inhibin A.
Edwards syndrome
- DNA contained in nucleus of cells
- “Hereditary material”
- Passed to successive generations of cells
Genome
- Portions of DNA/genome
- Code for proteins that carry out specific functions
Genes
- Rod-shaped, cellular organelles
- Single, continuous DNA double helix strand
- Contains a collection of genes (DNA)
Chromosome
- Chromosomes 1 through 22 plus X/Y (sex)
- Two copies each chromosome 1 through 22 (homologous)
46 chromosomes arranged in 23 pairs
Diploid: two sets of chromosomes (23 pairs)
Somatic cells (most body cells)
“Haploid”: one set of chromosomes
Gametes (reproductive cells)
- S phase of cell cycle
Chromosomes replicate → two sister chromatids - M phase (mitosis): Cell divides
- Daughter cells will contain copies of chromosomes
Mitosis
- “Haploid”: one set of chromosomes
- Produced by meiosis of germ line cells
- Male and female gametes merge in fertilization
- New “diploid” organism formed
Gametes (reproductive cells)
- Alternative forms of gene
- Many genes have several forms
- Often represented by letter (A, a)
Allele
Genes exist in multiple forms (alleles)
Genetic polymorphism
Location of allele on chromosome
Locus (plural loci)
DNA → gene → allele → locus → chromosome
Genetics
- Genetic makeup of a cell or individual
- Often refers to names of two copies of a gene
- Example: Gene A from father, Gene B from mother
- Genotype: AB
- Or two alleles of gene A (A and a): AA, Aa, aa
Genotype
- Physical characteristics that result from genotype
- Example: AB = blue eyes; BB = green eyes
Phenotype
- Common in most individuals
- Example: A = wild type
Wild type gene/allele
- Different from wild type
- Caused by a mutation
- Example: a = mutant
- Individual: AA, Aa, aa
Mutant gene/allele
Two identical copies of a gene (i.e. AA)
Homozygous
Two different copies of a gene (i.e. Aa)
Heterozygous
- DNA of sperm/eggs
- Transmitted to offspring
- Found in every cell in body
Germ line mutations
- Acquired during lifespan of cell
- Not transmitted to offspring
Somatic mutations
Determines phenotype even in individuals with single copy
* Often denoted with capital letters
* Example: Gene has two alleles: A, a
Dominant gene/allele
- Requires two copies to produce phenotype
- Often denoted with lower case letters
- Example: aa = a phenotype; Aa and AA = A phenotype
Recessive gene/allele
- Both alleles contribute to phenotype
- Classic example: ABO Blood Groups
- A gene = A antigen on blood cells
- B gene = B antigen
- O gene = No A or B antigen
- AB individuals
- Express A and B antigens
Codominance
- May cause early COPD and liver disease
- Mutations in AAT gene (produces α1 antitrypsin)
- M = normal allele
- S = moderately low levels protein
- Z = severely reduced protein levels
- Combination of alleles determines protein levels
- MM = normal
- ZZ = severe deficiency
- Other combinations = variable risk of disease
α-1 Antitrypsin Deficiency
- Proportion with allele that express phenotype
- Incomplete penetrance
- Not all individuals with disease mutation develop disease
- Commonly applied to autosomal dominant disorders
- Not all patients with AD disease gene develop disease
- Example BRCA1 and BRCA2 gene mutations
Penetrance
- Genetic mutations that lead to cancer
- Germline gene mutations
- Autosomal dominant
- Not all women with mutations develop cancer
- Implications:
- Variable cancer risk reduction from prophylactic surgery
BRCA1 and BRCA2
- Variations in phenotype of gene
- Different from penetrance
- Classic case: Neurofibromatosis type (NF1)
- Neurocutaneous disorder
- Brain tumors, skin findings
- Autosomal dominant disorder
- 100% penetrance (all individuals have disease)
- Variable disease severity (tumors, skin findings)
Expressivity
- One gene = multiple phenotypic effects and traits
Example: single gene mutation affects skin, brain, eyes - Clinical examples:
- Phenylketonuria (PKU): skin, body odor, mental disability
- Marfan syndrome: Limbs, eyes, blood vessels
- Cystic fibrosis: Lungs, pancreas
- Osteogenesis imperfecta: Bones, eyes, hearing
Pleiotropy
Mutations in tumor suppressor genes
* Genes with many roles
* Gatekeepers that regulate cell cycle progression
* DNA repair genes
* Heterozygous mutation = no disease
* Mutation of both alleles → cancer
* Cancer requires “two hits”
* “Loss of heterozygosity”
Two-Hit Origin of Cancer
Retinoblastoma
* Rare childhood eye malignancy
* Hereditary form (40% of cases)
* One gene mutated in all cells at birth (germline mutation)
* Second somatic mutation “hit”
* Cancer requires only one somatic mutation
* Frequent, multiple tumors
* Tumors at younger age
Two-Hit Origin of Cancer
* Classic example:
- Requires two somatic “hits”
- Two mutations in same cell = rare
- Often a single tumor
- Occurs at a later age
Retinoblastoma: Sporadic form (non-familial)
- Hereditary nonpolyposis colorectal cancer
- Inherited colorectal cancer syndrome
- Germline mutation in DNA mismatch repair genes
- Second allele is inactivated by mutation
Two-Hit Origin of Cancer
Other Examples: HNPCC (Lynch syndrome)
- Germline mutation of APC gene (tumor suppressor gene)
- Always (100%) progresses to colon cancer
- Treatment: Colon removal (colectomy)
Two-Hit Origin of Cancer
Other Examples: Familial Adenomatous Polyposis (FAP)
- Syndrome of multiple malignancies at an early age
- Sarcoma, Breast, Leukemia, Adrenal Gland (SBLA) cancer
syndrome - Germline mutation in tumor suppressor gene TP53
- Codes for tumor protein p53
- Delays cell cycle progression to allow for DNA repair
Two-Hit Origin of Cancer
Other Examples: Li-Fraumeni syndrome
- Gene differences in cells of same individual
- Mutations in cells → genetic changes
- Individual will be a mixture of cells
Mosaicism
- Can be passed to offspring
- Pure germline mosaicism difficult to detect
- Not present is blood/tissue samples used for analysis
- Offspring disease may appear sporadic
- Can present as recurrent “sporadic” disease in offspring
Mosaicism: Germline mosaicism
- Gene differences in tissues/organs
- 45X/46XX mosaic Turner syndrome (milder form)
- Rare forms of Down syndrome
Mosaicism: Somatic mosaicism
- Rare disorder
- Affects many endocrine organs
- Precocious puberty
Menstruation may occur 2 years old - Fibrous growth in bones
Fractures, deformity - Skin pigmentation
Café-au-lait spots
Irregular borders (“Coast of Maine”)
McCune-Albright Syndrome
- Caused by sporadic mutation in development
Not inherited - Somatic mutation of GNAS gene
- Codes for alpha subunit of G3 protein
- Activates adenylyl cyclase
- Continued stimulation of cAMP signalling
McCune-Albright Syndrome
- “Postzygotic” mutation
- Occurs after fertilization
- Only some tissues/organs affected (mosaicism)
- Clinical phenotype varies depending on which tissues affected
- Germline occurrences of mutation are lethal
- Entire body effected
- Cells with mutation survive only if mixed with normal cells
McCune-Albright Syndrome
- Same phenotype from different genes/mutations
- Different mutations of same allele → same disease
- Different gene (loci) mutations → same disease
- Multiple gene mutations often cause same disease
- Many diseases have multiple genotypes
Genetic Heterogeneity
- Allele = Alternative form of gene
- Allele 1 = mutation X
- Allele 2 = mutation Y
- Both X and Y cause same disease
- X and Y found at same chromosomal locus (position)
- Many alleles possess multiple mutant forms
- One disease = multiple genes = single location
Allelic heterogeneity
- Mutation in beta globin gene
- Wide spectrum of disease depending on mutation
- βo = no function; β1 = some function
Allelic heterogeneity: Beta Thalassemia
- Mutation in CFTR gene
- Over 1400 different mutations described
Allelic heterogeneity: Cystic Fibrosis
- Mutations in different loci cause same phenotype
- Example: Retinitis Pigmentosa
- Causes visual impairment
- Autosomal dominant, recessive, and X-linked forms
- Mutations at 43 different loci can lead to disease
- One disease = multiple genes = multiple locations
Locus heterogeneity
- During meiosis chromosomes exchange segments
- Child inherits “patchwork” of parental chromosomes
- Never exact copy of parental chromosomes
Genetic Recombination
- Suppose father has two alleles of F and M genes
- F and f
- M and m
- F and M found on different chromosomes
- Independent assortment
- Occurs if F and M genes can independently recombine
- 25% chance of each combination in gamete
Independent Assortment
- What if genes on same chromosome?
