18.5 Medical Genetics: Mendelian/Chromosomal/Multifactorial Disorders & Screening

Medical Genetics: Mendelian, Chromosomal, Multifactorial Disorders & Screening

Medical genetics (PA-CAT Bulletin of Information, rev. 20240815, Table 8 — Medical Genetics and Cancer) is the largest applied block of the 26-item genetics section. PA-CAT expects you to classify disorders by inheritance pattern and know screening and counseling principles.

Mendelian (Single-Gene) Disorders

Autosomal dominant (AD) — one mutant allele suffices for disease. Features: vertical transmission across generations, both sexes equally affected, 50% risk to offspring, often late onset, and many are structural protein, receptor, or gain-of-function defects. Examples: Huntington disease (CAG repeat expansion in HTT), Marfan syndrome (FBN1), familial hypercholesterolemia (LDLR), achondroplasia (FGFR3), neurofibromatosis type 1 (NF1). New mutations are common for severe AD disorders that reduce reproductive fitness.

Autosomal recessive (AR) — both alleles must be mutant. Features: horizontal transmission (siblings affected, parents are heterozygous carriers), often enzyme deficiencies, usually early onset, and increased risk with consanguinity. Examples: cystic fibrosis (CFTR ΔF508), sickle-cell disease (HBB Glu6Val), phenylketonuria (PAH), Tay-Sachs disease (HEXA). Carriers are typically asymptomatic.

X-linked recessive — males (hemizygous for X) are affected; female heterozygotes are usually unaffected carriers. Features: no male-to-male transmission, affected males pass the allele to all daughters (who become carriers) and to no sons. Examples: Duchenne muscular dystrophy (DMD), hemophilia A (F8), hemophilia B (F9), red–green color blindness, G6PD deficiency.

X-linked dominant — rarer; affected males transmit to all daughters and no sons; often lethal in males. Examples: hypophosphatemic rickets (XLH), Rett syndrome (MECP2, usually lethal in males).

Y-linked — very rare; male-to-male transmission only (e.g., some infertility loci).

Mitochondrial Disorders

Mitochondrial DNA (mtDNA) is maternally inherited — all children of an affected mother inherit it, but an affected father transmits none. Disorders show variable expressivity due to heteroplasmy (a cell's mixture of normal and mutant mtDNA) and a threshold effect (symptoms appear once the proportion of mutant mtDNA exceeds a tissue-specific threshold). Examples: MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibers), Leber hereditary optic neuropathy (LHON).

Chromosomal Disorders

Aneuploidies (abnormal chromosome number) usually arise from nondisjunction in meiosis I or II:

Structural aberrations include deletions (e.g., cri-du-chat syndrome, 5p−), duplications, inversions (pericentric vs paracentric), and translocations. Reciprocal translocations are usually balanced in carriers but cause semisterility through unbalanced gametes. Robertsonian translocations involve acrocentric chromosomes; t(14;21) accounts for ~4% of Down syndrome cases. The Philadelphia chromosome t(9;22) creates the BCR-ABL1 fusion oncogene in chronic myeloid leukemia.

Multifactorial Disorders

Multifactorial traits are polygenic (many genes, each with small effect) plus environmental contributors. Recurrence risk falls off rapidly with decreasing degree of relationship, unlike Mendelian disorders. Examples: cleft lip/palate, neural tube defects (spina bifida, anencephaly — maternal folic acid supplementation markedly reduces risk), type 2 diabetes, hypertension, schizophrenia, coronary artery disease, clubfoot.

Screening, Carrier Testing, Prenatal Diagnosis, and Counseling

• Population screening — tests offered to large groups regardless of individual risk. Examples: newborn screening for PKU, congenital hypothyroidism, sickle-cell disease, and galactosemia; pan-ethnic cystic fibrosis carrier screening.
• Carrier testing — identifies heterozygotes for AR conditions, particularly in high-risk populations (e.g., Ashkenazi Jewish panels for Tay-Sachs, Canavan, CF, Familial Dysautonomia).
• Prenatal diagnosis — amniocentesis (15–20 weeks; karyotype plus biochemical tests), chorionic villus sampling (CVS) (10–13 weeks; karyotype from chorionic villi), and cell-free fetal DNA (cffDNA) noninvasive prenatal testing (NIPT, from ~10 weeks; screens common aneuploidies with high sensitivity but as a screen, not a diagnostic test).
• Genetic counseling — nondirective communication of recurrence risks, inheritance patterns, natural history, and reproductive options, paired with informed consent and psychosocial support. Counselors help patients make autonomous decisions; they do not dictate choices.

Newborn Screening: Cutoff, Confirmatory Testing, and Follow-Up Workflow

The section above lists conditions screened, but PA-CAT items also test the two-stage logic of newborn screening: an initial high-sensitivity tier (with imperfect specificity) followed by confirmatory diagnostic testing. This workflow prevents two common errors — over-interpreting a borderline screen as disease, and dismissing a normal screen when clinical risk is high.

Two-Tier Logic

1. First-tier screen — quantitative assays (tandem mass spectrometry, immunoassays, enzyme activity, molecular panels) run on dried blood spots collected 24–48 hours after birth. Cutoffs are set intentionally low to minimize false negatives, accepting more false positives.
2. Abnormal or borderline result — triggers repeat screen or referral; not a diagnosis.
3. Confirmatory testing — disease-specific: plasma amino acids for PKU, CFTR sequencing for cystic fibrosis, hemoglobin electrophoresis for sickle-cell disease, thyroid panel for congenital hypothyroidism.
4. Clinical evaluation — a geneticist or metabolic specialist interprets confirmatory results in context.

Why Cutoffs Favor Sensitivity

Missing a treatable disorder like PKU or congenital hypothyroidism causes irreversible intellectual disability, while a false positive only adds short-term anxiety and a repeat test. So cutoffs sit near the low end of the abnormal range. Prematurity, illness, transfusion, and early discharge can elevate or suppress analytes; timing matters — specimens drawn before 24 hours miss cases of congenital hypothyroidism.

Cutoff Example