2.6 Mendelian Inheritance Patterns
Key Takeaways
- Autosomal dominant transmission shows vertical pedigree pattern with male-to-male transmission possible; each child of an affected heterozygote has a 50% chance of inheriting the pathogenic allele when segregation is Mendelian
- Autosomal recessive pedigrees are often horizontal; carrier × carrier matings yield 25% affected, 50% carrier, and 25% non-carrier offspring on average
- X-linked recessive disease typically spares transmitting fathers’ sons, affects hemizygous males, and can produce manifesting females when X-inactivation is skewed or the variant is severe
- Apparent de novo dominant disease still warrants discussion of germline (gonadal) mosaicism because recurrence risk is low but not absolute zero
- X-linked dominant patterns lack male-to-male transmission; male lethality or severe male phenotypes and female expressivity differences are classic counseling cues
2.6 Mendelian Inheritance Patterns
Quick Answer: Master four core Mendelian modes—autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XLR), and X-linked dominant (XLD)—by transmission rules on a pedigree, not by disease name alone. Then layer the exceptions boards love: de novo variants, germline mosaicism, and skewed X-inactivation in females.
Domain 2B items ask you to read a pedigree, predict who is at risk next, and explain why a “classic” pattern broke. Risk arithmetic lives in Domain 2A; here the job is pattern recognition and mechanism.
Autosomal Dominant (AD)
In classic AD disease, one pathogenic allele on an autosome is sufficient for disease predisposition (subject to penetrance—covered in 2.8).
| Rule | Clinical / exam meaning |
|---|---|
| Vertical transmission | Affected individuals in successive generations when penetrance is high |
| Male-to-male transmission | Possible and excludes X-linked inheritance |
| Segregation | Each child of an affected heterozygote has ~50% chance of inheriting the allele |
| Sex ratio | Males and females affected roughly equally (unless sex-limited expression) |
| Unaffected non-carriers | Do not transmit the familial allele (ignore mosaicism/non-paternity/new mutation for this idealization) |
Counseling anchors: Distinguish “has the familial variant” from “will develop the phenotype” when penetrance is incomplete. For severe pediatric AD conditions with fitness cost (e.g., many lethal skeletal dysplasias, some early neurodevelopmental disorders), a substantial fraction of index cases are de novo.
De Novo AD and Germline Mosaicism
A de novo pathogenic variant is present in the child but absent from parental blood (leukocyte) DNA. Parents are usually quoted a low empiric recurrence risk, but germline mosaicism (variant present in a fraction of parental gametes) means recurrence is not absolute zero. Exam-ready phrasing: “Most likely de novo; residual recurrence risk is low but not zero because of possible germline mosaicism; prenatal/preimplantation options can still be discussed if the familial variant is known.”
Somatic mosaicism in the affected person can produce milder or segmental phenotypes and may reduce transmission probability depending on germline involvement—do not equate blood-negative parents with “impossible recurrence” or mosaic probands with “cannot transmit.”
Autosomal Recessive (AR)
AR disease typically requires biallelic pathogenic variants (homozygous or compound heterozygous).
| Rule | Clinical / exam meaning |
|---|---|
| Horizontal pedigree | Multiple affected siblings; parents usually unaffected carriers |
| Consanguinity | Increases chance both parents share an ancestral allele |
| Carrier × carrier | On average 1/4 affected, 1/2 carriers, 1/4 non-carriers |
| Affected × non-carrier | All offspring carriers; none affected (assuming true non-carrier and complete genotyping) |
| Pseudodominance | Affected person partners with a carrier → vertical-looking pedigree that is still AR |
CGC traps: (1) Calling an isolated case “not genetic” because parents are healthy—AR and de novo AD both produce isolated cases. (2) Assuming ethnicity-based carrier rates replace partner testing when a familial variant is known—offer cascade testing for the known variant(s). (3) Confusing carrier probability after a negative screen (residual risk) with Mendelian segregation once genotypes are known.