- If very far apart, crossover may occur in meiosis
- Result: Same combinations as separate chromosomes
Independent Assortment
- If alleles close together: little crossover
- Low occurrence of recombination (Fm or fM)
Independent Assortment
- Frequency of recombined genes (Fm or fM)
- Denoted by Greek letter theta (θ)
- Ranges from zero to 0.5
- Key point: recombination frequency α distance
- Close together: θ = 0
- Far apart: θ = 0.5
- Used for genetic mapping of genes
Recombination Frequency
- Done by studying families
- Track frequency of genetic recombination
- Use frequency to determine relative gene location
Genetic Mapping: linkage Mapping
Tendency of alleles to transmit together
* More linkage = less independent assortment
* Close together (θ = 0) = tightly linked
* Far apart (θ = 0.5) = unlinked
Linkage
- Used to study genes that are very close together
- Recombination very rare
- Family studies impractical
- Done by studying large populations
Linkage Disequilibrium
- Gene A has two polymorphisms: A and a
- A found in 50% of individuals
- a in 50%
- Gene B has two polymorphisms: B and b
- B found in 90% of individuals
- b in 10%
Linkage Equilibrium
Population frequencies should be:
* AB = (0.5) x (0.9) = 0.45
* aB = (0.5) x (0.9) = 0.45
* Ab = (0.5) x (0.1) = 0.05
* ab = (0.5) x (0.1) = 0.05
This is linkage equilibrium
Linkage Equilibrium
- Population frequencies higher/lower than expected
- AB = 0.75 (higher than expected 0.45)
- This haplotype (AB) is in linkage disequilibrium
Linkage Disequilibrium
- Initially close to gene B
- AB transmitted together in a population
- Eventually A and B genes may recombine
- Depends on distance apart and size of population
- LD greatest when gene first enters population (i.e. mutation)
- Fades with successive generations (i.e. population size)
- Fades if distance between genes is greater
Linkage Disequilibrium: Consider new gene mutation A
- Linkage disequilibrium affected by:
- Genetic distance
- Time alleles have been present in population
- Different populations: different degrees of linkage
disequilibrium
Linkage Disequilibrium
- Diploid cells give rise to haploid cells (gametes)
- Unique to “germ cells”
- Spermatocytes
- Oocytes
- Two steps: Meiosis I and Meiosis II
Meiosis
- Diploid → Haploid (“reductive division”)
- Separates homologous chromosomes
Meiosis I
- Chromatids separate
- Four daughter cells
Meiosis II
- “Primary oocytes” form in utero
- Diploid cells
- Just beginning meiosis I
- Arrested in prophase of meiosis I until puberty
- At puberty
- A few primary oocytes complete meiosis 1 each cycle
- Some form polar bodies → degenerate
- Some form secondary oocytes (haploid)
- Meiosis II begins → arrests in metaphase
- Fertilization → completion of meiosis II
Oogenesis
- Abnormal chromosome number
Extra or missing chromosome - Disomy = two copies of a chromosome (normal)
- Monosomy = one copy
- Trisomy = three copies
Aneuploidy
- Failure of chromosome pairs to separate
- Most common mechanism of aneuploidy
- Can occur in meiosis I or II
Meiotic Nondisjunction
- Fertilization of 1n (normal) and 0n gamete
- Usually not viable
- Turner syndrome (45,X)
Only one sex chromosome
Monosomy
- Fertilization of 1n (normal) and 2n gametes
- Not compatible with life for most chromosomes
- Exceptions:
- Trisomy 21 = Down syndrome (95% cases due to NDJ)
- Trisomy 18 = Edward syndrome
- Trisomy 13 = Patau syndrome
Trisomy
- Meiosis I protracted in females
- Begins prenatally, completed at ovulation years later
- Advanced maternal age → ↑ risk trisomy
Maternal meiosis I NDJ errors are a common cause
- Father = 21A and 21B; Mother = 21C and 21D
- Trisomy 21 ACD = Meiosis I nondisjunction in mother
- Trisomy 21 ACC = Meiosis II nondisjunction in mother
Trisomy: cause of NJD suggested by trisomy genotype
- Child has two copies of one parent’s chromosomes
- No copies of other parent’s chromosomes
- Father = 21A and 21B; Mother = 21C and 21D
- Child AA (isodisomy) = Meiosis II error (father)
- Child CD (heterodisomy) = Meiosis I error (mother)
Uniparental Disomy
- Child is euploid
- Normal number of chromosomes
- No aneuploidy
- Usually normal phenotype
- Can lead to phenotype of recessive disease
- Father = Aa (recessive gene for disease)
- Child = aa (two copies of a from father)
Uniparental Disomy
- Fusion of long arms of two chromosomes
- Occurs in acrocentric chromosomes
Chromosomes with centromere near end (13, 14, 21, 22)
Robertsonian Translocation
- Carrier has only 45 chromosomes (one translocated)
- Loss of short arms → normal phenotype (no disease)
- 13-14 and 14-21 are most common
- Main clinical consequences
- Many monosomy and trisomy gametes
- Frequent spontaneous abortions
- Carrier may have child with Down syndrome (trisomy 21)
Robertsonian Translocation
- Can be done in couples with recurrent fetal losses
- Used to diagnose chromosomal imbalances
Karyotype
- Used in studies of populations
- Used to derive genotypes from allele frequencies
- Allelle: one of two or more alternative forms of the same gene
- Key point: Used to study single genes with multiple forms
- Not used for different genes at different loci/chromosomes
Hardy-Weinberg Law
- Given gene has two possible alleles: A and a
- Allele A found in 40% of genes (p=0.40)
- Allele a found in 60% of genes (q=0.60)
- What is frequency of genotypes AA, Aa, and aa?
