Genetic Basis of Developmental Disorders

Chromosomal Culprits - Blueprint Blips

• Aneuploidy: Abnormal chromosome number (e.g., $2n \pm 1$).
  • Trisomies (extra chromosome):
    • Down Syndrome (Trisomy 21): Intellectual disability, typical facies. 📌 Drinking Age 21.
    • Edwards Syndrome (Trisomy 18): Rocker-bottom feet, clenched hands.
    • Patau Syndrome (Trisomy 13): Polydactyly, cleft lip/palate.
  • Monosomy (missing chromosome):
    • Turner Syndrome (45,X0): Short stature, webbed neck, ovarian dysgenesis.
  • Sex Chromosome Aneuploidy:
    • Klinefelter Syndrome (47,XXY): Tall, gynecomastia, hypogonadism.
• Structural Abnormalities: Altered chromosome structure.
  • Deletions (e.g., Cri-du-chat: 5p-).
  • Duplications.
  • Translocations (e.g., Robertsonian).
  • Inversions.

⭐ Increased maternal age is the most significant risk factor for nondisjunction leading to trisomies like Down Syndrome.

Single-Gene Syndromes - Solo Saboteurs

• Defect in a single gene; Mendelian inheritance.
• Autosomal Dominant (AD):
  • One allele. Vertical. 50% risk.
  • E.g., Marfan (FBN1), Neurofibromatosis-1 (NF1), Achondroplasia (FGFR3).
• Autosomal Recessive (AR):
  • Two alleles. Horizontal. 25% risk (carriers).
  • E.g., Phenylketonuria (PAH), Cystic Fibrosis (CFTR), Spinal Muscular Atrophy (SMN1).
• X-Linked Recessive (XLR):
  • Males affected. Carrier females. No male-to-male.
  • E.g., Duchenne MD (DMD), Fragile X Syndrome (FMR1).
• X-Linked Dominant (XLD):
  • Affected ♂: all daughters, no sons affected.
  • E.g., Rett Syndrome (MECP2), Incontinentia Pigmenti.

⭐ Fragile X Syndrome (XLR), due to FMR1 gene mutation, is the leading inherited cause of intellectual disability.

Non-Mendelian Modes - Twisted Transcripts

• Mitochondrial Inheritance:
  • Maternal transmission only; males don't transmit.
  • Heteroplasmy: variable expression & severity.
  • E.g., LHON, MELAS, MERRF. 📌 (Mnemonic: My Lovely Mother - MELAS, LHON, MERRF)
• Genomic Imprinting:
  • Parent-of-origin specific gene expression (via DNA methylation).
  • E.g., Prader-Willi (paternal del/maternal UPD 15q11-q13), Angelman (maternal del/paternal UPD 15q11-q13).
• Trinucleotide Repeat Disorders:
  • Expansion of 3-bp repeats (e.g., CAG, CTG, CGG).
  • Anticipation: earlier onset / ↑ severity in successive generations.
  • E.g., Huntington's (CAG), Myotonic Dystrophy (CTG), Fragile X (CGG).
• Mosaicism:
  • Presence of ≥2 genetically distinct cell lines in one individual.
  • Somatic (affects individual, non-heritable) vs. Germline (can be transmitted).
• Uniparental Disomy (UPD):
  • Both homologous chromosomes inherited from a single parent.
  • Can cause imprinting disorders or unmask autosomal recessive diseases.

⭐ Anticipation, the phenomenon of increasing severity or earlier onset of a genetic disorder in successive generations, is a characteristic feature of trinucleotide repeat disorders like Huntington's disease and Myotonic Dystrophy.

Genetic Diagnostics - Code Quest

• Goal: Pinpoint genetic basis of developmental disorders for accurate diagnosis & management.
• Diagnostic Arsenal:
  • Karyotyping: Visualizes chromosomes; for aneuploidies (e.g., Trisomy 21), large structural changes.
  • FISH: Detects specific DNA sequences on chromosomes; for microdeletions (e.g., DiGeorge 22q11.2).
  • Chromosomal Microarray (CMA): High-resolution detection of CNVs (microdeletions/duplications) genome-wide.

    ⭐ CMA is the first-tier test for unexplained Developmental Delay (DD), Intellectual Disability (ID), or Autism Spectrum Disorder (ASD).

  • PCR: Amplifies specific DNA segments for targeted gene mutations (e.g., Fragile X CGG repeats).
  • NGS (Next-Gen Sequencing): Comprehensive analysis via gene panels, WES, WGS for complex cases.
• Prenatal Testing Options:
  • NIPT (Non-Invasive Prenatal Testing).
  • Invasive (diagnostic): CVS (10-13 wks), Amniocentesis (15-20 wks).

High‑Yield Points - ⚡ Biggest Takeaways

• Trisomy 21 (Down syndrome): Most common autosomal aneuploidy; intellectual disability, cardiac defects.
• Turner syndrome (45,X0): Short stature, ovarian dysgenesis in females.
• Klinefelter syndrome (47,XXY): Hypogonadism, tall stature, infertility in males.
• Fragile X syndrome: Leading inherited intellectual disability; CGG repeat in FMR1 gene.
• Genomic imprinting: Prader-Willi (paternal deletion 15q) & Angelman (maternal deletion 15q) syndromes.
• Microdeletion syndromes (e.g., 22q11.2 deletion) cause complex phenotypes including developmental delay.