Genetic Disorders

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Genetic Disorders — Key Facts for FMGE Core concept: Single-gene disorders follow Mendelian inheritance patterns; chromosomal disorders cause developmental abnormalities High-yield point: Know how to recognize and differentiate common inheritance patterns (autosomal dominant, recessive, X-linked) ⚡ Exam tip: Remember that autosomal dominant conditions often show variable expressivity and incomplete penetrance

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Genetic Disorders — FMGE Study Guide

Chromosomal Abnormalities

Numerical Abnormalities (Aneuploidy)

Euploidy: Exact multiple of haploid set (46 chromosomes) Aneuploidy: Abnormal chromosome number

Trisomy (one extra chromosome):

• Trisomy 21 (Down syndrome): Most common, features include flat facies, epicanthal folds, Brushfield spots, single palmar crease, sandal gap, intellectual disability. Associated with early-onset Alzheimer’s, ALL, hypothyroidism. Advanced maternal age is risk factor.
• Trisomy 18 (Edwards syndrome): Rocker bottom feet, clenched fists with overlapping fingers, micrognathia, severe intellectual disability, congenital heart defects. Most die before 1 year.
• Trisomy 13 (Patau syndrome): Holoprosencephaly, cleft lip/palate, polydactyly, cyclopia. Most die within first year.

Monosomy (one missing chromosome):

• Turner syndrome (45,XO): Short stature, webbed neck, shield chest, primary amenorrhea, coarctation of aorta. No intellectual disability typically.

Sex chromosome abnormalities:

• Klinefelter syndrome (47,XXY): Tall, eunuchoid, gynecomastia, small firm testes, azoospermia, mild intellectual disability. Most common male hypogonadism.
• Triple X syndrome (47,XXX): Phenotypically normal females, may have mild learning disabilities
• XYY syndrome (47,XYY): Tall males, normal phenotype (controversial “criminal” association disproven)

Structural Abnormalities

• Translocation: Exchange of genetic material between chromosomes
  • Robertsonian translocation: Between acrocentric chromosomes (13, 14, 15, 21, 22) - common cause of familial Down syndrome
• Deletion: Loss of chromosomal segment
  • Cri du chat syndrome: 5p deletion (microcephaly, cat-like cry)
  • DiGeorge syndrome: 22q11 deletion (cardiac defects, thymic aplasia, hypocalcemia)
• Duplication: Extra copy of chromosomal segment
• Inversion: Segment reversed within chromosome
• Ring chromosome: Deletion of both ends with fusion
• Isochromosome: One arm duplicated, one missing

Single Gene Disorders

Autosomal Dominant

• Condition manifests when only ONE copy of mutant gene is present
• Examples:
  • Huntington disease ( CAG repeats in huntingtin gene, anticipation)
  • Marfan syndrome (FBN1 gene, connective tissue disorder)
  • Familial hypercholesterolemia (LDL receptor mutation)
  • Neurofibromatosis type 1 (NF1 gene, café-au-lait spots, neurofibromas)
  • Polyposis coli (APC gene, colon polyps → cancer)
  • Acute intermittent porphyria
  • Osteogenesis imperfecta (COL1A1 gene)
• Features: Affects both sexes, affected child has at least one affected parent, vertical transmission
• Important concept: Variable expressivity (different severity) and incomplete penetrance (some gene carriers are asymptomatic)

Autosomal Recessive

• Condition manifests only when TWO copies of mutant gene present
• Examples:
  • Cystic fibrosis (CFTR mutation - most common lethal genetic disease in Caucasians)
  • Phenylketonuria (PKU) - phenylalanine hydroxylase deficiency
  • Galactosemia
  • Glycogen storage diseases (von Gierke, Pompe)
  • Sickle cell anemia
  • Friedreich ataxia
  • Wilson disease (ATP7B gene - copper accumulation)
  • Hemochromatosis
• Features: Both parents are carriers (heterozygous), 25% risk for each pregnancy, both sexes equally affected
• Consanguinity: Higher risk in children of related parents (increased chance of inheriting same recessive allele)