Hardy-Weinberg Law: Example
p2 + 2pq + q2 = 1
p+ q = 1
p = 0.4
q = 0.6
* Frequency of AA = p2 = 0.16
* Frequency Aa = 2pq = 0.48
* Frequency aa = q2 = 0.36
Hardy-Weinberg Law
p + q = 1
* p = 0.4 → 40% of GENES in population are A
* q = 0.6 → 60% of genes in population are a
p2 + 2pq + q2 = 1
* p2 = 0.16 → 16% of INDIVIDUALS in population are AA
* 2pq = 0.48 → 48% of individuals in population are Aa
* q2 = 0.36 → 36% of individuals in population are aa
Hardy-Weinberg Law
p = 0.4
q = 0.6
p2 = 0.16
2pq = 0.48
q2 = 0.36
Hardy-Weinberg Law
- Large population
- Completely random mating
- No mutations
- No migration in/out of population
- No natural selection
Hardy-Weinberg Law
- If assumptions met, allele frequencies do not change
from one generation to the next - “Hardy-Weinberg equilibrium”
Hardy-Weinberg Law
- Very useful in autosomal recessive diseases
- Disease (aa) frequency often known
- Example: 1/5000 individuals have disease
- Carrier (Aa) frequency often unknown
Hardy-Weinberg Law
- Disease X caused by recessive gene
- Disease X occurs in 1/4500 children
- q2 = 1/4500 = 0.0002
- q = SQRT (0.0002) = 0.015
- p + q = 1
- p = 1 – 0.015 = 0.985
- Carrier frequency = 2pq
- 2 (0.985) (0.015) = 0.029 = 3%
- Very rare diseases p close to 1.0
- Carrier frequency ≈ 2q
Hardy-Weinberg Law
- Special case: X linked disease
- Two male genotypes (XdY or XY)
- Three female genotypes (XX or XdXd or XdX)
Hardy-Weinberg Law
- Consider males and females separately
- Among males
- p + q = 1 (all males are either Xd or X)
- p = frequency healthy males (XY)
- q = frequency diseased males (XdY)
- Males/females have same allele frequencies
- p males = p females
- q males = q females
Hardy-Weinberg Law (X-linked Disease)
Among females
* p2 = frequency healthy females (XX)
* 2pq = frequency carrier females (XdX)
* q2 = frequency diseased females (XdXd)
Hardy-Weinberg Law (X-linked Disease)
- Visual representation of a family
- Often used to study single gene disorders
- Gene passed down through generations
- Some members have disease
- Some members are carriers
- Several typical patterns
- Autosomal recessive genes
- Autosomal dominant genes
- X-linked genes
Pedigree
- Two alleles for a gene (i.e. A = normal; a = disease)
- Only homozygotes (aa) have disease
Autosomal Recessive
- If both parents are carriers (Aa)
- Child can have disease (aa)
- Only 1 in 4 chance of child with disease
- 2 of 4 children will be carriers (Aa)
- 1 of 4 children NOT carriers (AA)
Autosomal Recessive
If both parents are carriers (Aa)
* 50% chance mother gives a to child
* 50% chance father gives a to child
* (0.5) x (0.5) = 0.25 chance child has disease
Autosomal Recessive
- Mother 1/50 chance of being carrier
- Father 1/100 chance of being carrier
- Chance BOTH carriers = (1/100) * (1/50) = 1/5,000
- Chance child affected = (1/4) * (1/5000) = 1/20,000
Autosomal Recessive
- Males and females affected equally
- Few family members with disease
- Often many generations without disease
- Increased risk: Consanguinity
- Parents are related
- Share common ancestors
Autosomal Recessive
- Cystic fibrosis
- Sickle cell anemia
- Hemochromatosis
- Wilson’s disease
- Many others
Autosomal Recessive
- Two alleles for a gene (i.e. A = disease; a = no disease)
- Heterozygotes(Aa) and homozygotes(AA) have disease
Autosomal Dominant
- Males and females affected equally
- One affected parent → 50% offspring with disease
- Male-to-male transmission occurs
Autosomal Dominant
- Familial hypercholesterolemia
- Huntington’s disease
- Marfan syndrome
- Hereditary spherocytosis
- Achondroplasia
- Many others
Autosomal Dominant
- Heterozygote phenotype different from homozygote
- Heterozygotes: less severe form of disease
- Homozygotes: more severe
Incomplete Dominance: semidominant
- Autosomal dominant disorder of bone growth
- Heterozygotes (Dd): Dwarfism
- Homozygotes (DD): Fatal
Incomplete Dominance: semidominant
Classic example: Achondroplasia
- Heterozygotes: total cholesterol 350–550mg/dL
- Homozygotes: 650–1000mg/dL
Incomplete Dominance
Semidominant:
Familial hypercholesterolemia
- Disease gene on X chromosome (Xd)
- Always affects males (XdY)
- Females (XdX) variable
- X-linked recessive = females usually NOT affected
- X-linked dominant = females can be affected
X-linked Disorders
- All males with disease gene have disease
- Most females with disease gene are carriers
X-linked Recessive
- No male-to-male transmission
All fathers pass Y chromosome to sons - Sons of heterozygous mothers: 50% affected
- Classic examples: Hemophilia A and B
X-linked Recessive
- Females very rarely develop disease
- Usually only occurs if homozygous for gene
- Father must have disease and mother must be carrier
- Females can develop disease with skewed lyonization
X-linked Recessive
Results in inactivated X chromosome in females
* One X chromosome undergoes “Lyonization”
* Condensed into heterochromatin with methylated DNA
* Creates a Barr body in female cells
Lyonization
- Random process
- Different inactive X chromosomes in different cells
- Occurs early in development (embryo <100 cells)
- Results in X mosaicism in females
- May cause symptoms in females X-recessive disorders
- “Skewed lyonization”
Lyonization
- Occur in both sexes
- Every daughter of affected male has disease
- All daughters get an X chromosome from father
- Affected father MUST give disease X chromosome to daughter
X-linked Dominant
- Can mimic autosomal dominant pattern
- Key difference: No male-to-male transmission
Fathers always pass Y chromosome to sons
X-linked Dominant
- More severe among males (absence of normal X)
Classic example: Fragile X syndrome
* 2nd most common genetic cause intellectual disability (Down)
* More severe in males
* Often features of autism
* Long, narrow face, large ears and jaw
X-linked Dominant
- Each mitochondria contains DNA (mtDNA)
- Code for mitochondrial proteins
- Organs most affected by gene mutations:
- CNS
- Skeletal muscle
- Rely heavily on aerobic metabolism
Mitochondrial Genes
- Multiple copies of mtDNA in each mitochondria
- Multiple mitochondria in each cell
- All normal or abnormal: Homoplasmy
- Mixture: Heteroplasmy
Mitochondrial Genes: Heteroplasmy
- Depends on amount of normal versus abnormal genes
- Also number of mutant mitochondria in each cell/tissue
Mitochondrial Genes: Mutant gene expression highly variable
- Mitochondrial DNA inherited from mother
- Sperm mitochondria eliminated from embryos
- Homoplasmic mothers → all children have mutation
- Heteroplasmic mothers → variable
Mitochondrial Disorders
- Rare disorders
- Weakness (myopathy), confusion, lactic acidosis
- Wide range of clinical disease expression
- Classic hallmark: Red, ragged fibers
- Seen on muscle biopsy with special stains
- Caused by compensatory proliferation of mitochondria
- Accumulation of mitochondria in muscle fibers visualized
- Mitochondria appear bright red against blue background
Mitochondrial Myopathies
Many traits/diseases depend on multiple genes
* Height
* Heart disease
* Cancer
* “Run in families”
* Do not follow a classic Mendelian pattern
Polygenic Inheritance
- Genes , lifestyle, environment → disease
- Seen in many diseases
- Diabetes
- Coronary artery disease
- Hypertension
Multifactorial Inheritance
Epigenetic phenomenon
* Alteration in gene expression
* Different expression in maternal/paternal genes
Imprinting
- Occurs during gametogenesis (before fertilization)
- Genes “marked” as being paternal/maternal in origin
- Often by methylation of cytosine in DNA
Imprinting
- After conception, imprinting controls gene expression
- “Imprinted genes”: Only one allele expressed
- Non-imprinted genes: Both alleles expressed
Imprinting
- Prader-Willi and Angelman syndromes
- Both involve abnormal chromosome 15q11-q13
- “PWS/AS region”
- Paternal copy abnormal: Prader-Willi
- Maternal copy abnormal: Angelman
- Differences due to imprinting
Imprinting Syndromes
- Normally expressed on paternal chromosome 15
- NOT normally expressed on maternal copy
PWS genes
- Normally expressed on maternal chromosome 15
- NOT normally expressed on paternal copy
UBE3A
- Loss of function of paternal copy of PWS gene
Prader-Willi Syndrome
- ~75% cases from deletion of paternal gene
- Most cases due to sporadic mutation
- ~25% from maternal uniparental disomy
- Two copies of maternal gene inherited
- No copies of paternal gene
Prader-Willi Syndrome
- Most common “syndromic” cause of obesity
- Hypotonia
- Newborn feeding problems
- Poor suck reflex
- Delayed milestones
- Hyperphagia and obesity
- Begins in early childhood
- Intellectual disability (mild)
- Contrast with AS (severe)
- Hypogonadism
- Delayed puberty
Prader-Willi Syndrom
Abnormal maternal chromosome 15q11-q13
* Lack of expression of UBE3A
Angelman Syndrome
- Majority of cases caused by deletions
- Only about 3-5% from uniparental disomy
- Paternal disomy much less common than maternal
- Non-disjunction less common
Angelman Syndrome
AAT is an inhibitor of the enzyme elastase. In its absence, elastase activity in neutrophils and alveolar macrophages is excessive. This leads to the ? similar to the pathology of emphysema and COPD.
Destruction of alveoli
The classic presentation of AAT deficiency is ?. Many patients are presumed to have asthma until the diagnosis of AAT deficiency is made.
a non-smoker with symptoms of chronic lung disease including cough, sputum production, and wheezing
AAT deficiency is an example of a genetic disorder with ?. Both copies of the AAT gene are expressed in affected individuals. The severity of the disease depends on both alleles because each contributes to the total amount of available AAT enzyme. This patient’s sister is heterozygous for the same AAT mutation as the patient but has no symptoms. She must have one functional copy of the gene which can make sufficient AAT enzyme such that lung disease does not occur.
Codominant inheritance
Genes for the A and B antigens on red cells are codominant meaning both alleles contribute to the phenotype. Since the baby has genes for A and B antigens, both the A and the B antigen will be ? on red blood cells leading to blood type AB in the child.
