GENETICS: BOARDS AND BEYOND

Question 1

A second-semester quadruple screening test reveals decreased levels of all biomarkers, a finding most concerning for

Answer 1

Edwards syndrome (trisomy 18).

Question 2

Edwards syndrome is most often caused by ?. Less common etiologies include mosaic trisomy 18 and partial trisomy 18.

Answer 2

Maternal nondisjunction during meiosis II

Question 3

While only associated with the nondisjunction-derived variation of the disease, is the most significant risk factor for autosomal trisomies.

Answer 3

Advanced maternal age

Question 4

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

Answer 4

Decreased β-hCG, alpha-fetoprotein (AFP), estriol (uE3), and inhibin A (note: inhibin A may also be within normal limits).

Question 5

Edwards syndrome: Additional screenings for definitive diagnosis include

Answer 5

• Ultrasound imaging
• Chorionic villi sampling
• Amniocentesis
• Cell-free fetal DNA

Question 6

Edwards syndrome: Characteristic features include

Answer 6

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.

Question 7

Edward syndrome carries an extremely poor prognosis, with the median survival ranging from ?

Answer 7

3 days to 2 weeks of age

Question 8

Aplasia cutis, holoprosencephaly, microphthalmia, and polydactyly are clinical features consistent with

Answer 8

Patau syndrome (trisomy 13)

Question 9

Patau syndrome is also most commonly caused by maternal nondisjunction and is associated with advanced maternal age; however, mothers typically have

Answer 9

A quadruple screen with normal levels of all biomarkers.

Question 10

A broad chest with widely spaced nipples, cystic hygroma, low-set ears, and a weblike neck are consistent with

Answer 10

Turner syndrome (TS)

Question 11

Brushfield spots, epicanthal folds, flat facies, and a single palmar crease are consistent with

Answer 11

Down syndrome (trisomy 21)

Question 12

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

Answer 12

Elevated β-hCG and inhibin A

Decreased AFP and estriol

Question 13

A high-pitched cry, microcephaly, moon facies, and widely spaced eyes are consistent with

Answer 13

Cri-du-chat syndrome

Question 14

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.

Answer 14

Cri-du-chat syndrome

Question 15

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.

Answer 15

Edwards syndrome

Question 16

• DNA contained in nucleus of cells
• “Hereditary material”
• Passed to successive generations of cells

Answer 16

Genome

Question 17

• Portions of DNA/genome
• Code for proteins that carry out specific functions

Answer 17

Genes

Question 18

• Rod-shaped, cellular organelles
• Single, continuous DNA double helix strand
• Contains a collection of genes (DNA)

Answer 18

Chromosome

Question 19

• Chromosomes 1 through 22 plus X/Y (sex)
• Two copies each chromosome 1 through 22 (homologous)

Answer 19

46 chromosomes arranged in 23 pairs

Question 20

Diploid: two sets of chromosomes (23 pairs)

Answer 20

Somatic cells (most body cells)

Question 21

“Haploid”: one set of chromosomes

Answer 21

Gametes (reproductive cells)

Question 22

• S phase of cell cycle
  Chromosomes replicate → two sister chromatids
• M phase (mitosis): Cell divides
• Daughter cells will contain copies of chromosomes

Answer 22

Mitosis

Question 23

• “Haploid”: one set of chromosomes
• Produced by meiosis of germ line cells
• Male and female gametes merge in fertilization
• New “diploid” organism formed

Answer 23

Gametes (reproductive cells)

Question 24

• Alternative forms of gene
• Many genes have several forms
• Often represented by letter (A, a)

Answer 24

Allele

Question 25

Genes exist in multiple forms (alleles)

Answer 25

Genetic polymorphism

Question 26

Location of allele on chromosome

Answer 26

Locus (plural loci)

Question 27

DNA → gene → allele → locus → chromosome

Answer 27

Genetics

Question 28

* 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

Answer 28

Genotype

Question 29

* Physical characteristics that result from genotype * Example: AB = blue eyes; BB = green eyes

Answer 29

Phenotype

Question 30

* Common in most individuals * Example: A = wild type

Answer 30

Wild type gene/allele

Question 31

* Different from wild type * Caused by a mutation * Example: a = mutant * Individual: AA, Aa, aa

Answer 31

Mutant gene/allele

Question 32

Two identical copies of a gene (i.e. AA)

Answer 32

Homozygous

Question 33

Two different copies of a gene (i.e. Aa)

Answer 33

Heterozygous

Question 34

* DNA of sperm/eggs * Transmitted to offspring * Found in every cell in body

Answer 34

Germ line mutations

Question 35

* Acquired during lifespan of cell * Not transmitted to offspring

Answer 35

Somatic mutations

Question 36

Determines phenotype even in individuals with single copy * Often denoted with capital letters * Example: Gene has two alleles: A, a

Answer 36

Dominant gene/allele

Question 37

* Requires two copies to produce phenotype * Often denoted with lower case letters * Example: aa = a phenotype; Aa and AA = A phenotype

Answer 37

Recessive gene/allele

Question 38

* 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

Answer 38

Codominance

Question 39

* 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

Answer 39

α-1 Antitrypsin Deficiency

Question 40

* 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

Answer 40

Penetrance

Question 41

* 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

Answer 41

BRCA1 and BRCA2

Question 42

* 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)

Answer 42

Expressivity

Question 43

* 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

Answer 43

Pleiotropy

Question 44

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”

Answer 44

Two-Hit Origin of Cancer

Question 45

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

Answer 45

Two-Hit Origin of Cancer * Classic example:

Question 46

* Requires two somatic “hits” * Two mutations in same cell = rare * Often a single tumor * Occurs at a later age

Answer 46

Retinoblastoma: Sporadic form (non-familial)

Question 47

* Hereditary nonpolyposis colorectal cancer * Inherited colorectal cancer syndrome * Germline mutation in DNA mismatch repair genes * Second allele is inactivated by mutation

Answer 47

Two-Hit Origin of Cancer Other Examples: HNPCC (Lynch syndrome)

Question 48

* Germline mutation of APC gene (tumor suppressor gene) * Always (100%) progresses to colon cancer * Treatment: Colon removal (colectomy)

Answer 48

Two-Hit Origin of Cancer Other Examples: Familial Adenomatous Polyposis (FAP)

Question 49

* 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

Answer 49

Two-Hit Origin of Cancer Other Examples: Li-Fraumeni syndrome

Question 50

* Gene differences in cells of same individual * Mutations in cells → genetic changes * Individual will be a mixture of cells

Answer 50

Mosaicism

Question 51

* 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

Answer 51

Mosaicism: Germline mosaicism

Question 52

* Gene differences in tissues/organs * 45X/46XX mosaic Turner syndrome (milder form) * Rare forms of Down syndrome

Answer 52

Mosaicism: Somatic mosaicism

Question 53

* 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”)

Answer 53

McCune-Albright Syndrome

Question 54

* 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

Answer 54

McCune-Albright Syndrome

Question 55

* “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

Answer 55

McCune-Albright Syndrome

Question 56

* 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

Answer 56

Genetic Heterogeneity

Question 57

* 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

Answer 57

Allelic heterogeneity

Question 58

* Mutation in beta globin gene * Wide spectrum of disease depending on mutation * βo = no function; β1 = some function

Answer 58

Allelic heterogeneity: Beta Thalassemia

Question 59

* Mutation in CFTR gene * Over 1400 different mutations described

Answer 59

Allelic heterogeneity: Cystic Fibrosis

Question 60

* 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

Answer 60

Locus heterogeneity

Question 61

* During meiosis chromosomes exchange segments * Child inherits “patchwork” of parental chromosomes * Never exact copy of parental chromosomes

