Inheritance Patterns

Short version. The pattern of affected and unaffected individuals across generations and sexes is what makes a pedigree informative. Six classical patterns (autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant, Y-linked, mitochondrial) plus a small set of non-classical mechanisms (imprinting, uniparental disomy, anticipation, heteroplasmy) cover almost all of single-locus inheritance. Each pattern has a small set of diagnostic features in pedigrees and a canonical example locus. Real families almost never fit one pattern cleanly.

Mendel's two laws

Gregor Mendel's 1866 paper (Verhandlungen des naturforschenden Vereines in Brünn 4:3-47, facsimile via the Biodiversity Heritage Library) gave classical genetics two laws. The law of segregation states that each parent transmits one of their two alleles at a locus at random to each gamete, so that an Aa parent transmits A or a with equal probability. The law of independent assortment states that alleles at different loci segregate independently of each other, producing the 9:3:3:1 dihybrid ratio when neither locus shows linkage. Independent assortment holds within the limits of physical proximity on the chromosome — loci on the same chromosome, sufficiently close, depart from independent assortment, which is the entire basis of linkage analysis.

Mendel's two laws define what is meant by a Mendelian phenotype: a phenotype determined by the genotype at a single locus, with predictable transmission ratios from parent to offspring. The laws plus a binary affected-status definition produce the classical patterns. The Mendelian inheritance calculator walks through the underlying arithmetic.

Autosomal dominant

Diagnostic features in a pedigree:

Affected individuals in every generation — vertical transmission from parent to offspring.
Both sexes affected with roughly equal frequency.
Approximately 50% of the offspring of an affected parent are affected (when the parent is heterozygous, which is the usual case).
Male-to-male transmission is allowed (and observed). This is the diagnostic test that distinguishes autosomal dominant from X-linked dominant.
An unaffected individual does not transmit (under full penetrance and no germline mosaicism — both caveats below).

Worked loci: FBN1 in Marfan syndrome (OMIM 154700); NF1 in neurofibromatosis type 1 (OMIM 162200); HTT in Huntington disease (OMIM 143100); FGFR3 p.Gly380Arg in achondroplasia (OMIM 100800); BRCA1 and BRCA2 in hereditary breast and ovarian cancer (OMIM 113705, 600185).

Real autosomal dominant pedigrees depart from the textbook ratio for three reasons. Reduced penetrance: not every heterozygote develops the phenotype within the observation window (Huntington at age 25, BRCA1-associated breast cancer at age 40). Variable expressivity: heterozygotes with the same variant present with very different combinations of features (NF1 again, with café-au-lait macules, neurofibromas, optic glioma, and Lisch nodules in different proportions). Anticipation: the trinucleotide-repeat disorders (Huntington, myotonic dystrophy, several spinocerebellar ataxias) where the repeat expands across generations, producing earlier and more severe phenotypes in successive generations. The textbook computation is at autosomal dominant calculator.

Autosomal recessive

Diagnostic features:

Affected individuals appear in a single generation, typically in a sibship (the proband's brothers and sisters).
The parents of an affected individual are typically unaffected obligate carriers (one variant allele each).
Both sexes affected with roughly equal frequency.
The condition often skips generations: it appears in the proband's generation but not in the parental or grandparental generations.
Consanguinity raises the prior probability of an autosomal recessive condition. A double horizontal line in the pedigree is therefore a Bayesian piece of evidence in itself; see consanguinity calculator.
Approximately 25% recurrence in subsequent sibs of two carrier parents.

Worked loci: CFTR in cystic fibrosis (OMIM 219700); HBB in sickle-cell anaemia and beta-thalassaemia (OMIM 603903); HEXA in Tay-Sachs disease (OMIM 272800); PAH in phenylketonuria (OMIM 261600); HGD in alkaptonuria (OMIM 203500) — Garrod's original 1902 case.

Population-specific allele frequencies matter for autosomal recessive conditions. Founder effects produce regionally elevated carrier frequencies (the HEXA 1278insTATC variant in Ashkenazi Jewish populations, the CFTR p.Phe508del variant in northern European populations, the HBB sickle-cell variant in populations of West African descent). Hardy-Weinberg-derived priors are covered on the pedigree analysis page; the recessive computation is at autosomal recessive calculator.