Expressed
What is Neurofibromatosis Type 1 (NF1)?
NF1 is a neurocutaneous syndrome characterized by skin, nervous system, and eye abnormalities.
What type of inheritance pattern does NF1 follow?
NF1 is an autosomal dominant disorder.
Which gene is mutated in NF1, and on which chromosome is it located?
NF1 gene mutations occur on chromosome 17.
Where are freckles commonly found in individuals with NF1?
Freckles are often found in skin folds like the axilla, groin, or elbow.
What are neurofibromas, and how do they appear?
Neurofibromas are benign tumors that develop in cutaneous nerves, appearing as soft, fleshy, pedunculated growths on the skin.
Are neurofibromas malignant or benign?
Neurofibromas are benign but can be the most disfiguring aspect of NF1.
What are neurocutaneous disorders?
Neurocutaneous disorders involve structures derived from the ectoderm, including the skin, nervous system, and eyes.
NFT1 is famous for
Variable expressivity
What is the inheritance pattern of NF1?
NF1 is an autosomal dominant disorder.
What does 100% penetrance mean for NF1?
It means that all individuals with the disease gene will develop the disease.
Can individuals with NF1 have differing clinical presentations?
Yes, individuals can have differing clinical presentations and severity of symptoms.
Penetrance is different from expressivity. Penetrance refers to the proportion of affected individuals who will show evidence of disease. NFT has 100% penetrance, not incomplete penetrance.
All carriers have evidence of disease to some degree
What is gene imprinting?
Imprinting refers to alterations in gene expression among different cells in the same individual.
Does gene imprinting occur in Neurofibromatosis Type 1 (NF1)?
No, imprinting does not occur in NF1.
In which syndromes does gene imprinting occur?
Gene imprinting occurs in Prader-Willi and Angelman syndromes.
Somatic mosaicism occurs when mutations arise during early development in utero after some normal cells without the mutation have formed. This leads to a mosaic (i.e., mixture) of somatic cells, some with the disease gene (derived from the original cell with the mutation) and others without the disease gene (derived from normal cells that formed in utero prior to the mutation).
Somatic mosaicism occurs among new mutations that develop in the embryo. Inherited mutations that run in families cannot lead to somatic mosaicism as the gene mutation is inherited and therefore present in all cells.
What is the significance of imprinting in Prader-Willi and Angelman syndromes?
The expression of genes differs depending on whether the gene is inherited from the mother or the father, leading to distinct clinical features in these syndromes
Refers to a mutation present in some but not all germline cells (i.e., eggs and sperm) of an affected individual.
Germline mosaicism
What is germline mosaicism?
Germline mosaicism refers to a mutation present in some but not all germline cells (eggs and sperm) of an affected individual.
How does germline mosaicism affect genetic testing results?
A parent may test negative for a mutation using standard techniques that sample DNA from somatic cells, even if they carry the mutation in germline cells.
In the case of a parent who is a germline mosaic for an OI mutation, what might happen during genetic testing?
The mutation can be missed even if germline cells are tested, as it may only be present in some of the germline cells.
Why might standard genetic testing fail to detect certain mutations in germline mosaicism?
Because the mutation is not present in all germline cells, leading to potential false negatives in testing.
Locus heterogeneity refers to disorders that derive from more than one gene mutation.
Retinitis pigmentosa is a classic example.
What is phenylketonuria (PKU)?
KU is a rare enzyme deficiency syndrome caused by a lack of activity of phenylalanine hydroxylase (PAH).
What happens to phenylalanine in children with PKU?
They cannot metabolize phenylalanine into tyrosine, leading to accumulation of phenylalanine and its metabolites.
What are some symptoms of PKU?
Symptoms include a musty body odor and central nervous system dysfunction.
Why do affected children with PKU often have blond hair and pale skin?
This is due to the lack of tyrosine, which is used to synthesize the pigment melanin.
How does newborn screening affect the prevalence of PKU?
Widespread newborn screening has made PKU rarely seen in the developed world.
What is pleiotropy in genetics?
Pleiotropy refers to the production of multiple effects caused by a single mutation affecting different systems or organs.
Why is liver dysfunction not a prominent feature of PKU despite the presence of the PAH mutation in hepatocytes?
While all cells carry the mutation, the liver’s dysfunction is not as pronounced as the effects seen in the skin and nervous system.
Name other single-gene disorders that demonstrate pleiotropic effects.
Examples include Marfan syndrome, cystic fibrosis, and osteogenesis imperfecta.
How can liver transplantation help in treating PKU?
Liver transplantation can correct PKU because the donor organ can produce the PAH enzyme.
HLA genes often display
Linkage disequilibrium
Linkage disequilibrium
Refers to genes found together at a frequency different than expected by independent assortment.
In the question, the frequency of DRB10301 is 0.2 and that of DRB11501 is 0.4. If these two genes sorted independently, the combined frequency should be 0.2 x 0.4 = 0.08. Instead, the combined frequency is higher at 0.3.
This is evidence of linkage disequilibrium.
If natural selection favors a particular combination of alleles, that combination will display LD because certain recombinants will either die or live longer. LD may also occur when an allele first arises from a new mutation. It takes many generations for recombination to occur to a significant degree. Before this happens, gene combinations may display LD. For this reason, LD is an important tool in evolutionary biology. Other potential causes of LD are
Random genetic drift and non-random mating.
Down syndrome occurs in children born with three copies of chromosome 21 instead of the usual two (trisomy 21). Most commonly, this occurs due to spontaneous maternal nondisjunction in meiosis I. More than 90% of cases of Down syndrome result from this type of genetic error. When this happens, the risk of a second child with Down syndrome is relatively low (about 1%) although higher than for women without a prior Down syndrome child.
In about 3% of cases of Down syndrome, a ? in one parent leads to trisomy 21.
Robertsonian translocation
In a Robertsonian translocation, the long arms of two chromosomes are fused. The carrier of a Robertsonian translocation will have no evidence of a genetic disorder but will have ? instead of 46 chromosomes. If the fused chromosome is passed to an offspring, the child may develop trisomy.
Aneuploidy with 45
Chromosomes 14 and 21 commonly fuse in a Robertsonian translocation due to their acrocentric size. In these chromosomes, the centromere is close to the end making a large long arm and very small short arm. If a parent passes the fused 21;14 chromosome and a normal chromosome 21 to an offspring,
Down syndrome will occur
When do oocytes form and when do they enter meiosis I?
Oocytes form in utero and enter meiosis I during fetal development.
What are the stages of meiosis?
Meiosis progresses through prophase, metaphase, anaphase, and telophase.
At what stage do oocytes arrest until puberty?
Oocytes remain arrested in prophase of meiosis I until puberty.
What stimulates oocytes to progress through meiosis during the menstrual cycle?
Follicle-stimulating hormone (FSH) stimulates oocytes to progress.
How many follicles are typically activated during each ovarian cycle?
About 20 follicles are activated during each ovarian cycle.
How many follicles usually mature from the activated ones?
Usually, only one follicle matures.
At what stage do oocytes arrest after completing meiosis I?
Oocytes arrest in metaphase of meiosis II until fertilization.
What happens to oocytes when a woman begins in vitro fertilization?
Her ovaries will contain many oocytes arrested in meiosis I, which will be stimulated by FSH to complete meiosis I and begin meiosis II.
Oocytes arrest in metaphase of meiosis II at the time of ovulation, after stimulation by
FSH
What causes non-disjunction of chromosome 21 during meiosis I?
Certain substances can cause non-disjunction, leading to oocytes with either zero or two copies of chromosome 21.
What happens if an oocyte with non-disjunction is fertilized by a normal sperm?
It results in offspring with either 45 or 47 chromosomes.
What is the outcome for zygotes with 45 chromosomes?
Zygotes with 45 chromosomes are not viable.
What condition results from zygotes with 47 chromosomes?
Zygotes with 47 chromosomes will have Down syndrome, also known as trisomy 21.
What does “double Y male” mean?
A double Y male has two Y chromosomes, resulting in a rare genetic disorder.
What are the typical characteristics of a double Y male?
Affected males are often phenotypically normal, taller than average, and may have learning disabilities.
How does a child end up with two Y chromosomes?
This occurs due to an error in meiosis II, specifically nondisjunction.
What is the result of nondisjunction in meiosis II?
It leads to two identical copies of a parental chromosome (e.g., two Y chromosomes) being passed to the child.