Answer 61

Genetic Recombination

Question 62

* 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

Answer 62

Independent Assortment

Question 63

* What if genes on same chromosome? * If very far apart, crossover may occur in meiosis * Result: Same combinations as separate chromosomes

Answer 63

Independent Assortment

Question 64

* If alleles close together: little crossover * Low occurrence of recombination (Fm or fM)

Answer 64

Independent Assortment

Question 65

* 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

Answer 65

Recombination Frequency

Question 66

* Done by studying families * Track frequency of genetic recombination * Use frequency to determine relative gene location

Answer 66

Genetic Mapping: linkage Mapping

Question 67

Tendency of alleles to transmit together * More linkage = less independent assortment * Close together (θ = 0) = tightly linked * Far apart (θ = 0.5) = unlinked

Answer 67

Linkage

Question 68

* Used to study genes that are very close together - Recombination very rare - Family studies impractical * Done by studying large populations

Answer 68

Linkage Disequilibrium

Question 69

* 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%

Answer 69

Linkage Equilibrium

Question 70

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

Answer 70

Linkage Equilibrium

Question 71

* Population frequencies higher/lower than expected - AB = 0.75 (higher than expected 0.45) - This haplotype (AB) is in linkage disequilibrium

Answer 71

Linkage Disequilibrium

Question 72

* 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

Answer 72

Linkage Disequilibrium: Consider new gene mutation A

Question 73

* Linkage disequilibrium affected by: - Genetic distance - Time alleles have been present in population * Different populations: different degrees of linkage disequilibrium

Answer 73

Linkage Disequilibrium

Question 74

* Diploid cells give rise to haploid cells (gametes) * Unique to “germ cells” - Spermatocytes - Oocytes * Two steps: Meiosis I and Meiosis II

Answer 74

Meiosis

Question 75

* Diploid → Haploid (“reductive division”) * Separates homologous chromosomes

Answer 75

Meiosis I

Question 76

* Chromatids separate * Four daughter cells

Answer 76

Meiosis II

Question 77

* “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

Answer 77

Oogenesis

Question 78

* Abnormal chromosome number Extra or missing chromosome * Disomy = two copies of a chromosome (normal) * Monosomy = one copy * Trisomy = three copies

Answer 78

Aneuploidy

Question 79

* Failure of chromosome pairs to separate * Most common mechanism of aneuploidy * Can occur in meiosis I or II

Answer 79

Meiotic Nondisjunction

Question 80

* Fertilization of 1n (normal) and 0n gamete * Usually not viable * Turner syndrome (45,X) Only one sex chromosome

Answer 80

Monosomy

Question 81

* 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

Answer 81

Trisomy

Question 82

* Meiosis I protracted in females * Begins prenatally, completed at ovulation years later * Advanced maternal age → ↑ risk trisomy

Answer 82

Maternal meiosis I NDJ errors are a common cause

Question 83

* Father = 21A and 21B; Mother = 21C and 21D * Trisomy 21 ACD = Meiosis I nondisjunction in mother * Trisomy 21 ACC = Meiosis II nondisjunction in mother

Answer 83

Trisomy: cause of NJD suggested by trisomy genotype

Question 84

* 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)

Answer 84

Uniparental Disomy

Question 85

* 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)

Answer 85

Uniparental Disomy

Question 86

* Fusion of long arms of two chromosomes * Occurs in acrocentric chromosomes Chromosomes with centromere near end (13, 14, 21, 22)

Answer 86

Robertsonian Translocation

Question 87

* 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)

Answer 87

Robertsonian Translocation

Question 88

* Can be done in couples with recurrent fetal losses * Used to diagnose chromosomal imbalances

Answer 88

Karyotype

Question 89

* 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

Answer 89

Hardy-Weinberg Law

Question 90

* 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?

Answer 90

Hardy-Weinberg Law: Example

Question 91

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

Answer 91

Hardy-Weinberg Law

Question 92

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

Answer 92

Hardy-Weinberg Law

Question 93

p = 0.4 q = 0.6 p2 = 0.16 2pq = 0.48 q2 = 0.36

Answer 93

Hardy-Weinberg Law

Question 94

* Large population * Completely random mating * No mutations * No migration in/out of population * No natural selection

Answer 94

Hardy-Weinberg Law

Question 95

* If assumptions met, allele frequencies do not change from one generation to the next * “Hardy-Weinberg equilibrium”

Answer 95

Hardy-Weinberg Law

Question 96

* Very useful in autosomal recessive diseases * Disease (aa) frequency often known * Example: 1/5000 individuals have disease * Carrier (Aa) frequency often unknown

Answer 96

Hardy-Weinberg Law

Question 97

* 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

Answer 97

Hardy-Weinberg Law

Question 98

* Special case: X linked disease * Two male genotypes (XdY or XY) * Three female genotypes (XX or XdXd or XdX)

Answer 98

Hardy-Weinberg Law

Question 99

* 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

Answer 99

Hardy-Weinberg Law (X-linked Disease)

Question 100

Among females * p2 = frequency healthy females (XX) * 2pq = frequency carrier females (XdX) * q2 = frequency diseased females (XdXd)

Answer 100

Hardy-Weinberg Law (X-linked Disease)

Question 101

* 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

Answer 101

Pedigree

Question 102

* Two alleles for a gene (i.e. A = normal; a = disease) * Only homozygotes (aa) have disease

Answer 102

Autosomal Recessive

Question 103

* 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)

Answer 103

Autosomal Recessive

Question 104

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

Answer 104

Autosomal Recessive

Question 105

* 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

Answer 105

Autosomal Recessive

Question 106

* Males and females affected equally * Few family members with disease * Often many generations without disease * Increased risk: Consanguinity - Parents are related - Share common ancestors

Answer 106

Autosomal Recessive

Question 107

* Cystic fibrosis * Sickle cell anemia * Hemochromatosis * Wilson’s disease * Many others

Answer 107

Autosomal Recessive

Question 108

* Two alleles for a gene (i.e. A = disease; a = no disease) * Heterozygotes(Aa) and homozygotes(AA) have disease

Answer 108

Autosomal Dominant

Question 109

* Males and females affected equally * One affected parent → 50% offspring with disease * Male-to-male transmission occurs

Answer 109

Autosomal Dominant

Question 110

* Familial hypercholesterolemia * Huntington’s disease * Marfan syndrome * Hereditary spherocytosis * Achondroplasia * Many others

Answer 110

Autosomal Dominant

Question 111

* Heterozygote phenotype different from homozygote - Heterozygotes: less severe form of disease - Homozygotes: more severe

Answer 111

Incomplete Dominance: semidominant

Question 112

* Autosomal dominant disorder of bone growth * Heterozygotes (Dd): Dwarfism * Homozygotes (DD): Fatal

Answer 112

Incomplete Dominance: semidominant Classic example: Achondroplasia

Question 113

* Heterozygotes: total cholesterol 350–550mg/dL * Homozygotes: 650–1000mg/dL

Answer 113

Incomplete Dominance Semidominant: Familial hypercholesterolemia

Question 114

* 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

Answer 114

X-linked Disorders

Question 115

* All males with disease gene have disease * Most females with disease gene are carriers

Answer 115

X-linked Recessive

Question 116

* No male-to-male transmission All fathers pass Y chromosome to sons * Sons of heterozygous mothers: 50% affected * Classic examples: Hemophilia A and B

Answer 116

X-linked Recessive

Question 117

* 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

Answer 117

X-linked Recessive

Question 118

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

Answer 118

Lyonization

Question 119

* 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”

Answer 119

Lyonization

Question 120

* 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

Answer 120

X-linked Dominant

Question 121

* Can mimic autosomal dominant pattern * Key difference: No male-to-male transmission Fathers always pass Y chromosome to sons

