Medical Genetics, Molecular Biology & Chromosomal Syndromes

Nucleotide Excision Repair (NER) operates primarily during the G1 phase to recognize bulky helix-distorting lesions—specifically ultraviolet (UV)-B induced pyrimidine (thymine-thymine) dimers—excising the damaged oligonucleotide via endonucleases and filling the gap with DNA polymerase and ligase. Autosomal recessive defects in NER cause Xeroderma Pigmentosum, presenting in early childhood with severe photosensitivity, dry poikilodermatous skin, freckling, corneal ulcerations, and a >1,000-fold increased risk of basal cell carcinoma, squamous cell carcinoma, and melanoma. Base Excision Repair (BER) operates throughout the cell cycle to correct spontaneous deamination, depurination, or alkylation of individual bases via the Sequential action of DNA glycosylase (creates an apurinic/apyrimidinic site), AP endonuclease (cleaves the 5' phosphodiester bond), AP lyase (cleaves the 3' bond), DNA polymerase beta, and DNA ligase (remembered as “GEL PLease”); MUTYH-associated polyposis is a classic BER defect. Mismatch Repair (MMR) operates predominantly in the S/G2 phase to correct replication slippage errors; autosomal dominant germline mutations in MLH1, MSH2, MSH6, or PMS2 cause Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer [HNPCC]), characterized by microsatellite instability and high lifetime risk of right-sided colorectal adenocarcinoma, endometrial carcinoma, and ovarian cancer.

Homologous Recombination uses the intact sister chromatid during late S/G2 as an error-free template to repair double-strand breaks; mutations in BRCA1 (chromosome 17, triple-negative breast and ovarian cancer) or BRCA2 (chromosome 13, male breast cancer, pancreatic and prostate cancer) cripple homologous recombination and render tumors exquisitely sensitive to synthetic lethality with PARP inhibitors (olaparib), while Fanconi anemia impairs interstrand cross-link repair, causing aplastic anemia, cafe-au-lait spots, radial/thumb hypoplasia, and short stature. Non-Homologous End Joining (NHEJ) brings broken DNA ends together without a homologous template (required for physiological V(D)J recombination of T-cell and B-cell antigen receptors); defects in the ATM gene (which senses double-strand breaks) cause Ataxia-Telangiectasia, presenting with cerebellar ataxia (elevated AFP), ocular/cutaneous telangiectasias, IgA deficiency (recurrent sinopulmonary infections), and extreme sensitivity to ionizing X-ray radiation.

Mitochondrial DNA (mtDNA) is inherited exclusively from the mother's oocyte cytoplasm; therefore, an affected mother transmits the mutation to 100% of her offspring (both sons and daughters) with variable phenotypic severity due to heteroplasmy (random mitotic segregation of normal and mutant mitochondria during cell division), whereas an affected father transmits the disease to 0% of his children. Mitochondrial myopathies preferentially damage high-energy tissues (central nervous system, skeletal muscle, retina, cochlea) and demonstrate characteristic ragged-red fibers on Gomori trichrome muscle biopsy (representing compensatory subsarcolemmal proliferation of abnormal mitochondria). Classic syndromes include MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes in young adults), MERRF (Myoclonic Epilepsy with Ragged-Red Fibers), and Leber Hereditary Optic Neuropathy (acute bilateral painless central vision loss in young men).

Genomic imprinting is the parent-of-origin epigenetic silencing of one allele via DNA cytosine methylation during gametogenesis, leaving only a single functional copy of the gene in offspring. Deletion or mutation of the active allele—or uniparental disomy (UPD), in which a child inherits both copies of chromosome 15 from the silenced parent via trisomy rescue—ablates gene expression despite a normal 46,XX or 46,XY karyotype. On chromosome 15q11-q13, loss of the paternally expressed SNRPN/NDN locus (70% paternal 15q11-q13 microdeletion, 25% maternal uniparental disomy) causes Prader-Willi syndrome, presenting with neonatal hypotonia/poor feeding followed in childhood by insatiable hyperphagia (elevated ghrelin), morbid obesity, intellectual disability, hypogonadism, and almond-shaped eyes. Conversely, loss of the maternally expressed UBE3A ubiquitin ligase gene on 15q11-q13 (maternal microdeletion or paternal uniparental disomy) causes Angelman syndrome, presenting with severe intellectual disability, ataxia/jerky puppet-like gait, seizures, absent speech, and paroxysms of inappropriate laughter (“happy demeanor”).