X-Linked Recessive (XLR)
Pathogenic variants on the X chromosome; hemizygous males express disease; heterozygous females are usually unaffected or milder, with important exceptions.
| Transmission clue | Interpretation |
|---|---|
| No male-to-male transmission | Fathers transmit their Y—not their X—to sons |
| Affected male → daughters | All daughters inherit his X → all are obligate carriers (or affected if the condition is XLD / highly expressing) |
| Affected male → sons | Sons get his Y → not at risk for that paternal X variant |
| Carrier female → sons | Each son has 50% chance of being affected |
| Carrier female → daughters | Each daughter has 50% chance of being a carrier |
| Manifesting female | Possible with skewed X-inactivation, chromosomal anomalies (e.g., X;autosome translocation), compound heterozygosity/homozygosity, or mild alleles |
Skewed X-inactivation: Random X-inactivation (lyonization) normally mosaics female tissues. Non-random skewing can silence the normal allele in enough cells that a heterozygous female shows disease features (classic teaching examples include some dystrophinopathy carriers or other XLR disorders). Boards test the concept: female phenotype does not automatically prove autosomal inheritance.
X-Linked Dominant (XLD)
One pathogenic X allele can produce phenotype in females; males may be more severely affected or nonviable for some loci.
| Feature | Exam use |
|---|---|
| No male-to-male transmission | Same X biology as XLR |
| Affected females common | Pedigrees may show more affected females if male lethality occurs |
| Male severity | Hemizygous males often more severe; embryonic male lethality yields pedigree gaps |
| Examples (pattern recognition) | Conditions such as Rett syndrome (MECP2) are often framed as X-linked with frequent de novo occurrence in females; incontinentia pigmenti illustrates male lethality patterns |
Do not memorize every XLD disease list; memorize how the pedigree behaves and when to suspect male lethality versus ascertainment bias.
Pattern Discrimination Table
| Pattern | Male-to-male? | Typical parents of isolated case | Key exception to teach |
|---|---|---|---|
| AD | Yes possible | Often one affected parent; or de novo | Germline mosaicism; incomplete penetrance |
| AR | Yes possible among affected relatives’ lines, but parents usually unaffected | Both carriers | Consanguinity; pseudodominance |
| XLR | No | Mother often carrier; may be de novo in male | Manifesting females / skewing |
| XLD | No | Mother affected or de novo | Male lethality; variable female severity |
Putting Mendelian Rules into a Session
- Draw or interpret the pedigree symbols and transmission arrows before naming a syndrome.
- Ask whether male-to-male transmission is present or possible—this single check separates autosomal from X-linked hypotheses.
- For severe AD presentations in a child with negative parental studies, counsel de novo + residual germline mosaicism honestly.
- For X-linked families, explicitly map risk to daughters of affected males versus sons of carrier females.
- Reserve quantitative Bayesian updates and population carrier frequencies for Domain 2A calculations—here, nail the mode.
Fluent Mendelian pattern language is what lets you later attach mitochondrial, imprinting, and multifactorial exceptions without collapsing everything into “50% or 25%.”
A pedigree shows an affected father, an unaffected mother, two affected sons, and an affected daughter. Which inheritance pattern is incompatible with this constellation if the father’s phenotype is caused by a single-gene Mendelian variant he transmits?
Parents of a child with a severe autosomal dominant condition have negative blood testing for the child’s pathogenic variant. What is the most accurate recurrence-risk counseling point?
Two unaffected parents have a child with a classic autosomal recessive metabolic disease; molecular testing confirms both parents are heterozygous carriers of pathogenic variants. For their next pregnancy, what Mendelian probabilities apply to genotypes at that locus?
A woman whose father has a documented X-linked recessive disorder asks about her sons’ risk. Assuming she inherited her father’s pathogenic X variant, what is the best immediate counseling statement?