Answer 121

X-linked Dominant

Question 122

* 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

Answer 122

X-linked Dominant

Question 123

* Each mitochondria contains DNA (mtDNA) - Code for mitochondrial proteins * Organs most affected by gene mutations: - CNS - Skeletal muscle - Rely heavily on aerobic metabolism

Answer 123

Mitochondrial Genes

Question 124

* Multiple copies of mtDNA in each mitochondria * Multiple mitochondria in each cell * All normal or abnormal: Homoplasmy * Mixture: Heteroplasmy

Answer 124

Mitochondrial Genes: Heteroplasmy

Question 125

* Depends on amount of normal versus abnormal genes * Also number of mutant mitochondria in each cell/tissue

Answer 125

Mitochondrial Genes: Mutant gene expression highly variable

Question 126

* Mitochondrial DNA inherited from mother * Sperm mitochondria eliminated from embryos * Homoplasmic mothers → all children have mutation * Heteroplasmic mothers → variable

Answer 126

Mitochondrial Disorders

Question 127

* 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

Answer 127

Mitochondrial Myopathies

Question 128

Many traits/diseases depend on multiple genes * Height * Heart disease * Cancer * “Run in families” * Do not follow a classic Mendelian pattern

Answer 128

Polygenic Inheritance

Question 129

* Genes , lifestyle, environment → disease * Seen in many diseases * Diabetes * Coronary artery disease * Hypertension

Answer 129

Multifactorial Inheritance

Question 130

Epigenetic phenomenon * Alteration in gene expression * Different expression in maternal/paternal genes

Answer 130

Imprinting

Question 131

* Occurs during gametogenesis (before fertilization) - Genes “marked” as being paternal/maternal in origin - Often by methylation of cytosine in DNA

Answer 131

Imprinting

Question 132

* After conception, imprinting controls gene expression * “Imprinted genes”: Only one allele expressed * Non-imprinted genes: Both alleles expressed

Answer 132

Imprinting

Question 133

* 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

Answer 133

Imprinting Syndromes

Question 134

* Normally expressed on paternal chromosome 15 * NOT normally expressed on maternal copy

Answer 134

PWS genes

Question 135

* Normally expressed on maternal chromosome 15 * NOT normally expressed on paternal copy

Answer 135

UBE3A

Question 136

* Loss of function of paternal copy of PWS gene

Answer 136

Prader-Willi Syndrome

Question 137

* ~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

Answer 137

Prader-Willi Syndrome

Question 138

* 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

Answer 138

Prader-Willi Syndrom

Question 139

Abnormal maternal chromosome 15q11-q13 * Lack of expression of UBE3A

Answer 139

Angelman Syndrome

Question 140

* Majority of cases caused by deletions * Only about 3-5% from uniparental disomy - Paternal disomy much less common than maternal - Non-disjunction less common

Answer 140

Angelman Syndrome

Question 141

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.

Answer 141

Destruction of alveoli

Question 142

The classic presentation of AAT deficiency is ?. Many patients are presumed to have asthma until the diagnosis of AAT deficiency is made.

Answer 142

a non-smoker with symptoms of chronic lung disease including cough, sputum production, and wheezing

Question 143

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.

Answer 143

Codominant inheritance

Question 144

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.

Answer 144

Expressed

Question 145

What is Neurofibromatosis Type 1 (NF1)?

Answer 145

NF1 is a neurocutaneous syndrome characterized by skin, nervous system, and eye abnormalities.

Question 146

What type of inheritance pattern does NF1 follow?

Answer 146

NF1 is an autosomal dominant disorder.

Question 147

Which gene is mutated in NF1, and on which chromosome is it located?

Answer 147

NF1 gene mutations occur on chromosome 17.

Question 148

Where are freckles commonly found in individuals with NF1?

Answer 148

Freckles are often found in skin folds like the axilla, groin, or elbow.

Question 149

What are neurofibromas, and how do they appear?

Answer 149

Neurofibromas are benign tumors that develop in cutaneous nerves, appearing as soft, fleshy, pedunculated growths on the skin.

Question 150

Are neurofibromas malignant or benign?

Answer 150

Neurofibromas are benign but can be the most disfiguring aspect of NF1.

Question 151

What are neurocutaneous disorders?

Answer 151

Neurocutaneous disorders involve structures derived from the ectoderm, including the skin, nervous system, and eyes.

Question 152

NFT1 is famous for

Answer 152

Variable expressivity

Question 153

What is the inheritance pattern of NF1?

Answer 153

NF1 is an autosomal dominant disorder.

Question 154

What does 100% penetrance mean for NF1?

Answer 154

It means that all individuals with the disease gene will develop the disease.

Question 155

Can individuals with NF1 have differing clinical presentations?

Answer 155

Yes, individuals can have differing clinical presentations and severity of symptoms.

Question 156

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.

Answer 156

All carriers have evidence of disease to some degree

Question 157

What is gene imprinting?

Answer 157

Imprinting refers to alterations in gene expression among different cells in the same individual.

Question 158

Does gene imprinting occur in Neurofibromatosis Type 1 (NF1)?

Answer 158

No, imprinting does not occur in NF1.

Question 159

In which syndromes does gene imprinting occur?

Answer 159

Gene imprinting occurs in Prader-Willi and Angelman syndromes.

Question 160

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).

Answer 160

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.

Question 160

What is the significance of imprinting in Prader-Willi and Angelman syndromes?

Answer 160

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

Question 161

Refers to a mutation present in some but not all germline cells (i.e., eggs and sperm) of an affected individual.

Answer 161

Germline mosaicism

Question 162

What is germline mosaicism?

Answer 162

Germline mosaicism refers to a mutation present in some but not all germline cells (eggs and sperm) of an affected individual.

Question 163

How does germline mosaicism affect genetic testing results?

Answer 163

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.

Question 164

In the case of a parent who is a germline mosaic for an OI mutation, what might happen during genetic testing?

Answer 164

The mutation can be missed even if germline cells are tested, as it may only be present in some of the germline cells.

Question 165

Why might standard genetic testing fail to detect certain mutations in germline mosaicism?

Answer 165

Because the mutation is not present in all germline cells, leading to potential false negatives in testing.

Question 166

Locus heterogeneity refers to disorders that derive from more than one gene mutation.

Answer 166

Retinitis pigmentosa is a classic example.

Question 167

What is phenylketonuria (PKU)?

Answer 167

KU is a rare enzyme deficiency syndrome caused by a lack of activity of phenylalanine hydroxylase (PAH).

Question 168

What happens to phenylalanine in children with PKU?

Answer 168

They cannot metabolize phenylalanine into tyrosine, leading to accumulation of phenylalanine and its metabolites.

Question 169

What are some symptoms of PKU?

Answer 169

Symptoms include a musty body odor and central nervous system dysfunction.

Question 170

Why do affected children with PKU often have blond hair and pale skin?

Answer 170

This is due to the lack of tyrosine, which is used to synthesize the pigment melanin.

Question 171

How does newborn screening affect the prevalence of PKU?

Answer 171

Widespread newborn screening has made PKU rarely seen in the developed world.

Question 172

What is pleiotropy in genetics?

Answer 172

Pleiotropy refers to the production of multiple effects caused by a single mutation affecting different systems or organs.

Question 173

Why is liver dysfunction not a prominent feature of PKU despite the presence of the PAH mutation in hepatocytes?

Answer 173

While all cells carry the mutation, the liver's dysfunction is not as pronounced as the effects seen in the skin and nervous system.

Question 174

Name other single-gene disorders that demonstrate pleiotropic effects.

Answer 174

Examples include Marfan syndrome, cystic fibrosis, and osteogenesis imperfecta.

Question 175

How can liver transplantation help in treating PKU?

Answer 175

Liver transplantation can correct PKU because the donor organ can produce the PAH enzyme.