How does nondisjunction in meiosis I differ from meiosis II?
Nondisjunction in meiosis I results in an extra chromosome that is not identical, while in meiosis II, the extra chromosome is identical.
When does meiosis II occur in males?
Meiosis II occurs during spermatogenesis as secondary spermatocytes develop into spermatids.
What is cystic fibrosis?
Cystic fibrosis is an autosomal recessive disorder that leads to chronic lung disease in children. Diagnosis is often made in utero based on ultrasound findings.
What is the classic presentation of cystic fibrosis at birth?
The classic presentation is meconium ileus, where the first stool is thick and sticky, potentially obstructing the bowel.
What symptoms can meconium ileus cause in cystic fibrosis patients?
Symptoms include vomiting and abdominal distention.
How is meconium ileus treated?
Treatment options include enemas or surgery.
What is the typical inheritance pattern for autosomal recessive disorders like cystic fibrosis?
Affected individuals usually have two parents who are carriers of the disease gene.
What is uniparental disomy?
Uniparental disomy occurs when a child receives two copies of a chromosome from one parent and none from the other.
How can uniparental disomy lead to cystic fibrosis in a child with only one carrier parent?
If a gamete from the carrier parent has two copies of the cystic fibrosis gene and fuses with a gamete from the other parent with none, the child can inherit the disorder.
What are the two types of uniparental disomy?
Heterodisomy (non-identical chromosomes from one parent) and isodisomy (two identical chromosomes from one parent).
How does isodisomy affect inheritance of autosomal recessive diseases?
In isodisomy, two copies of a gene for an autosomal recessive disease can be passed to a child, leading to the disease despite having only one parent as a carrier.
Causes cystic fibrosis by leading to abnormal protein folding in affected cells.
The delta 508 CFTR mutation
What does it mean if a brother has an autosomal recessive disease?
It means both parents must be carriers of the disease allele since neither parent has the disease.
What is the chance that a healthy individual with a sibling who has an autosomal recessive disease is a carrier?
The chance is 2/3
Why is the chance of being a carrier for the healthy sibling 2/3?
In the offspring of two carrier parents, there is a 1/4 chance of a child being homozygous for the disease (two disease alleles).
What are the possible genotypes for a healthy individual with a sibling that has an autosomal recessive disease?
The healthy individual can have either two normal alleles (homozygous normal) or one normal allele and one disease allele (heterozygous carrier).
How do the possible genotypes relate to carrier status?
Out of the three possible genotypes (two normal alleles or one of each), two of these result in a carrier state (one normal and one disease allele).
What is the significance of understanding carrier probabilities in genetics?
It helps assess the risk of passing on genetic conditions in families, especially for autosomal recessive diseases.
Can males be unaffected carriers of X-linked disorders?
No, males cannot be unaffected carriers; they either have the disease or do not have the disease gene.
What is the frequency of diseased males equal to in the male population for X-linked disorders?
The frequency of diseased males is equal to the frequency of the disease gene in the male population.
If 1/50,000 males have an X-linked disease, what does that tell us about the frequency of the disease gene?
It means 1/50,000 males have the disease gene.
How does the frequency of the disease gene in females compare to that in males for X-linked disorders?
The frequency of the disease gene is the same; 1/50,000 females also carry the disease gene
How can females be carriers for X-linked disorders?
Females can have one normal allele and one disease allele, making them carriers.
According to Hardy-Weinberg principles, what does
q represent?
q represents the frequency of the disease gene, which is 1/50,000 in this case.
How do you calculate the rate of carrier females for an X-linked disorder?
The rate of carrier females is calculated using 2pq from Hardy-Weinberg Law.
For rare diseases, what is the assumption for p?
For rare diseases, p is assumed to be equal to 1.
What is the rate of carrier females for the X-linked disorder in this scenario?
The rate of carrier females is
2×(1/50,000)×1=1/25,000
What is Hardy-Weinberg equilibrium?
It is a state in which allele frequencies in a population remain stable over generations, indicating no evolution for that gene.
What are the Hardy-Weinberg equations used for?
They are used to estimate frequencies of allele combinations in a population.
What is one of the key assumptions for Hardy-Weinberg equilibrium?
An absence of natural selection.
How does the sickle cell carrier state relate to natural selection?
If being a carrier protects against malaria, it creates a natural selection pressure that violates Hardy-Weinberg assumptions.
What effect would a protective carrier state have on allele frequencies?
It would increase the survival of carriers, leading to more carriers and fewer non-carriers over time.
What can result from a natural selection pressure in relation to Hardy-Weinberg equilibrium?
It can prevent Hardy-Weinberg equilibrium from occurring by altering allele frequencies in the population.
Name one other assumption that must be met for Hardy-Weinberg equilibrium.
Random mating within the population.
What type of genetic disorder is sickle cell anemia?
Sickle cell anemia is an autosomal recessive disorder.
What is the frequency of the disease given as?
The frequency of the disease is given as 16/100.
In Hardy-Weinberg Law, how is the frequency of the disease represented?
The frequency of the disease (homozygotes for the disease gene) is represented by q(cuadrada)
What is the frequency of the disease allele given in the scenario?
The frequency of the disease allele is 1/100 or 1%.
In Hardy-Weinberg terms, what does q represent?
q represents the frequency of the disease allele.
For rare diseases, what can p be approximated as?
1
What is Prader-Willi syndrome (PWS)?
Genetic disorder related to the PWS gene on chromosome 15, characterized by a range of symptoms including failure to thrive and developmental delays in infants.
What are some classic features of PWS in childhood?
Insatiable appetite leading to obesity, intellectual impairment, small hands and feet, “almond-shaped” eyes, and a thin upper lip.
What does it mean for the PWS gene to be imprinted?
In imprinted genes, only one allele (either maternal or paternal) is expressed. For the PWS gene, only the paternal gene is expressed.
What percentage of PWS cases is caused by a sporadic deletion in the paternal copy of the PWS gene?
About 75%
Why is the maternal copy of the PWS gene inactive in PWS?
Due to imprinting.
What is uniparental disomy?
A child inherits two copies of a chromosome from one parent and none from the other.
How can uniparental disomy lead to PWS?
If a child inherits two maternal copies of the PWS gene and no paternal copies, it results in no functional paternal PWS gene activity.
What percentage of PWS cases is caused by uniparental disomy?
About 25%
How does uniparental disomy occur during gamete formation?
A gamete forms with two chromosomes instead of one and fuses with a gamete having zero copies of that chromosome.
What is methylation in the context of genetics?
Tthe addition of a methyl group to DNA bases, such as cytosine, marking genes as being of maternal or paternal origin.
What does the absence of paternal PWS gene activity indicate in an individual with PWS?
It indicates that either the paternal gene has been deleted or that both copies inherited are from the mother (as seen in uniparental disomy).
Can methylation alone explain the lack of paternal PWS gene activity in affected individuals?
No, while methylation explains the imprinting mechanism, it does not fully account for the absence of paternal gene activity in PWS
What role does genetic imprinting play in conditions like PWS?
Genetic imprinting leads to the expression of only one allele, which can result in disorders when the active allele is lost or inactive.
What is Angelman syndrome?
A genetic disorder primarily affecting the nervous system, characterized by developmental delay, seizures, microcephaly, frequent smiling, and hand flapping.
What are some key features of Angelman syndrome?
Developmental delay, seizures, small head (microcephaly), frequent smiling, and hand flapping.
What type of genetic mechanism is involved in Angelman syndrome?
Involves imprinted genes, where only one allele is expressed.
Which gene is primarily associated with Angelman syndrome?
The UBE3A gene.
Why is Angelman syndrome considered an imprinting disorder?
Because the disorder arises from the loss of function of the expressed allele, while the non-expressed allele remains inactive
What should prompt consideration of Angelman syndrome in a young child?
Poor development and frequent smiling.
What is MELAS?
MELAS is a mitochondrial myopathy characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
What are common neurologic features of mitochondrial disorders like MELAS?
Weakness and lactic acidosis.
What is the hallmark symptom of MELAS?
Stroke-like episodes that can lead to hemiparesis and hemianopia (loss of half of the visual field).
What other features may occur in MELAS?
Hearing loss and seizures.
What causes MELAS?
Mutations affecting mitochondrial DNA.
What is heteroplasmy?
The presence of more than one genome within a cell, which can lead to variable signs and symptoms in mitochondrial disorders.