X-linked recessive

Morgan's 1910 white-eye paper (Science 32:120, JSTOR 1635471) established the X-linked pattern in Drosophila, and the same pattern is the most diagnostically distinctive in human pedigrees. Diagnostic features:

Predominantly affected males. A female homozygote is possible but rare; the carrier-female phenotype (in an X-inactivation skewed individual) is occasionally observed.
No male-to-male transmission. An affected father cannot transmit an X-linked recessive condition to a son (the son inherits the father's Y, not his X). This is the single most diagnostic feature.
Daughters of affected males are obligate carriers. Every daughter of an affected father inherits the father's X.
Affected males inherit from carrier mothers. The mother of an affected male is a carrier (modulo de novo events, which are common in X-linked lethal conditions because of selection).
Roughly 50% of the sons of a carrier mother are affected and 50% of her daughters are carriers.

Worked loci: DMD in Duchenne and Becker muscular dystrophy (OMIM 310200; see also Duchenne pedigree); F8 in haemophilia A (OMIM 306700) — the famous pedigree of Queen Victoria's descendants is the canonical teaching example; F9 in haemophilia B (OMIM 306900); FMR1 in fragile X syndrome (OMIM 300624); G6PD in glucose-6-phosphate dehydrogenase deficiency (OMIM 305900).

Selection against affected males in lethal conditions (Duchenne is the canonical example) means that approximately one third of cases at any given time are de novo mutations in the maternal germline rather than transmitted from a known carrier. This is the Haldane equilibrium argument and is the reason that an apparently isolated affected male in an X-linked lethal disorder is not necessarily evidence of a non-carrier mother. The before-and-after probability arithmetic for carrier estimation in the mother is at carrier probability calculator and worked through on the pedigree analysis page. The interactive calculator is at x-linked recessive calculator.

X-linked dominant

X-linked dominant conditions are diagnosable from a pedigree by the asymmetry between affected fathers and affected mothers:

Affected in every generation, like autosomal dominant.
An affected male transmits the condition to all his daughters and none of his sons. This is the diagnostic feature.
An affected female transmits to roughly 50% of her offspring of either sex.
In several X-linked dominant conditions (incontinentia pigmenti, Rett syndrome, the OFD1 phenotype) the condition is lethal in hemizygous males, producing pedigrees with affected females, recurrent miscarriages of male foetuses, and a striking female:male ratio in liveborn affected children.

Worked loci: MECP2 in Rett syndrome (OMIM 312750); IKBKG (NEMO) in incontinentia pigmenti (OMIM 308300); PHEX in X-linked hypophosphataemic rickets (OMIM 307800); OFD1 in oral-facial-digital syndrome type 1 (OMIM 311200). See x-linked dominant pedigree for a worked pedigree.

Y-linked

Y-linked (holandric) inheritance is rare and easy to recognise. The condition is transmitted exclusively from father to son: every son of an affected father is affected, and no daughter is ever affected. The Y chromosome carries fewer than a hundred protein-coding genes and most known Y-linked conditions are male-infertility phenotypes (AZF region deletions). Strict Y-linked single-locus disease beyond infertility is unusual.

Mitochondrial

Mitochondrial DNA is transmitted maternally because mitochondria in the zygote are overwhelmingly of maternal origin (paternal mitochondria are degraded shortly after fertilisation). Diagnostic features:

Maternal transmission only. An affected father cannot transmit a mitochondrial condition to any offspring.
An affected mother transmits to all her children, but with variable severity.
Heteroplasmy — the proportion of mutant to wild-type mitochondrial genomes within an individual cell, tissue, or person — varies between siblings and across tissues, producing variable expressivity within a sibship.
A mitochondrial condition typically affects energy-demanding tissues (brain, muscle, retina, cochlea) preferentially.

Worked examples: Leber hereditary optic neuropathy (LHON, MT-ND1/4/6, OMIM 535000); MELAS (MT-TL1, OMIM 540000); mitochondrial DNA-encoded forms of non-syndromic deafness (MT-RNR1). See mitochondrial inheritance pedigree for the pedigree pattern.