Question 176

HLA genes often display

Answer 176

Linkage disequilibrium

Question 177

Linkage disequilibrium

Answer 177

Refers to genes found together at a frequency different than expected by independent assortment.

Question 178

In the question, the frequency of DRB1*0301 is 0.2 and that of DRB1*1501 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.

Answer 178

This is evidence of linkage disequilibrium.

Question 179

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

Answer 179

Random genetic drift and non-random mating.

Question 180

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.

Answer 180

Robertsonian translocation

Question 181

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.

Answer 181

Aneuploidy with 45

Question 182

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,

Answer 182

Down syndrome will occur

Question 183

When do oocytes form and when do they enter meiosis I?

Answer 183

Oocytes form in utero and enter meiosis I during fetal development.

Question 184

What are the stages of meiosis?

Answer 184

Meiosis progresses through prophase, metaphase, anaphase, and telophase.

Question 185

At what stage do oocytes arrest until puberty?

Answer 185

Oocytes remain arrested in prophase of meiosis I until puberty.

Question 186

What stimulates oocytes to progress through meiosis during the menstrual cycle?

Answer 186

Follicle-stimulating hormone (FSH) stimulates oocytes to progress.

Question 187

How many follicles are typically activated during each ovarian cycle?

Answer 187

About 20 follicles are activated during each ovarian cycle.

Question 188

How many follicles usually mature from the activated ones?

Answer 188

Usually, only one follicle matures.

Question 189

At what stage do oocytes arrest after completing meiosis I?

Answer 189

Oocytes arrest in metaphase of meiosis II until fertilization.

Question 190

What happens to oocytes when a woman begins in vitro fertilization?

Answer 190

Her ovaries will contain many oocytes arrested in meiosis I, which will be stimulated by FSH to complete meiosis I and begin meiosis II.

Question 191

Oocytes arrest in metaphase of meiosis II at the time of ovulation, after stimulation by

Answer 191

FSH

Question 192

What causes non-disjunction of chromosome 21 during meiosis I?

Answer 192

Certain substances can cause non-disjunction, leading to oocytes with either zero or two copies of chromosome 21.

Question 193

What happens if an oocyte with non-disjunction is fertilized by a normal sperm?

Answer 193

It results in offspring with either 45 or 47 chromosomes.

Question 194

What is the outcome for zygotes with 45 chromosomes?

Answer 194

Zygotes with 45 chromosomes are not viable.

Question 195

What condition results from zygotes with 47 chromosomes?

Answer 195

Zygotes with 47 chromosomes will have Down syndrome, also known as trisomy 21.

Question 196

What does "double Y male" mean?

Answer 196

A double Y male has two Y chromosomes, resulting in a rare genetic disorder.

Question 197

What are the typical characteristics of a double Y male?

Answer 197

Affected males are often phenotypically normal, taller than average, and may have learning disabilities.

Question 198

How does a child end up with two Y chromosomes?

Answer 198

This occurs due to an error in meiosis II, specifically nondisjunction.

Question 199

What is the result of nondisjunction in meiosis II?

Answer 199

It leads to two identical copies of a parental chromosome (e.g., two Y chromosomes) being passed to the child.

Question 200

How does nondisjunction in meiosis I differ from meiosis II?

Answer 200

Nondisjunction in meiosis I results in an extra chromosome that is not identical, while in meiosis II, the extra chromosome is identical.

Question 201

When does meiosis II occur in males?

Answer 201

Meiosis II occurs during spermatogenesis as secondary spermatocytes develop into spermatids.

Question 202

What is cystic fibrosis?

Answer 202

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.

Question 203

What is the classic presentation of cystic fibrosis at birth?

Answer 203

The classic presentation is meconium ileus, where the first stool is thick and sticky, potentially obstructing the bowel.

Question 204

What symptoms can meconium ileus cause in cystic fibrosis patients?

Answer 204

Symptoms include vomiting and abdominal distention.

Question 205

How is meconium ileus treated?

Answer 205

Treatment options include enemas or surgery.

Question 206

What is the typical inheritance pattern for autosomal recessive disorders like cystic fibrosis?

Answer 206

Affected individuals usually have two parents who are carriers of the disease gene.

Question 207

What is uniparental disomy?

Answer 207

Uniparental disomy occurs when a child receives two copies of a chromosome from one parent and none from the other.

Question 208

How can uniparental disomy lead to cystic fibrosis in a child with only one carrier parent?

Answer 208

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.

Question 209

What are the two types of uniparental disomy?

Answer 209

Heterodisomy (non-identical chromosomes from one parent) and isodisomy (two identical chromosomes from one parent).

Question 210

How does isodisomy affect inheritance of autosomal recessive diseases?

Answer 210

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.

Question 211

Causes cystic fibrosis by leading to abnormal protein folding in affected cells.

Answer 211

The delta 508 CFTR mutation

Question 212

What does it mean if a brother has an autosomal recessive disease?

Answer 212

It means both parents must be carriers of the disease allele since neither parent has the disease.

Question 213

What is the chance that a healthy individual with a sibling who has an autosomal recessive disease is a carrier?

Answer 213

The chance is 2/3

Question 214

Why is the chance of being a carrier for the healthy sibling 2/3?

Answer 214

In the offspring of two carrier parents, there is a 1/4 chance of a child being homozygous for the disease (two disease alleles).

Question 215

What are the possible genotypes for a healthy individual with a sibling that has an autosomal recessive disease?

Answer 215

The healthy individual can have either two normal alleles (homozygous normal) or one normal allele and one disease allele (heterozygous carrier).

Question 216

How do the possible genotypes relate to carrier status?

Answer 216

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).

Question 217

What is the significance of understanding carrier probabilities in genetics?

Answer 217

It helps assess the risk of passing on genetic conditions in families, especially for autosomal recessive diseases.

Question 218

Can males be unaffected carriers of X-linked disorders?

Answer 218

No, males cannot be unaffected carriers; they either have the disease or do not have the disease gene.

Question 219

What is the frequency of diseased males equal to in the male population for X-linked disorders?

Answer 219

The frequency of diseased males is equal to the frequency of the disease gene in the male population.

Question 220

If 1/50,000 males have an X-linked disease, what does that tell us about the frequency of the disease gene?

Answer 220

It means 1/50,000 males have the disease gene.

Question 221

How does the frequency of the disease gene in females compare to that in males for X-linked disorders?

Answer 221

The frequency of the disease gene is the same; 1/50,000 females also carry the disease gene

Question 222

How can females be carriers for X-linked disorders?

Answer 222

Females can have one normal allele and one disease allele, making them carriers.

Question 223

According to Hardy-Weinberg principles, what does q represent?

Answer 223

q represents the frequency of the disease gene, which is 1/50,000 in this case.

Question 224

How do you calculate the rate of carrier females for an X-linked disorder?

Answer 224

The rate of carrier females is calculated using 2pq from Hardy-Weinberg Law.

Question 225

For rare diseases, what is the assumption for p?

Answer 225

For rare diseases, p is assumed to be equal to 1.

Question 226

What is the rate of carrier females for the X-linked disorder in this scenario?

Answer 226

The rate of carrier females is 2×(1/50,000)×1=1/25,000

Question 227

What is Hardy-Weinberg equilibrium?

Answer 227

It is a state in which allele frequencies in a population remain stable over generations, indicating no evolution for that gene.

Question 228

What are the Hardy-Weinberg equations used for?

Answer 228

They are used to estimate frequencies of allele combinations in a population.

Question 229

What is one of the key assumptions for Hardy-Weinberg equilibrium?

Answer 229

An absence of natural selection.

Question 230

How does the sickle cell carrier state relate to natural selection?

Answer 230

If being a carrier protects against malaria, it creates a natural selection pressure that violates Hardy-Weinberg assumptions.