How does heteroplasmy affect symptoms in MELAS?
The mutation may affect some mitochondrial DNA but not all, leading to a variable distribution of normal to abnormal DNA across cells and mitochondria, resulting in different symptoms among affected family members.
Why should mitochondrial disorders be considered when lactic acidosis occurs with neurologic symptoms?
These features are common indicators of mitochondrial dysfunction, including disorders like MELAS.
Name a type of cancer associated with tumor suppressor gene mutations.
Retinoblastoma
Hereditary nonpolyposis colorectal cancer (HNPCC)
X-linked recessive inheritance leads to disorders that affect males with the disease gene. Females with the disease gene are carriers, and rarely develop disease.
The pattern described in the question of disease that affects a maternal aunt and the boy’s sister would be unlikely in an X-linked recessive disorder.
Germline mutations occur in germ cells like oocytes and spermatozoa, but are absent in other cells of the body. These mutations may be passed to a child of parents with no evidence of disease since the mutation is present only in germline cells.
This boy has multiple family members (aunt, uncle, sister) with disease making an isolated germline mutation very unlikely.
What is Duchenne muscular dystrophy (DMD)?
An X-linked recessive disorder that primarily affects males, causing progressive muscle weakness.
How is DMD inherited?
It is inherited in an X-linked recessive manner, predominantly affecting males.
Why do most mothers of boys with DMD not exhibit symptoms of the disease?
Most mothers are carriers with one normal X chromosome that prevents the development of the disease.
What percentage of female carriers of DMD may develop symptoms?
About 8% of female carriers may develop symptoms of muscle weakness.
What is skewed lyonization?
Skewed lyonization occurs when the inactivation of X chromosomes is unequal, allowing a significant number of X chromosomes carrying the disease gene to remain active.
How do symptoms in female carriers of DMD compare to affected males?
Female carriers typically exhibit milder muscular features than affected males.
What is aneuploidy?
A condition characterized by an abnormal number of chromosomes.
Meiotic nondisjunction leads to
Aneuploidy
X-linked dominant inheritance leads to X-linked disorders where
Both males and females are affected.
Is a classic example of a X-linked dominant disorder.
Fragile X syndrome
What is hereditary spherocytosis?
An autosomal dominant disorder characterized by the presence of spherically shaped red blood cells.
How is hereditary spherocytosis inherited?
It is inherited in an autosomal dominant manner.
What does the pedigree of a family with hereditary spherocytosis typically show?
Multiple family members with the disease in each generation.
What is incomplete penetrance?
A condition where not all individuals with the disease gene exhibit symptoms of the disease.
What does penetrance refer to?
The proportion of individuals with a particular genotype who show evidence of the associated phenotype.
Why might a woman with hereditary spherocytosis not show evidence of the disease?
This is consistent with incomplete penetrance, where she carries the gene but does not express the disease.
Is hereditary spherocytosis known to exhibit incomplete penetrance?
Yes, it is a well-described disorder with incomplete penetrance.
What is somatic mosaicism?
The presence of two or more populations of somatic cells with different genotypes within an individual.
How does somatic mosaicism affect an individual’s health?
It can lead to variable expression of genetic traits or diseases, but it does not necessarily explain the absence of symptoms in affected individuals.
What is familial hypercholesterolemia (FH)?
An autosomal dominant genetic disorder characterized by high levels of LDL cholesterol in the blood.
What causes FH in its most common form?
A gene mutation that leads to underproduction of LDL receptors, preventing LDL clearance from plasma.
What are the serum LDL cholesterol levels in homozygotes with FH?
LDL levels may be as high as 1000 mg/dL (normal is <200 mg/dL).
What is the typical outcome for untreated homozygotes with FH?
They often die before age twenty due to coronary or vascular disease.
How does the severity of FH differ between homozygotes and heterozygotes?
Homozygotes have more severe disease, while heterozygotes experience milder symptoms.
What phenomenon describes the differing severity of disease in homozygotes vs. heterozygotes?
Incomplete dominance (or semidominance)
What are two classic disorders that exhibit incomplete dominance?
Familial hypercholesterolemia (FH) and achondroplasia.
What are two classic disorders that exhibit incomplete dominance?
Familial hypercholesterolemia (FH) and achondroplasia.
A 55-year-old man presents for an annual physical. He has a history of hemophilia A. Among his family members, others with hemophilia include his brother and his maternal grandfather. His mother, father, and daughter do not have hemophilia. He asks about his daughter who is pregnant. Her husband has no family history of hemophilia. Which of the following is the chance that her child will have hemophilia?
25%
What is the increased risk of developing Acute lymphoblastic leukemia (ALL) in children with Down syndrome?
Ten to twenty times higher than in children without Down syndrome.
What are common nonspecific clinical features at the presentation of ALL?
Fatigue, malaise, or fever.
What physical examination findings are often present in children with ALL?
Hepatosplenomegaly.
How does infiltration of the bone marrow by malignant cells affect blood counts in ALL?
It can lead to anemia and thrombocytopenia.
What complication can low platelet counts cause in children with leukemia?
Increased predisposition to bruising.
What is the condition of the bone marrow in acute lymphoblastic leukemia (ALL)?
Hypercellular and filled with lymphoblasts.
Besides ALL, what other type of leukemia are children with Down syndrome at increased risk for?
Acute myeloid leukemia (AML). (M7)
What is the confirmatory test of choice for Down syndrome in the first trimester?
Chorionic villus sampling (CVS).
How is chorionic villus sampling (CVS) performed?
A sample of the placenta is obtained either through the cervix or abdominal wall.
What do the placental chorionic villi derive from?
Fetal trophoblast tissue
What is the diagnostic procedure used in the second trimester for Down syndrome?
Amniocentesis.
Fetal ultrasound may identify increased nuchal translucency which raises the likelihood of a fetus with Down syndrome. But this is a screening test not a diagnostic test.
Fetal ultrasound cannot make a definitive diagnosis of Down syndrome.
Serum pregnancy-associated plasma protein-A, total human chorionic gonadotropin, and alpha-fetoprotein are screening tests for Down syndrome similar to fetal ultrasound.
. They do not provide genetic material from the fetus, and are not used to definitively diagnose Down syndrome.
What are some physical features of Down syndrome?
Flat nasal bridge, low set ears, and Brushfield spots on the irises.
What are the most likely causes of bowel obstruction in a newborn with Down syndrome?
Duodenal atresia or stenosis.
What percentage of newborns with Down syndrome have congenital anomalies of the GI tract?
About 5%.
What are the most common congenital GI anomalies in newborns with Down syndrome?
Duodenal atresia and stenosis
How can vomiting be classified?
Bilious and non-bilious.
What characterizes bilious vomiting?
It is green and indicates a lack of bile flow due to intestinal obstruction.
Where does bile enter the gastrointestinal tract?
At the ampulla of Vater in the duodenum.
At what age does pyloric stenosis typically present in infants?
About 3 to 6 weeks old
What are the classic symptoms of pyloric stenosis?
Projectile, non-bilious vomiting after feeding.
What is malrotation with volvulus?
A congenital anomaly that causes intestinal obstruction and bilious vomiting due to abnormal positioning of the cecum and twisting of the intestines.
Where is the cecum positioned in malrotation?
In the right mid to upper quadrant instead of the right lower quadrant.
What complication can occur due to malrotation?
Volvulus, which is a twisting of the intestines around the mesentery leading to obstruction.
What type of vomiting is associated with malrotation with volvulus?
Bilious vomiting.
Which gastrointestinal congenital malformation is more common in Down syndrome?
Duodenal atresia.
How does the presentation of duodenal atresia differ from pyloric stenosis?
Duodenal atresia typically presents with bilious vomiting, while pyloric stenosis presents with non-bilious vomiting.
Is a telescoping of the intestine into itself causing abdominal pain and bowel obstruction. This can be seen in children, usually due to an idiopathic cause.
Intussusception
What are some physical features of Down syndrome?
Short neck, protruding tongue, flat facial profile, brachycephaly, and upslanting palpebral fissures.
What percentage of children with Down syndrome have congenital heart disease?
Approximately 50%.
What is the most common type of congenital heart defect in children with Down syndrome?
Atrioventricular septal defect (AV septal defect).
What structures are involved in an atrioventricular septal defect?
The atrial septum, ventricular septum, and the AV valves (tricuspid and mitral valves)
From which embryological structures do the defects in AV septal defects arise?