X-linked Recessive

• Gene located on X chromosome
• Examples:
  • Hemophilia A and B (Factor VIII and IX deficiency)
  • Duchenne/Becker muscular dystrophy (dystrophin gene)
  • Red-green color blindness
  • G6PD deficiency
  • Lesch-Nyhan syndrome (HGPRT deficiency)
  • Ornithine transcarbamylase deficiency
• Features: Primarily affects males, carrier females may show mild symptoms, no male-to-male transmission, affected male mother is carrier
• Key: Affected males → all daughters carriers (no affected sons since father gives Y to sons)

X-linked Dominant

• Examples:
  • Vitamin D-resistant rickets (hypophosphatemia)
  • Rett syndrome (mostly affects females)
• Features: Both males and females affected, but often more severe in males

Mitochondrial Inheritance

• Inherited exclusively from mother (mitochondria come from egg)
• Examples:
  • Leber hereditary optic neuropathy (LHON) - maternal transmission
  • MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)
  • MERFF (myoclonic epilepsy with ragged red fibers)
• Features: All children of affected mother affected, no transmission from father

Multifactorial Inheritance

• Combination of multiple genes + environmental factors
• Examples:
  • Cleft lip/palate
  • Neural tube defects (spina bifida, anencephaly)
  • Congenital heart defects
  • Diabetes mellitus type 1
  • Schizophrenia, bipolar disorder
  • Essential hypertension
  • Rheumatoid arthritis
• Recurrence risk: Higher with more affected family members, more severe expression

Important Genetic Concepts

Anticipation

• Disease severity increases and age of onset decreases in successive generations
• CAG trinucleotide repeat disorders: Huntington disease, myotonic dystrophy, Friedreich ataxia
• CGG repeat: Fragile X syndrome

Imprinting

• Genes expressed differently depending on whether inherited from mother or father
• Examples:
  • Prader-Willi syndrome: Paternal deletion (15q11-13) → hypotonia, obesity, intellectual disability
  • Angelman syndrome: Maternal deletion/silencing of same region → ataxia, seizures, happy demeanor
  • Beckwith-Wiedemann syndrome: IGF2 imprinting (paternal duplication)

Uniparental Disomy

• Both chromosomes of a pair inherited from one parent (loss of other parent’s chromosome + duplication)
• Can cause disease if child inherits two copies of mutated gene (CFTR)

Teratogenicity

Known Teratogens

• Thalidomide: Limb defects (phocomelia)
• Alcohol (Fetal Alcohol Syndrome): Growth retardation, facial anomalies, CNS dysfunction
• Isotretinoin: Craniofacial, cardiac, CNS malformations
• Warfarin: Nasal hypoplasia, stippled epiphyses, growth retardation
• DES (Diethylstilbestrol): Clear cell adenocarcinoma of vagina in daughters
• Lead: CNS damage
• Infections: TORCH (Toxoplasma, Others, Rubella, CMV, Herpes)

Critical Periods

• Weeks 1-2: All-or-none effect (either survives or not)
• Weeks 3-8 (organogenesis): Most vulnerable to teratogens
• After 8 weeks: Organ growth and development continue, but major structural defects less common

Genetic Testing

Karyotype Analysis

• Detects large chromosomal abnormalities
• Used for: prenatal diagnosis, suspected chromosomal syndromes, recurrent miscarriage

FISH (Fluorescence In Situ Hybridization)

• Detects specific chromosomal regions
• Used for microdeletions (DiGeorge 22q11, Cri du chat 5p)

Microarray (CGH)

• Detects submicroscopic deletions/duplications
• Higher resolution than karyotype

Molecular Testing

• PCR, sequencing for single gene disorders
• Used for: cystic fibrosis, Huntington disease, sickle cell, thalassemia

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