Question 231

What effect would a protective carrier state have on allele frequencies?

Answer 231

It would increase the survival of carriers, leading to more carriers and fewer non-carriers over time.

Question 232

What can result from a natural selection pressure in relation to Hardy-Weinberg equilibrium?

Answer 232

It can prevent Hardy-Weinberg equilibrium from occurring by altering allele frequencies in the population.

Question 233

Name one other assumption that must be met for Hardy-Weinberg equilibrium.

Answer 233

Random mating within the population.

Question 234

What type of genetic disorder is sickle cell anemia?

Answer 234

Sickle cell anemia is an autosomal recessive disorder.

Question 235

What is the frequency of the disease given as?

Answer 235

The frequency of the disease is given as 16/100.

Question 236

In Hardy-Weinberg Law, how is the frequency of the disease represented?

Answer 236

The frequency of the disease (homozygotes for the disease gene) is represented by q(cuadrada)

Question 237

What is the frequency of the disease allele given in the scenario?

Answer 237

The frequency of the disease allele is 1/100 or 1%.

Question 238

In Hardy-Weinberg terms, what does q represent?

Answer 238

q represents the frequency of the disease allele.

Question 239

For rare diseases, what can p be approximated as?

Answer 239

1

Question 240

What is Prader-Willi syndrome (PWS)?

Answer 240

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.

Question 241

What are some classic features of PWS in childhood?

Answer 241

Insatiable appetite leading to obesity, intellectual impairment, small hands and feet, "almond-shaped" eyes, and a thin upper lip.

Question 242

What does it mean for the PWS gene to be imprinted?

Answer 242

In imprinted genes, only one allele (either maternal or paternal) is expressed. For the PWS gene, only the paternal gene is expressed.

Question 243

What percentage of PWS cases is caused by a sporadic deletion in the paternal copy of the PWS gene?

Answer 243

About 75%

Question 244

Why is the maternal copy of the PWS gene inactive in PWS?

Answer 244

Due to imprinting.

Question 245

What is uniparental disomy?

Answer 245

A child inherits two copies of a chromosome from one parent and none from the other.

Question 246

How can uniparental disomy lead to PWS?

Answer 246

If a child inherits two maternal copies of the PWS gene and no paternal copies, it results in no functional paternal PWS gene activity.

Question 247

What percentage of PWS cases is caused by uniparental disomy?

Answer 247

About 25%

Question 248

How does uniparental disomy occur during gamete formation?

Answer 248

A gamete forms with two chromosomes instead of one and fuses with a gamete having zero copies of that chromosome.

Question 249

What is methylation in the context of genetics?

Answer 249

Tthe addition of a methyl group to DNA bases, such as cytosine, marking genes as being of maternal or paternal origin.

Question 250

What does the absence of paternal PWS gene activity indicate in an individual with PWS?

Answer 250

It indicates that either the paternal gene has been deleted or that both copies inherited are from the mother (as seen in uniparental disomy).

Question 251

Can methylation alone explain the lack of paternal PWS gene activity in affected individuals?

Answer 251

No, while methylation explains the imprinting mechanism, it does not fully account for the absence of paternal gene activity in PWS

Question 252

What role does genetic imprinting play in conditions like PWS?

Answer 252

Genetic imprinting leads to the expression of only one allele, which can result in disorders when the active allele is lost or inactive.

Question 253

What is Angelman syndrome?

Answer 253

A genetic disorder primarily affecting the nervous system, characterized by developmental delay, seizures, microcephaly, frequent smiling, and hand flapping.

Question 254

What are some key features of Angelman syndrome?

Answer 254

Developmental delay, seizures, small head (microcephaly), frequent smiling, and hand flapping.

Question 255

What type of genetic mechanism is involved in Angelman syndrome?

Answer 255

Involves imprinted genes, where only one allele is expressed.

Question 256

Which gene is primarily associated with Angelman syndrome?

Answer 256

The UBE3A gene.

Question 257

Why is Angelman syndrome considered an imprinting disorder?

Answer 257

Because the disorder arises from the loss of function of the expressed allele, while the non-expressed allele remains inactive

Question 258

What should prompt consideration of Angelman syndrome in a young child?

Answer 258

Poor development and frequent smiling.

Question 259

What is MELAS?

Answer 259

MELAS is a mitochondrial myopathy characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Question 260

What are common neurologic features of mitochondrial disorders like MELAS?

Answer 260

Weakness and lactic acidosis.

Question 261

What is the hallmark symptom of MELAS?

Answer 261

Stroke-like episodes that can lead to hemiparesis and hemianopia (loss of half of the visual field).

Question 262

What other features may occur in MELAS?

Answer 262

Hearing loss and seizures.

Question 263

What causes MELAS?

Answer 263

Mutations affecting mitochondrial DNA.

Question 264

What is heteroplasmy?

Answer 264

The presence of more than one genome within a cell, which can lead to variable signs and symptoms in mitochondrial disorders.

Question 265

How does heteroplasmy affect symptoms in MELAS?

Answer 265

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.

Question 266

Why should mitochondrial disorders be considered when lactic acidosis occurs with neurologic symptoms?

Answer 266

These features are common indicators of mitochondrial dysfunction, including disorders like MELAS.

Question 267

Name a type of cancer associated with tumor suppressor gene mutations.

Answer 267

Retinoblastoma Hereditary nonpolyposis colorectal cancer (HNPCC)

Question 268

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.

Answer 268

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.

Question 269

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.

Answer 269

This boy has multiple family members (aunt, uncle, sister) with disease making an isolated germline mutation very unlikely.

Question 270

What is Duchenne muscular dystrophy (DMD)?

Answer 270

An X-linked recessive disorder that primarily affects males, causing progressive muscle weakness.

Question 271

How is DMD inherited?

Answer 271

It is inherited in an X-linked recessive manner, predominantly affecting males.

Question 272

Why do most mothers of boys with DMD not exhibit symptoms of the disease?

Answer 272

Most mothers are carriers with one normal X chromosome that prevents the development of the disease.

Question 273

What percentage of female carriers of DMD may develop symptoms?

Answer 273

About 8% of female carriers may develop symptoms of muscle weakness.

Question 274

What is skewed lyonization?

Answer 274

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.

Question 275

How do symptoms in female carriers of DMD compare to affected males?

Answer 275

Female carriers typically exhibit milder muscular features than affected males.

Question 276

What is aneuploidy?

Answer 276

A condition characterized by an abnormal number of chromosomes.

Question 277

Meiotic nondisjunction leads to

Answer 277

Aneuploidy

Question 278

X-linked dominant inheritance leads to X-linked disorders where

Answer 278

Both males and females are affected.

Question 279

Is a classic example of a X-linked dominant disorder.

Answer 279

Fragile X syndrome

Question 280

What is hereditary spherocytosis?

Answer 280

An autosomal dominant disorder characterized by the presence of spherically shaped red blood cells.

Question 281

How is hereditary spherocytosis inherited?

Answer 281

It is inherited in an autosomal dominant manner.

Question 282

What does the pedigree of a family with hereditary spherocytosis typically show?

Answer 282

Multiple family members with the disease in each generation.

Question 283

What is incomplete penetrance?

Answer 283

A condition where not all individuals with the disease gene exhibit symptoms of the disease.

Question 284

What does penetrance refer to?

Answer 284

The proportion of individuals with a particular genotype who show evidence of the associated phenotype.

Question 285

Why might a woman with hereditary spherocytosis not show evidence of the disease?

Answer 285

This is consistent with incomplete penetrance, where she carries the gene but does not express the disease.

Question 286

Is hereditary spherocytosis known to exhibit incomplete penetrance?

Answer 286

Yes, it is a well-described disorder with incomplete penetrance.

Question 287

What is somatic mosaicism?