Endocardial cushions.
What are the alternative names for an atrioventricular septal defect?
AV canal defect, AV septal defect, and endocardial cushion defect.
What additional abnormalities might be present in a child with Down syndrome and an AV canal defect?
Atrial septal defect, ventricular septal defect, abnormal mitral valve, or abnormal tricuspid valve.
What is a complete AV septal defect?
lesion involving abnormalities in the atrial septum, ventricular septum, and both AV valves.
What type of murmur is associated with ventricular septal defect or mitral regurgitation?
Holosystolic murmur.
What is the test of choice to define the anatomy of congenital heart defects in Down syndrome?
Echocardiography.
This boy has features consistent with Down syndrome including a flat nasal bridge, low set ears, and Brushfield spots on the irises. The chromosomal analysis shows some euploid cells with a normal number of chromosomes (46). Other cells have an extra chromosome (47) indicating the presence of trisomy 21. This is consistent with somatic mosaicism.
In somatic mosaicism, a mitotic error occurs in early embryo development. This leads to a mixture of cell types (i.e., a mosaic). Some have trisomy 21, others do not. This form of Down syndrome is unrelated to advanced maternal age in contrast to the more common form due to meiotic nondisjunction. Children with mosaic Down syndrome may have milder features since some cells do not have trisomy.
Meiosis I nondisjunction is the most common cause of trisomy 21. Meiosis II nondisjunction is less common. Both lead to a uniform population of cells in the baby, all containing an extra chromosome 21.
A Robertsonian translocation occurs when the long arms of two chromosomes are fused. If this fused chromosome is passed to an offspring, the child may have aneuploidy including trisomy 21. All cells in the offspring would have the same genetic content.
In uniparental disomy, a child receives two copies of a chromosome from one parent, and none from the other. All cells in children with uniparental disomy will have the same genetic.
What is Klinefelter syndrome?
A genetic condition in males caused by an extra X chromosome (47, XXY).
- Tall stature and long limbs.
- Learning disabilities and a quiet personality.
What cognitive effects are often seen in individuals with Klinefelter syndrome?
Learning disabilities and a quiet personality.
What is the state of the testes in men with Klinefelter syndrome?
Testes are typically small and firm.
What hormonal imbalance occurs in Klinefelter syndrome?
Underproduction of testosterone leads to increased estrogen effects.
What common breast condition can occur in males with Klinefelter syndrome?
Gynecomastia.
What is a rare cancer that has an increased risk in men with Klinefelter syndrome?
Male breast cancer.
Are associated with Turner syndrome which occurs in girls missing an X chromosome (45, XO).
Aortic coarctation, diabetes II, hypothyroidism, and osteoporosis
In Klinefelter syndrome, the underproduction of testosterone allows estrogen effects to
Increase
Hypogonadism in Klinefelter syndromes leads to decreased production of testosterone and inhibin B from the testes. The pituitary gland responds with increased release of
LH and FSH
Patient’s with Turner’s syndrome have “streak ovaries” meaning ovaries with fibrous tissue and few or no oocytes. Because the ovaries lack eggs, ? has the best chance of leading to a successful pregnancy.
Oocyte donation with in-vitro fertilization
What is the standard diagnostic test for Turner syndrome?
Karyotype analysis to establish the presence of 45,XO cells
How is the karyotype analysis for Turner syndrome typically performed?
Using lymphocytes obtained from a blood sample.
Why is a minimum of 30 cells analyzed in karyotype studies for Turner syndrome?
To detect mosaicism, where some cells may be normal and others may be 45,XO.
Historically, a buccal smear was obtained to look for Barr bodies. Barr bodies are condensed chromatic seen in cells with two X chromosomes. They should be present in girls but are absent in patients with Turner syndrome.
This test is inaccurate and no longer used.
What prenatal finding is commonly associated with Turner syndrome (TS)?
Cystic hygroma, a fluid-filled sac caused by lymphatic obstruction.
Where is cystic hygroma typically found in cases of Turner syndrome?
At the base of the head attached to the neck.
What is a common renal anomaly associated with Turner syndrome?
Horseshoe kidney, formed by the fusion of the right and left kidneys.
What percentage of Turner syndrome cases report renal anomalies, including horseshoe kidney?
Up to 70%.
Besides renal anomalies, what other cardiovascular anomalies are associated with Turner syndrome?
Bicuspid aortic valve and coarctation of the aorta.
When is recombinant human growth hormone therapy recommended for girls with Turner syndrome?
When their height falls below the 5th percentile for their age group.
At what age is growth hormone therapy typically initiated in girls with Turner syndrome?
Between two and five years of age.
Are girls with Turner syndrome growth hormone deficient?
No, they are not growth hormone deficient.
Is used to induce puberty in girls with Turner syndrome. Therapy with progestins can be added to limit breakthrough uterine bleeding.
Estradiol
What is a significant risk for pregnant women with Turner syndrome?
Increased risk for aortic dissection.
What cardiac conditions are commonly associated with Turner syndrome that elevate the risk of aortic dissection?
Bicuspid aortic valves and aortic coarctation.
How does pregnancy itself affect the risk of aortic dissection?
Pregnancy is associated with a slightly increased risk of aortic dissection, even in women without Turner syndrome.
What do some society guidelines recommend regarding pregnancy in women with Turner syndrome?
They may consider Turner syndrome a contraindication to pregnancy due to the elevated risk of aortic dissection.
What is a recommended monitoring strategy for women with Turner syndrome during pregnancy?
Serial imaging of the aorta, with surgery if aortic enlargement occurs.
Patients with Turner syndrome commonly have bicuspid aortic valves which carry a higher risk of ? than normal valves. This is not, however, the major risk among women with Turner who are pregnant.
Endocarditis
What are classic features of Edward syndrome?
Small, abnormally shaped head; low set ears; abnormal jaw; clenched fists with overlapping fingers; rocker-bottom feet.
How can serum HCG levels help in screening for Edward syndrome during pregnancy?
HCG levels are decreased in women carrying fetuses with Edward syndrome and Patau syndrome, distinguishing them from Down syndrome where HCG levels are high.
What is the trend for serum AFP levels in trisomy disorders, including Edward syndrome?
Serum AFP is decreased in all trisomy disorders, including Edward’s, Patau, and Down syndrome.
How does estradiol level change in trisomy disorders?
Decreased estradiol levels are seen in all trisomies, including Edward syndrome.
What do low levels of AFP and estradiol indicate regarding fetal health?
Low levels indicate potential abnormalities such as aneuploidy.
What are classic features of Patau syndrome?
Microphthalmia (small eyes), anophthalmia (absent eyes), cleft lip or palate, and extra digits.
What major brain abnormality is commonly associated with Patau syndrome?
Holoprosencephaly.
How prevalent is holoprosencephaly in babies with trisomy 13?
About 50% of cases of holoprosencephaly occur in babies with trisomy 13.
Are a classic feature of Edward syndrome which occurs with trisomy 18.
Overlapping fingers
Occurs in fetal alcohol syndrome.
A smooth philtrum
What gene is mutated in Duchenne muscular dystrophy?
The DMD gene, which codes for the protein dystrophin.
How is DMD inherited?
It is an X-linked disorder.
At what age do symptoms of DMD typically present?
Symptoms usually present in boys between the ages of 3 to 5 years.
What is Gower’s sign?
A classic finding where a child uses their hands to push up from a seated position due to leg weakness.
What gait characteristic is common in children with DMD?
A waddling gait, often walking on the balls of the feet or toes.
What spinal condition may develop in children with DMD?
Scoliosis due to weakening back and chest muscles.
What happens to calf muscles in DMD?
Muscle tissue is replaced with fat, leading to calf enlargement, known as “pseudohypertrophy.”
What is the role of dystrophin in muscle cells?
Dystrophin binds intracellularly to actin
Dystrophin binds actin intracellularly, and also binds to ?which are found in the cell membrane.
Alpha-dystroglycan and beta-dystroglycan
How are DMD and BMD inherited?
Both are X-linked disorders
At what age do symptoms typically present for DMD?
Symptoms usually present between ages 3 to 5 years.
At what age do symptoms typically present for BMD?
5 to 15 years.
What type of mutation is associated with DMD?
A frameshift mutation leading to an early stop codon in the dystrophin gene.
What type of mutation is associated with BMD?
A non-frameshift mutation resulting in dystrophin of abnormal molecular weight.