Huntington disease is an autosomal dominant expansion of CAG repeats (≥40 repeats) within the coding exon of the HTT gene on chromosome 4, producing a toxic gain-of-function polyglutamine-expanded huntingtin protein that aggregates in neurons and induces NMDA receptor-mediated glutamate excitotoxicity. Patients present at age 30–50 years (earlier with paternal transmission anticipation) with chorea, athetosis, aggression, depression, and dementia; coronal brain MRI demonstrates profound atrophy of the caudate nucleus and putamen (striatum) with ex vacuo ventriculomegaly of the frontal horns, accompanied by decreased striatal GABA and acetylcholine and relatively increased dopamine (treated symptomatically with VMAT2 inhibitors tetrabenazine or deutetrabenazine). Fragile X syndrome is an X-linked dominant disorder (the most common inherited cause of intellectual disability and second most common genetic cause after Down syndrome) caused by CGG repeat expansion (>200 full mutation repeats; 55–200 premutation causes Fragile X-associated tremor/ataxia syndrome and premature ovarian insufficiency) in the 5' untranslated region of the FMR1 gene, triggering hypermethylation and transcriptional silencing of FMRP. Affected males present with a long face, large everted ears, prominent jaw, postpubertal macroorchidism (enlarged testes), mitral valve prolapse, autism spectrum behaviors, and hypermobile joints.

Friedreich ataxia is the only autosomal recessive trinucleotide repeat disorder, caused by GAA repeat expansion in the first intron of the FXN gene on chromosome 9, silencing mitochondrial frataxin (an iron-chaperone protein essential for iron-sulfur cluster assembly). Mitochondrial iron overload and free-radical oxidative damage destroy the dorsal columns (loss of vibration and proprioception), spinocerebellar tracts (ataxia, dysmetria, wide-based gait), lateral corticospinal tracts (spastic weakness, Babinski sign), and dorsal root ganglia (absent deep tendon reflexes), presenting in adolescence alongside kyphoscoliosis, pes cavus, diabetes mellitus, and fatal hypertrophic cardiomyopathy (the #1 cause of death). Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant CTG repeat expansion in the 3' untranslated region of the DMPK gene on chromosome 19; the expanded CUG mRNA hairpins sequester muscleblind-like splicing factors (RNA toxicity), causing myotonia (inability to relax grip after a handshake or percussion of the thenar eminence), distal muscle weakness, hatchet-facies (temporal and masseter wasting), frontal balding, posterior subcapsular Christmas-tree cataracts, testicular atrophy, and cardiac conduction blocks/arrhythmias.

Down syndrome (Trisomy 21; 95% maternal Meiosis I nondisjunction, 4% Robertsonian t(14;21), 1% mosaicism) presents with flat facies, upslanting palpebral fissures, epicanthal folds, Brushfield iris spots, single palmar (simian) crease, wide gap between 1st and 2nd toes, endocardial cushion defect (atrioventricular septal defect), duodenal atresia (“double-bubble” sign) or Hirschsprung disease, atlantoaxial (C1–C2) instability, acute lymphoblastic/megakaryoblastic leukemia, and early-onset Alzheimer dementia by age 40 (because the APP amyloid precursor protein gene resides on chromosome 21); quad screen shows Low AFP, Low Estriol, High beta-hCG, and High Inhibin A. Edwards syndrome (Trisomy 18) presents with severe intellectual disability, prominent occiput, micrognathia, low-set ears, clenched fists with overlapping fingers (index over 3rd, 5th over 4th), rocker-bottom feet, congenital heart disease (VSD/PDA), and death before age 1; quad screen shows universally decreased AFP, Estriol, beta-hCG, and Inhibin A. Patau syndrome (Trisomy 13) results from failed prechordal mesoderm/Sonic Hedgehog signaling at 3–4 weeks gestation, causing midline defects: holoprosencephaly, microcephaly, microphthalmia, bilateral cleft lip/palate, cutis aplasia, polydactyly, polycystic kidneys, and rocker-bottom feet.

Turner syndrome (45,XO, the only viable monosomy; or 45,X/46,XX mosaicism) presents in phenotypic females with short stature (SHOX gene haploinsufficiency; treated with growth hormone), neonatal lymphedema of hands and feet, cystic hygroma and webbed neck (pterygium colli), shield chest with widely spaced nipples, streak ovaries with primary amenorrhea and hypergonadotropic hypogonadism (elevated FSH/LH, low estrogen, absent Barr body), bicuspid aortic valve, coarctation of the aorta, and horseshoe kidney (fused inferior poles trapped beneath the inferior mesenteric artery). Klinefelter syndrome (47,XXY) presents in phenotypic males with tall eunuchoid stature (long extremities), small firm testes due to seminiferous tubule dysgenesis/hyalinization, azoospermia/infertility, gynecomastia (increased male breast cancer risk), mild intellectual impairment, and one inactivated X chromosome (Barr body); inhibin B and testosterone are decreased while FSH, LH, and estradiol (via Leydig cell aromatase upregulation) are elevated.