Answer 287

The presence of two or more populations of somatic cells with different genotypes within an individual.

Question 288

How does somatic mosaicism affect an individual's health?

Answer 288

It can lead to variable expression of genetic traits or diseases, but it does not necessarily explain the absence of symptoms in affected individuals.

Question 289

What is familial hypercholesterolemia (FH)?

Answer 289

An autosomal dominant genetic disorder characterized by high levels of LDL cholesterol in the blood.

Question 290

What causes FH in its most common form?

Answer 290

A gene mutation that leads to underproduction of LDL receptors, preventing LDL clearance from plasma.

Question 291

What are the serum LDL cholesterol levels in homozygotes with FH?

Answer 291

LDL levels may be as high as 1000 mg/dL (normal is <200 mg/dL).

Question 292

What is the typical outcome for untreated homozygotes with FH?

Answer 292

They often die before age twenty due to coronary or vascular disease.

Question 293

How does the severity of FH differ between homozygotes and heterozygotes?

Answer 293

Homozygotes have more severe disease, while heterozygotes experience milder symptoms.

Question 294

What phenomenon describes the differing severity of disease in homozygotes vs. heterozygotes?

Answer 294

Incomplete dominance (or semidominance)

Question 295

What are two classic disorders that exhibit incomplete dominance?

Answer 295

Familial hypercholesterolemia (FH) and achondroplasia.

Question 296

What are two classic disorders that exhibit incomplete dominance?

Answer 296

Familial hypercholesterolemia (FH) and achondroplasia.

Question 297

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?

Answer 297

25%

Question 298

What is the increased risk of developing Acute lymphoblastic leukemia (ALL) in children with Down syndrome?

Answer 298

Ten to twenty times higher than in children without Down syndrome.

Question 299

What are common nonspecific clinical features at the presentation of ALL?

Answer 299

Fatigue, malaise, or fever.

Question 300

What physical examination findings are often present in children with ALL?

Answer 300

Hepatosplenomegaly.

Question 301

How does infiltration of the bone marrow by malignant cells affect blood counts in ALL?

Answer 301

It can lead to anemia and thrombocytopenia.

Question 302

What complication can low platelet counts cause in children with leukemia?

Answer 302

Increased predisposition to bruising.

Question 303

What is the condition of the bone marrow in acute lymphoblastic leukemia (ALL)?

Answer 303

Hypercellular and filled with lymphoblasts.

Question 304

Besides ALL, what other type of leukemia are children with Down syndrome at increased risk for?

Answer 304

Acute myeloid leukemia (AML). (M7)

Question 305

What is the confirmatory test of choice for Down syndrome in the first trimester?

Answer 305

Chorionic villus sampling (CVS).

Question 306

How is chorionic villus sampling (CVS) performed?

Answer 306

A sample of the placenta is obtained either through the cervix or abdominal wall.

Question 307

What do the placental chorionic villi derive from?

Answer 307

Fetal trophoblast tissue

Question 308

What is the diagnostic procedure used in the second trimester for Down syndrome?

Answer 308

Amniocentesis.

Question 309

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.

Answer 309

Fetal ultrasound cannot make a definitive diagnosis of Down syndrome.

Question 310

Serum pregnancy-associated plasma protein-A, total human chorionic gonadotropin, and alpha-fetoprotein are screening tests for Down syndrome similar to fetal ultrasound.

Answer 310

. They do not provide genetic material from the fetus, and are not used to definitively diagnose Down syndrome.

Question 311

What are some physical features of Down syndrome?

Answer 311

Flat nasal bridge, low set ears, and Brushfield spots on the irises.

Question 312

What are the most likely causes of bowel obstruction in a newborn with Down syndrome?

Answer 312

Duodenal atresia or stenosis.

Question 313

What percentage of newborns with Down syndrome have congenital anomalies of the GI tract?

Answer 313

About 5%.

Question 314

What are the most common congenital GI anomalies in newborns with Down syndrome?

Answer 314

Duodenal atresia and stenosis

Question 315

How can vomiting be classified?

Answer 315

Bilious and non-bilious.

Question 316

What characterizes bilious vomiting?

Answer 316

It is green and indicates a lack of bile flow due to intestinal obstruction.

Question 317

Where does bile enter the gastrointestinal tract?

Answer 317

At the ampulla of Vater in the duodenum.

Question 318

At what age does pyloric stenosis typically present in infants?

Answer 318

About 3 to 6 weeks old

Question 319

What are the classic symptoms of pyloric stenosis?

Answer 319

Projectile, non-bilious vomiting after feeding.

Question 320

What is malrotation with volvulus?

Answer 320

A congenital anomaly that causes intestinal obstruction and bilious vomiting due to abnormal positioning of the cecum and twisting of the intestines.

Question 321

Where is the cecum positioned in malrotation?

Answer 321

In the right mid to upper quadrant instead of the right lower quadrant.

Question 322

What complication can occur due to malrotation?

Answer 322

Volvulus, which is a twisting of the intestines around the mesentery leading to obstruction.

Question 323

What type of vomiting is associated with malrotation with volvulus?

Answer 323

Bilious vomiting.

Question 324

Which gastrointestinal congenital malformation is more common in Down syndrome?

Answer 324

Duodenal atresia.

Question 325

How does the presentation of duodenal atresia differ from pyloric stenosis?

Answer 325

Duodenal atresia typically presents with bilious vomiting, while pyloric stenosis presents with non-bilious vomiting.

Question 326

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.

Answer 326

Intussusception

Question 327

What are some physical features of Down syndrome?

Answer 327

Short neck, protruding tongue, flat facial profile, brachycephaly, and upslanting palpebral fissures.

Question 328

What percentage of children with Down syndrome have congenital heart disease?

Answer 328

Approximately 50%.

Question 329

What is the most common type of congenital heart defect in children with Down syndrome?

Answer 329

Atrioventricular septal defect (AV septal defect).

Question 330

What structures are involved in an atrioventricular septal defect?

Answer 330

The atrial septum, ventricular septum, and the AV valves (tricuspid and mitral valves)

Question 331

From which embryological structures do the defects in AV septal defects arise?

Answer 331

Endocardial cushions.

Question 332

What are the alternative names for an atrioventricular septal defect?

Answer 332

AV canal defect, AV septal defect, and endocardial cushion defect.

Question 333

What additional abnormalities might be present in a child with Down syndrome and an AV canal defect?

Answer 333

Atrial septal defect, ventricular septal defect, abnormal mitral valve, or abnormal tricuspid valve.

Question 334

What is a complete AV septal defect?

Answer 334

lesion involving abnormalities in the atrial septum, ventricular septum, and both AV valves.

Question 335

What type of murmur is associated with ventricular septal defect or mitral regurgitation?

Answer 335

Holosystolic murmur.

Question 336

What is the test of choice to define the anatomy of congenital heart defects in Down syndrome?

Answer 336

Echocardiography.

Question 337

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.

Answer 337

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.

Question 338

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.

Answer 338

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.

Question 339

What is Klinefelter syndrome?

Answer 339

A genetic condition in males caused by an extra X chromosome (47, XXY). - Tall stature and long limbs. - Learning disabilities and a quiet personality.

Question 340

What cognitive effects are often seen in individuals with Klinefelter syndrome?

Answer 340

Learning disabilities and a quiet personality.

Question 341

What is the state of the testes in men with Klinefelter syndrome?

Answer 341

Testes are typically small and firm.

Question 342

What hormonal imbalance occurs in Klinefelter syndrome?

Answer 342

Underproduction of testosterone leads to increased estrogen effects.

Question 343

What common breast condition can occur in males with Klinefelter syndrome?

Answer 343

Gynecomastia.

Question 344

What is a rare cancer that has an increased risk in men with Klinefelter syndrome?

Answer 344

Male breast cancer.