How is dystrophin affected in BMD patients?
In most cases (80%), dystrophin proteins are smaller than normal.
May occur in both DMD and BMD.
Elevated serum creatinine kinase
Children with muscular dystrophy are ? with 46 chromosomes.
Euploid
What is the typical age of onset for myotonic dystrophy?
Usually between 20 and 30 years of age.
What is a classic feature of myotonic dystrophy?
Myotonia, or prolonged muscle contractions, such as the inability to relax a clenched fist.
What facial changes are associated with myotonic dystrophy?
A long, narrow face with hollowed cheeks due to muscle wasting.
What other symptoms are commonly seen in myotonic dystrophy?
Muscle weakness, intellectual disability, and hypogonadism.
What gene is affected in myotonic dystrophy?
The DMPK gene on chromosome 19.
What does the DMPK gene code for?
The enzyme myotonic dystrophy protein kinase.
Random X inactivation can lead to muscle weakness in females who are carriers of the DMD gene mutation that causes Duchene muscular dystrophy. This is an X-linked disorder that predominantly affects only boys. Some women develop mild symptoms due to
“skewed lionization”
Is an inflammatory muscle disorder that affects older patients, usually women ages 40 to 50. It presents with proximal muscle weakness.
Polymyositis
What is Friedrich’s ataxia (FA)?
A genetic disorder caused by expanded trinucleotide repeat segments affecting the frataxin gene.
What chromosome is the frataxin gene located on?
Chromosome 9.
What type of genetic mutation is associated with FA?
An excessive number of repeating GAA segments in the frataxin gene.
At what age does Friedrich’s ataxia typically present?
Between ages 5 and 15.
What are common symptoms of Friedrich’s ataxia?
Loss of position and vibratory sense, ataxia, falls, neuromuscular weakness, and abnormal reflexes.
What cardiovascular condition do over 95% of FA patients develop?
Cardiac hypertrophy, which can enlarge the cardiac silhouette on chest X-ray.
What skeletal deformities are commonly associated with Friedrich’s ataxia?
Kyphoscoliosis and foot deformities, such as pes cavus (high arch of the foot).
What is a key distinguishing feature of Friedrich’s ataxia (FA) compared to Charcot-Marie-Tooth (CMT) disease?
FA is associated with cardiomyopathy, which does not occur in CMT.
Is a major feature of Huntington’s disease
Basal ganglia degeneration
What genetic mutation causes Huntington’s disease, and what are its key symptoms?
Huntington’s disease is caused by expanded CAG repeats in the gene for the huntingtin protein. Key symptoms include chorea (involuntary movements), cognitive decline, and behavioral changes such as agitation. The disorder is autosomal dominant and often exhibits anticipation, with earlier onset in successive generations
Occurs in the Fragile X syndrome
DNA methylation
Guillain-Barre syndrome, Krabbe’s disease, and Charcot-Marie-Tooth disease
Demyelination
Is seen in Alzheimer’s disease, which may also cause dementia
Amyloid deposition
What are the key features and symptoms of myotonic dystrophy (MD), and how does it differ from other muscular dystrophies?
Myotonic dystrophy (MD) is characterized by expanded trinucleotide repeats and typically presents in adulthood. Major symptoms include skeletal muscle weakness and myotonia (sustained muscle contractions). Unlike other muscular dystrophies, MD has significant non-muscular features such as cataracts, glucose intolerance, and hypogonadism, leading to infertility in men.
Cataracts in younger patients (under 60) with muscle symptoms suggest
Myotonic dystrophy.
What is Fragile X syndrome?
A genetic disorder caused by expanded CGG repeats in the FMR1 gene on the X chromosome.
What are the key developmental features of Fragile X syndrome?
Delayed development and intellectual disability.
What are the physical characteristics associated with Fragile X syndrome?
Long, narrow face; large forehead, chin, and ears.
At what age should boys with Fragile X be able to speak in one- or two-word sentences?
By two years of age.
What is a classic feature of Fragile X that appears during puberty?
Testicular enlargement, typically occurring between ages 8 to 12.
How does the expansion of CGG repeats affect the FMR1 gene?
It leads to DNA methylation, which silences gene activity.
What is DNA methylation?
An epigenetic phenomenon where methyl groups are added to DNA segments, decreasing gene transcription.
Occur in Friedrich’s Ataxia, also a trinucleotide repeat disorder.
Expanded GAA repeats
A married couple requests counseling for a family history of Fragile X syndrome. They wish to conceive their first child. The husband does not have Fragile X but has two brothers with the disorder. He also has a sister who does not have Fragile X. The wife has no family history of the disorder. Which of the following is the best estimate of the chance this couple will have a child with Fragile X syndrome?
0%
How does Fragile X syndrome affect males?
All males carrying the disease gene will be affected.
If a father has brothers with Fragile X syndrome but is not affected, what does that indicate?
He cannot be a disease gene carrier and cannot pass the disease gene to his children.
What is a key point regarding carriers of X-linked disorders?
What is a key point regarding carriers of X-linked disorders?
What genetic abnormality causes Cri-du-chat syndrome?
Deletion of the short arm of chromosome 5.
What are common developmental characteristics of children with Cri-du-chat syndrome?
Developmental delay and an unusual high-pitched cry.
Why is Cri-du-chat syndrome named as such?
“Cri-du-chat” means “call of the cat” in French, referring to the characteristic cry that sounds like a cat.
What are some facial features associated with Cri-du-chat syndrome?
A small head and widely spaced eyes (hypertelorism).
What type of congenital heart disease is commonly seen in children with Cri-du-chat syndrome?
Conditions like ventricular septal defects and patent ductus arteriosus.
What genetic abnormality causes Williams syndrome?
A partial deletion of the long arm of chromosome 7.
Describe the characteristic facial appearance of children with Williams syndrome.
They have an “elfin” appearance, including a broad forehead, wide mouth, small chin, and long/broad philtrum.
What developmental challenges do children with Williams syndrome typically face?
Impaired development and intellectual disability.
What gene is affected in Williams syndrome, and what is its function?
The gene for elastin, a connective-tissue protein found in the walls of blood vessels.
What cardiovascular condition is commonly associated with Williams syndrome?
Supravalvular aortic stenosis (narrowing of the aorta above the aortic valve).
Besides the aorta, which other vessels may develop stenosis in Williams syndrome?
The pulmonary artery, coronary arteries, and renal arteries.
What genetic abnormality is associated with Marfan syndrome?
Abnormal expression of the fibrillin gene.
What is a characteristic physical feature of patients with Marfan syndrome?
They are tall with a long wingspan.
What serious cardiovascular risk do patients with Marfan syndrome face?
Increased risk for aortic dissection.
What type of disorder is Marfan syndrome classified as?
A connective tissue disorder.
Mutations of collagen type III genes are involved in some forms of
Ehlers-Danlos syndrome
What protein is affected in Williams syndrome, and what is its function?
Elastin; it is a connective-tissue protein found in the walls of blood vessels.
What cardiovascular issue is commonly associated with Williams syndrome?
Supravalvular aortic stenosis (narrowing of the aorta above the aortic valve).
Besides aortic stenosis, what other vascular issue can occur in children with Williams syndrome?
Renal artery stenosis, which can lead to hypertension.
What is a common management issue for providers caring for children with Williams syndrome?
Blood pressure control due to hypertension from renal artery stenosis.
What calcium-related condition is commonly observed in children with Williams syndrome?
Hypercalcemia.
What are common symptoms of hypercalcemia in children with Williams syndrome?
Often asymptomatic, but can include constipation, irritability, and kidney stones
What are common symptoms of hypocalcemia?
Muscle twitching, seizures, leg spasms, paresthesias.
What is the classic clinical feature of hypocalcemia?
Tetany (intermittent muscle spasms).
What sensation is commonly experienced in hypocalcemia?
Paresthesias (a “pins and needles” sensation).
What is the most common congenital heart defect in children with Down syndrome?
Atrioventricular septal defect (AVSD), also known as atrioventricular canal defect.
What structures are involved in atrioventricular septal defects?
What structures are involved in atrioventricular septal defects?
A 1-day-old girl is evaluated in the newborn nursery. She has a short neck, protruding tongue, flat facial profile, and brachycephaly. The opening between her eyelids is slanted upward. On exam, there is a III/VI holosystolic murmur. This murmur is most likely due to an abnormality in which of the following structures?
Atrioventricular canal