22q11.2 Deletion Syndrome (encompassing DiGeorge and Velocardiofacial syndromes) results from defective neural crest migration into the 3rd and 4th pharyngeal pouches, summarized by CATCH-22: Conotruncal cardiac anomalies (truncus arteriosus, tetralogy of Fallot, interrupted aortic arch), Abnormal facies, Thymic aplasia/hypoplasia (absent thymic shadow on chest X-ray and recurrent viral/fungal T-cell infections), Cleft palate, and Hypocalcemic tetany (Positive Chvostek and Trousseau signs from parathyroid aplasia). Williams syndrome is a microdeletion on chromosome 7q11.23 spanning the elastin gene; patients exhibit elfin facies, extreme friendliness with strangers (“cocktail-party personality”) paired with intellectual disability, supravalvular aortic stenosis, renal artery stenosis, and idiopathic hypercalcemia (due to vitamin D hypersensitivity). Cri-du-chat syndrome results from terminal deletion of the short arm of chromosome 5 (5p-), presenting with microcephaly, severe intellectual disability, epicanthal folds, ventricular septal defect, and a high-pitched mewing cat-like cry in infancy.

Neurofibromatosis Type 1 (von Recklinghausen disease; AD, Chr 17, neurofibromin) presents with ≥6 cafe-au-lait macules, axillary/inguinal freckling, iris hamartomas (Lisch nodules), cutaneous plexiform neurofibromas, optic pathway gliomas, sphenoid wing dysplasia, and pheochromocytoma. Neurofibromatosis Type 2 (AD, Chr 22, merlin) presents with bilateral vestibular schwannomas (CN VIII acoustic neuromas causing sensorineural deafness and tinnitus), juvenile cataracts, meningiomas, and ependymomas (“NF2 has 2 ears, 2 eyes, and chromosome 22”). Tuberous Sclerosis (AD, TSC1/TSC2) causes cortical tubers, subependymal giant cell astrocytomas, infantile spasms (West syndrome with hypsarrhythmia on EEG), hypomelanotic ash-leaf spots (visualized under Wood lamp), facial angiofibromas, shagreen patches, cardiac rhabdomyomas, and renal angiomyolipomas. Von Hippel-Lindau disease (AD, Chr 3p, VHL) prevents degradation of hypoxia-inducible factor 1a (HIF-1a), driving VEGF/EPO overexpression and causing cerebellar/retinal hemangioblastomas (with secondary polycythemia), bilateral clear cell renal cell carcinomas, and pheochromocytomas. Sturge-Weber syndrome is a sporadic, non-inherited somatic mosaic activating mutation in GNAQ, presenting with a unilateral trigeminal (V1/V2) port-wine stain (nevus flammeus), ipsilateral leptomeningeal angiomatosis (tram-track cortical calcifications, seizures, intellectual disability), and episcleral hemangioma causing early-onset open-angle glaucoma.

To solve any autosomal recessive Hardy-Weinberg problem in under 15 seconds: (1) Set disease incidence equal to q squared (e.g., if incidence = 1/10,000, then q squared = 1/10,000); (2) Take the square root to find the mutant allele frequency q (q = 1/100 = 0.01); (3) Because p is approximately 1 for rare diseases (p = 0.99 ≈ 1), the heterozygous carrier frequency 2pq simplifies to 2q (2 × 1/100 = 1/50 = 2%). A major board trap involves the healthy sibling of a child with an autosomal recessive disease: because both parents are obligate heterozygotes (Aa × Aa), the Punnett square produces 1/4 AA, 2/4 Aa, and 1/4 aa. Once you know the sibling does not have the disease (excluding the 1/4 aa outcome), three possibilities remain (AA, Aa, Aa)—meaning the healthy sibling has a 2/3 (66.7%) probability of being a carrier, not 1/2 (50%).

For X-linked recessive disorders (such as hemophilia A, Duchenne muscular dystrophy, or color blindness), hemizygous males have only one X chromosome; therefore, the incidence of the disease in males equals q directly (not q squared!), whereas the incidence of affected homozygous females equals q squared and female carrier frequency equals 2pq. When calculating the probability that two parents will have an affected autosomal recessive child: multiply (Parent 1 carrier probability) × (Parent 2 carrier probability) × (1/4 probability of transmitting both recessive alleles). For example, if a woman whose brother has Cystic Fibrosis (her carrier risk = 2/3) marries an unrelated man from a population where CF carrier frequency is 1/25, their probability of having an affected child is (2/3) × (1/25) × (1/4) = 2/300 = 1/150.