Question 345

Are associated with Turner syndrome which occurs in girls missing an X chromosome (45, XO).

Answer 345

Aortic coarctation, diabetes II, hypothyroidism, and osteoporosis

Question 346

In Klinefelter syndrome, the underproduction of testosterone allows estrogen effects to

Answer 346

Increase

Question 347

Hypogonadism in Klinefelter syndromes leads to decreased production of testosterone and inhibin B from the testes. The pituitary gland responds with increased release of

Answer 347

LH and FSH

Question 348

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.

Answer 348

Oocyte donation with in-vitro fertilization

Question 349

What is the standard diagnostic test for Turner syndrome?

Answer 349

Karyotype analysis to establish the presence of 45,XO cells

Question 350

How is the karyotype analysis for Turner syndrome typically performed?

Answer 350

Using lymphocytes obtained from a blood sample.

Question 351

Why is a minimum of 30 cells analyzed in karyotype studies for Turner syndrome?

Answer 351

To detect mosaicism, where some cells may be normal and others may be 45,XO.

Question 352

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.

Answer 352

This test is inaccurate and no longer used.

Question 353

What prenatal finding is commonly associated with Turner syndrome (TS)?

Answer 353

Cystic hygroma, a fluid-filled sac caused by lymphatic obstruction.

Question 354

Where is cystic hygroma typically found in cases of Turner syndrome?

Answer 354

At the base of the head attached to the neck.

Question 355

What is a common renal anomaly associated with Turner syndrome?

Answer 355

Horseshoe kidney, formed by the fusion of the right and left kidneys.

Question 356

What percentage of Turner syndrome cases report renal anomalies, including horseshoe kidney?

Answer 356

Up to 70%.

Question 357

Besides renal anomalies, what other cardiovascular anomalies are associated with Turner syndrome?

Answer 357

Bicuspid aortic valve and coarctation of the aorta.

Question 358

When is recombinant human growth hormone therapy recommended for girls with Turner syndrome?

Answer 358

When their height falls below the 5th percentile for their age group.

Question 359

At what age is growth hormone therapy typically initiated in girls with Turner syndrome?

Answer 359

Between two and five years of age.

Question 360

Are girls with Turner syndrome growth hormone deficient?

Answer 360

No, they are not growth hormone deficient.

Question 361

Is used to induce puberty in girls with Turner syndrome. Therapy with progestins can be added to limit breakthrough uterine bleeding.

Answer 361

Estradiol

Question 362

What is a significant risk for pregnant women with Turner syndrome?

Answer 362

Increased risk for aortic dissection.

Question 363

What cardiac conditions are commonly associated with Turner syndrome that elevate the risk of aortic dissection?

Answer 363

Bicuspid aortic valves and aortic coarctation.

Question 364

How does pregnancy itself affect the risk of aortic dissection?

Answer 364

Pregnancy is associated with a slightly increased risk of aortic dissection, even in women without Turner syndrome.

Question 365

What do some society guidelines recommend regarding pregnancy in women with Turner syndrome?

Answer 365

They may consider Turner syndrome a contraindication to pregnancy due to the elevated risk of aortic dissection.

Question 366

What is a recommended monitoring strategy for women with Turner syndrome during pregnancy?

Answer 366

Serial imaging of the aorta, with surgery if aortic enlargement occurs.

Question 367

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.

Answer 367

Endocarditis

Question 368

What are classic features of Edward syndrome?

Answer 368

Small, abnormally shaped head; low set ears; abnormal jaw; clenched fists with overlapping fingers; rocker-bottom feet.

Question 369

How can serum HCG levels help in screening for Edward syndrome during pregnancy?

Answer 369

HCG levels are decreased in women carrying fetuses with Edward syndrome and Patau syndrome, distinguishing them from Down syndrome where HCG levels are high.

Question 370

What is the trend for serum AFP levels in trisomy disorders, including Edward syndrome?

Answer 370

Serum AFP is decreased in all trisomy disorders, including Edward's, Patau, and Down syndrome.

Question 371

How does estradiol level change in trisomy disorders?

Answer 371

Decreased estradiol levels are seen in all trisomies, including Edward syndrome.

Question 372

What do low levels of AFP and estradiol indicate regarding fetal health?

Answer 372

Low levels indicate potential abnormalities such as aneuploidy.

Question 373

What are classic features of Patau syndrome?

Answer 373

Microphthalmia (small eyes), anophthalmia (absent eyes), cleft lip or palate, and extra digits.

Question 374

What major brain abnormality is commonly associated with Patau syndrome?

Answer 374

Holoprosencephaly.

Question 375

How prevalent is holoprosencephaly in babies with trisomy 13?

Answer 375

About 50% of cases of holoprosencephaly occur in babies with trisomy 13.

Question 376

Are a classic feature of Edward syndrome which occurs with trisomy 18.

Answer 376

Overlapping fingers

Question 377

Occurs in fetal alcohol syndrome.

Answer 377

A smooth philtrum

Question 378

What gene is mutated in Duchenne muscular dystrophy?

Answer 378

The DMD gene, which codes for the protein dystrophin.

Question 379

How is DMD inherited?

Answer 379

It is an X-linked disorder.

Question 380

At what age do symptoms of DMD typically present?

Answer 380

Symptoms usually present in boys between the ages of 3 to 5 years.

Question 381

What is Gower’s sign?

Answer 381

A classic finding where a child uses their hands to push up from a seated position due to leg weakness.

Question 382

What gait characteristic is common in children with DMD?

Answer 382

A waddling gait, often walking on the balls of the feet or toes.

Question 383

What spinal condition may develop in children with DMD?

Answer 383

Scoliosis due to weakening back and chest muscles.

Question 384

What happens to calf muscles in DMD?

Answer 384

Muscle tissue is replaced with fat, leading to calf enlargement, known as "pseudohypertrophy."

Question 385

What is the role of dystrophin in muscle cells?

Answer 385

Dystrophin binds intracellularly to actin

Question 386

Dystrophin binds actin intracellularly, and also binds to ?which are found in the cell membrane.

Answer 386

Alpha-dystroglycan and beta-dystroglycan

Question 387

How are DMD and BMD inherited?

Answer 387

Both are X-linked disorders

Question 388

At what age do symptoms typically present for DMD?

Answer 388

Symptoms usually present between ages 3 to 5 years.

Question 389

At what age do symptoms typically present for BMD?

Answer 389

5 to 15 years.

Question 390

What type of mutation is associated with DMD?

Answer 390

A frameshift mutation leading to an early stop codon in the dystrophin gene.

Question 391

What type of mutation is associated with BMD?

Answer 391

A non-frameshift mutation resulting in dystrophin of abnormal molecular weight.

Question 392

How is dystrophin affected in BMD patients?

Answer 392

In most cases (80%), dystrophin proteins are smaller than normal.

Question 393

May occur in both DMD and BMD.

Answer 393

Elevated serum creatinine kinase

Question 394

Children with muscular dystrophy are ? with 46 chromosomes.

Answer 394

Euploid

Question 395

What is the typical age of onset for myotonic dystrophy?

Answer 395

Usually between 20 and 30 years of age.

Question 396

What is a classic feature of myotonic dystrophy?

Answer 396

Myotonia, or prolonged muscle contractions, such as the inability to relax a clenched fist.

Question 397

What facial changes are associated with myotonic dystrophy?

Answer 397

A long, narrow face with hollowed cheeks due to muscle wasting.

Question 398

What other symptoms are commonly seen in myotonic dystrophy?

Answer 398

Muscle weakness, intellectual disability, and hypogonadism.

Question 399

What gene is affected in myotonic dystrophy?

Answer 399

The DMPK gene on chromosome 19.

Question 400

What does the DMPK gene code for?

Answer 400

The enzyme myotonic dystrophy protein kinase.

