Medical Genetics
Genetic Inheritance
Mendelian patterns — autosomal dominant, recessive, X-linked, mitochondrial
Mendelian inheritance describes how single-gene disorders pass through families. Autosomal dominant — one mutated copy causes disease (Huntington, Marfan, neurofibromatosis 1, familial hypercholesterolemia, achondroplasia); each child of an affected parent has 50% risk; vertical transmission through generations. Autosomal recessive — both copies mutated (cystic fibrosis, sickle cell, Tay-Sachs, phenylketonuria, hemochromatosis); two carrier parents give 25% affected, 50% carrier, 25% unaffected; horizontal pattern. X-linked recessive — males affected (hemophilia A/B, Duchenne muscular dystrophy, color blindness, G6PD deficiency); skip generations through carrier mothers. X-linked dominant rare (Rett, fragile X — though complex). Mitochondrial — maternal transmission only (Leber's optic neuropathy, MELAS, MERRF). Penetrance and expressivity modify the picture.
- Autosomal dominant50% offspring affected; vertical
- Autosomal recessive25% affected from two carriers
- X-linked recessiveMales affected; carrier females
- MitochondrialOnly maternal transmission
- PenetranceProbability genotype produces phenotype
- ExpressivitySeverity of phenotype with same genotype
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Why inheritance patterns matter
- Genetic counseling. Recurrence risk depends on inheritance mode.
- Newborn screening. Phenylketonuria, galactosemia, MCAD prevent disability.
- Cancer surveillance. BRCA1/2, Lynch syndrome enable early detection.
- Reproductive decisions. Carrier screening, prenatal diagnosis, PGT.
- Pharmacogenomics. Codeine in CYP2D6 metabolizers, warfarin in CYP2C9/VKORC1.
- Cardiology. HCM, long QT, familial hypercholesterolemia screened in relatives.
- Neurology. Huntington predictive testing follows ethical protocol.
Common errors
- Calling de novo cases sporadic. Achondroplasia is 80% de novo dominant — parents unaffected.
- Missing X-linked dominant. Affected fathers transmit to all daughters but no sons.
- Ignoring incomplete penetrance. Skipped generations don't rule out dominant inheritance.
- Forgetting mosaicism. Apparent de novo cases may recur in siblings.
- Conflating heritability and inheritance. Heritability is population concept; inheritance is family-level.
- Disclosing genetic results without consent protocols. Predictive testing for adult-onset diseases requires preparation.
Frequently asked questions
How are Mendelian patterns recognized?
Pedigree analysis. Autosomal dominant — affected in every generation, both sexes affected, male-to-male transmission possible. Autosomal recessive — skip generations, parents typically unaffected carriers, often consanguinity, increased risk in founder populations (Ashkenazi Tay-Sachs, French Canadian Tay-Sachs). X-linked recessive — mostly males, all daughters of affected males are obligate carriers, no male-to-male transmission. X-linked dominant — affected fathers transmit to all daughters, no sons. Mitochondrial — affected mothers transmit to all children; affected fathers to none.
What is incomplete penetrance?
Some carriers of a disease-causing variant never develop the disease. BRCA1 has ~70% lifetime penetrance for breast cancer — meaning 30% of carriers won't develop it. Hereditary nonpolyposis colorectal cancer (Lynch syndrome) has variable penetrance. Affects genetic counseling — carrier status increases risk but doesn't guarantee disease. Variable expressivity is related — severity varies among affected individuals (NF1 with cafe-au-lait spots only vs neurofibromas vs malignancy).
How does CF carrier screening work?
Cystic fibrosis is autosomal recessive in CFTR gene. Carrier frequency 1/25 in Northern Europeans. Two carriers — 25% chance of affected child each pregnancy. Screening targets common variants (F508del most common in Europeans). Couple-based screening recommended preconception or prenatal. Positive carrier — partner testing; if both positive, consider prenatal diagnosis (CVS, amniocentesis) or PGT-M. Newborn screening detects affected infants for early treatment.
What is anticipation?
Disease worsens or appears earlier in successive generations. Trinucleotide repeat disorders — Huntington (CAG in HTT, >35 disease, longer = earlier onset), myotonic dystrophy (CTG in DMPK), Friedreich ataxia (GAA in FXN), fragile X (CGG in FMR1). Repeats expand during meiosis, especially male spermatogenesis for Huntington, female oogenesis for myotonic and fragile X. Predicting age of onset based on repeat length now possible.
What's mosaicism?
Individual has two or more genetically distinct cell lines from postzygotic mutation. Somatic mosaicism — mutation in tissue but not germline; segmental NF1, McCune-Albright. Germline (gonadal) mosaicism — mutation only in germ cells; explains apparent recurrence in offspring of unaffected parents in disorders like Duchenne and osteogenesis imperfecta. Affects recurrence risk counseling — cannot reassure parents based on personal genetic test.
What about consanguinity?
First cousins share ~1/8 of genes. Risks of autosomal recessive disorders increase modestly. Background recessive disease risk 2-3%; first cousin offspring 4-7%. Higher risk in populations with high background carrier frequencies and founder mutations. Genetic counseling recommended for consanguineous couples — targeted carrier screening, family history. Specific concerns vary by ancestry — Mediterranean (thalassemia), Ashkenazi (Tay-Sachs, Canavan, Gaucher), French Canadian (multiple), Amish.
How do you read a pedigree?
Squares = males, circles = females, filled = affected, half-filled = carriers (recessive carriers shown only when known), arrow = proband, double line = consanguinity, diagonal slash = deceased. Roman numerals for generations, Arabic for individuals within. Diamond = unknown sex. Look for inheritance pattern across generations — vertical (dominant), horizontal (recessive), male predominance (X-linked), maternal-only (mitochondrial). Consider de novo mutation if no family history.