Imprinting and uniparental disomy

Imprinting is the parent-of-origin-specific silencing of one of the two parental alleles at a locus, established by differential methylation of regulatory elements during gametogenesis. The textbook locus is the 15q11-q13 imprinted cluster. Reik and Walter's review (Nature Reviews Genetics 2:21, 2001, PMID 11253064) is a standard reference.

Prader-Willi syndrome (OMIM 176270) results from loss of expression of paternally inherited genes in the 15q11-q13 region (including SNRPN and the SNORD116 snoRNA cluster). Mechanisms: paternal 15q11-q13 deletion (~70%), maternal uniparental disomy 15 (~25%), imprinting-centre defect (~5%).
Angelman syndrome (OMIM 105830) results from loss of expression of the maternally inherited copy of UBE3A in 15q11-q13. Mechanisms: maternal 15q11-q13 deletion (~70%), paternal uniparental disomy 15 (~5%), imprinting-centre defect (~5%), UBE3A point mutation (~10%).
Beckwith-Wiedemann syndrome (OMIM 130650) involves the 11p15.5 imprinted region (IGF2, H19, CDKN1C, KCNQ1OT1) and presents with overgrowth, macroglossia, and a raised prior of embryonal tumours.
Russell-Silver syndrome involves the same 11p15.5 region with the opposite epigenetic configuration (OMIM 180860).

Uniparental disomy (UPD) is the inheritance of both copies of a chromosome (or chromosome segment) from a single parent. UPD becomes phenotype-relevant when the chromosome carries an imprinted region (giving rise to Prader-Willi or Angelman by UPD, as above) or when it converts a heterozygous parent into a homozygous offspring at a recessive locus on that chromosome (so-called isodisomy). Robertsonian translocations and trisomy rescue are the main mechanisms by which UPD arises. See imprinting and UPD pedigree for the pedigree-level features.

Anticipation, two hits, and locus heterogeneity

Anticipation — earlier age of onset and / or greater severity in successive generations — is the hallmark of trinucleotide-repeat disorders. The molecular basis is meiotic instability of the repeat: paternal transmission of HTT CAG repeats produces the largest expansions and explains the classical observation that paternally inherited Huntington presents earlier than maternally inherited. The two-hit hypothesis (Knudson 1971, PNAS 68:820, PMID 5279523) explains the dominant inheritance of cancer-predisposition syndromes (retinoblastoma was the original example, with RB1) by positing that the inherited variant is the first hit and that a somatic event in the affected tissue is the second. Locus heterogeneity — the same phenotype produced by variants at different loci — is the rule rather than the exception: hereditary non-syndromic deafness has more than 100 known loci (DFNA, DFNB, DFNX series), retinitis pigmentosa has more than 80 loci, and the "BRCAX" cancer-predisposition phenotype is the explicit acknowledgement that not every familial breast / ovarian / pancreatic cancer cluster maps to BRCA1 or BRCA2.

When the pattern does not fit

Real pedigrees frequently fail to match a single textbook pattern. Reduced penetrance, variable expressivity, age-dependent penetrance, de novo events, germline mosaicism, X-inactivation skewing, locus heterogeneity, and phenocopies all contribute. The next page in this pillar — pedigree analysis and variable expression — covers each of these explicitly, including the standard Bayesian arithmetic for refining a carrier probability given a non-textbook pedigree.

Evagene is an academic, research, and educational pedigree modelling platform; outputs from the calculators above are illustrative and for educational and research purposes only.

Key references

Mendel G. 1866. Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brünn 4:3-47. Biodiversity Heritage Library.
Morgan TH. 1910. Sex limited inheritance in Drosophila. Science 32:120-122. JSTOR 1635471.
Knudson AG. 1971. Mutation and cancer: statistical study of retinoblastoma. PNAS 68:820-823. PMID 5279523.
Reik W, Walter J. 2001. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21-32. PMID 11253064.
Online Mendelian Inheritance in Man (OMIM). omim.org.
GeneReviews. NIH/NCBI Bookshelf. ncbi.nlm.nih.gov/books/NBK1116.