Question 401

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

Answer 401

“skewed lionization”

Question 402

Is an inflammatory muscle disorder that affects older patients, usually women ages 40 to 50. It presents with proximal muscle weakness.

Answer 402

Polymyositis

Question 403

What is Friedrich’s ataxia (FA)?

Answer 403

A genetic disorder caused by expanded trinucleotide repeat segments affecting the frataxin gene.

Question 404

What chromosome is the frataxin gene located on?

Answer 404

Chromosome 9.

Question 405

What type of genetic mutation is associated with FA?

Answer 405

An excessive number of repeating GAA segments in the frataxin gene.

Question 406

At what age does Friedrich’s ataxia typically present?

Answer 406

Between ages 5 and 15.

Question 407

What are common symptoms of Friedrich’s ataxia?

Answer 407

Loss of position and vibratory sense, ataxia, falls, neuromuscular weakness, and abnormal reflexes.

Question 408

What cardiovascular condition do over 95% of FA patients develop?

Answer 408

Cardiac hypertrophy, which can enlarge the cardiac silhouette on chest X-ray.

Question 409

What skeletal deformities are commonly associated with Friedrich’s ataxia?

Answer 409

Kyphoscoliosis and foot deformities, such as pes cavus (high arch of the foot).

Question 410

What is a key distinguishing feature of Friedrich’s ataxia (FA) compared to Charcot-Marie-Tooth (CMT) disease?

Answer 410

FA is associated with cardiomyopathy, which does not occur in CMT.

Question 411

Is a major feature of Huntington’s disease

Answer 411

Basal ganglia degeneration

Question 412

What genetic mutation causes Huntington’s disease, and what are its key symptoms?

Answer 412

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

Question 413

Occurs in the Fragile X syndrome

Answer 413

DNA methylation

Question 414

Guillain-Barre syndrome, Krabbe’s disease, and Charcot-Marie-Tooth disease

Answer 414

Demyelination

Question 415

Is seen in Alzheimer’s disease, which may also cause dementia

Answer 415

Amyloid deposition

Question 416

What are the key features and symptoms of myotonic dystrophy (MD), and how does it differ from other muscular dystrophies?

Answer 416

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.

Question 417

Cataracts in younger patients (under 60) with muscle symptoms suggest

Answer 417

Myotonic dystrophy.

Question 418

What is Fragile X syndrome?

Answer 418

A genetic disorder caused by expanded CGG repeats in the FMR1 gene on the X chromosome.

Question 419

What are the key developmental features of Fragile X syndrome?

Answer 419

Delayed development and intellectual disability.

Question 420

What are the physical characteristics associated with Fragile X syndrome?

Answer 420

Long, narrow face; large forehead, chin, and ears.

Question 421

At what age should boys with Fragile X be able to speak in one- or two-word sentences?

Answer 421

By two years of age.

Question 422

What is a classic feature of Fragile X that appears during puberty?

Answer 422

Testicular enlargement, typically occurring between ages 8 to 12.

Question 423

How does the expansion of CGG repeats affect the FMR1 gene?

Answer 423

It leads to DNA methylation, which silences gene activity.

Question 424

What is DNA methylation?

Answer 424

An epigenetic phenomenon where methyl groups are added to DNA segments, decreasing gene transcription.

Question 425

Occur in Friedrich’s Ataxia, also a trinucleotide repeat disorder.

Answer 425

Expanded GAA repeats

Question 426

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?

Answer 426

0%

Question 427

How does Fragile X syndrome affect males?

Answer 427

All males carrying the disease gene will be affected.

Question 428

If a father has brothers with Fragile X syndrome but is not affected, what does that indicate?

Answer 428

He cannot be a disease gene carrier and cannot pass the disease gene to his children.

Question 429

What is a key point regarding carriers of X-linked disorders?

Answer 429

What is a key point regarding carriers of X-linked disorders?

Question 430

What genetic abnormality causes Cri-du-chat syndrome?

Answer 430

Deletion of the short arm of chromosome 5.

Question 431

What are common developmental characteristics of children with Cri-du-chat syndrome?

Answer 431

Developmental delay and an unusual high-pitched cry.

Question 432

Why is Cri-du-chat syndrome named as such?

Answer 432

"Cri-du-chat" means "call of the cat" in French, referring to the characteristic cry that sounds like a cat.

Question 433

What are some facial features associated with Cri-du-chat syndrome?

Answer 433

A small head and widely spaced eyes (hypertelorism).

Question 434

What type of congenital heart disease is commonly seen in children with Cri-du-chat syndrome?

Answer 434

Conditions like ventricular septal defects and patent ductus arteriosus.

Question 435

What genetic abnormality causes Williams syndrome?

Answer 435

A partial deletion of the long arm of chromosome 7.

Question 436

Describe the characteristic facial appearance of children with Williams syndrome.

Answer 436

They have an "elfin" appearance, including a broad forehead, wide mouth, small chin, and long/broad philtrum.

Question 437

What developmental challenges do children with Williams syndrome typically face?

Answer 437

Impaired development and intellectual disability.

Question 438

What gene is affected in Williams syndrome, and what is its function?

Answer 438

The gene for elastin, a connective-tissue protein found in the walls of blood vessels.

Question 439

What cardiovascular condition is commonly associated with Williams syndrome?

Answer 439

Supravalvular aortic stenosis (narrowing of the aorta above the aortic valve).

Question 440

Besides the aorta, which other vessels may develop stenosis in Williams syndrome?

Answer 440

The pulmonary artery, coronary arteries, and renal arteries.

Question 441

What genetic abnormality is associated with Marfan syndrome?

Answer 441

Abnormal expression of the fibrillin gene.

Question 442

What is a characteristic physical feature of patients with Marfan syndrome?

Answer 442

They are tall with a long wingspan.

Question 443

What serious cardiovascular risk do patients with Marfan syndrome face?

Answer 443

Increased risk for aortic dissection.

Question 444

What type of disorder is Marfan syndrome classified as?

Answer 444

A connective tissue disorder.

Question 445

Mutations of collagen type III genes are involved in some forms of

Answer 445

Ehlers-Danlos syndrome

Question 446

What protein is affected in Williams syndrome, and what is its function?

Answer 446

Elastin; it is a connective-tissue protein found in the walls of blood vessels.

Question 447

What cardiovascular issue is commonly associated with Williams syndrome?

Answer 447

Supravalvular aortic stenosis (narrowing of the aorta above the aortic valve).

Question 448

Besides aortic stenosis, what other vascular issue can occur in children with Williams syndrome?

Answer 448

Renal artery stenosis, which can lead to hypertension.

Question 449

What is a common management issue for providers caring for children with Williams syndrome?

Answer 449

Blood pressure control due to hypertension from renal artery stenosis.

Question 450

What calcium-related condition is commonly observed in children with Williams syndrome?

Answer 450

Hypercalcemia.

Question 451

What are common symptoms of hypercalcemia in children with Williams syndrome?

Answer 451

Often asymptomatic, but can include constipation, irritability, and kidney stones

Question 452

What are common symptoms of hypocalcemia?

Answer 452

Muscle twitching, seizures, leg spasms, paresthesias.

Question 453

What is the classic clinical feature of hypocalcemia?

Answer 453

Tetany (intermittent muscle spasms).

Question 454

What sensation is commonly experienced in hypocalcemia?

Answer 454

Paresthesias (a “pins and needles” sensation).

Question 455

What is the most common congenital heart defect in children with Down syndrome?

Answer 455

Atrioventricular septal defect (AVSD), also known as atrioventricular canal defect.

Question 456

What structures are involved in atrioventricular septal defects?

Answer 456

What structures are involved in atrioventricular septal defects?

Question 457

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?

Answer 457

Atrioventricular canal