Inheritance Patterns: A Clinical and Board Review Guide

Inheritance patterns matter for both genetic counseling and medical genetics reasoning: they shape recurrence risk, who should be offered testing, and how a result is explained to a family. The patterns below are teaching models. Real families often require condition-specific information, penetrance estimates, and test results before a risk can be given.

If you want a worked pedigree calculation first, start with the pedigree practice guide. For written practice, the free Pedigree Workbook is a companion resource.

Autosomal Dominant (AD) Inheritance

Core features under a simple model:

• An affected heterozygous parent has a 1/2 probability of transmitting the variant with each pregnancy.
• Males and females can be affected.
• A variant can appear in successive generations, but not every dominant condition appears in every generation.
• An unaffected person can carry and transmit a variant when penetrance is reduced or onset is age-related.

Conditions often used to teach AD concepts: Huntington disease, Marfan syndrome, neurofibromatosis type 1, achondroplasia, familial hypercholesterolemia, and some hereditary cancer syndromes such as BRCA1/2-associated cancer.

Important qualifications:

• Penetrance is the proportion of people with a genotype who show the phenotype. An unaffected carrier is possible when penetrance is incomplete.
• Variable expressivity describes different severity among affected people with the same variant.
• Anticipation describes earlier onset or greater severity in successive generations for some repeat-expansion disorders, such as Huntington disease. It is not a general feature of all dominant conditions.
• De novo variants are common in some severe dominant conditions and can explain an affected child with unaffected parents.
• Clinical expression is not identical across sexes. BRCA1/2-associated cancer risk is a clear example: a simple statement that males and females are affected "equally" would be misleading.

Transmission probability and clinical outcome are separate questions. An affected parent may have a 1/2 chance of transmitting a variant, while the chance of clinical disease also depends on penetrance and other factors.

Autosomal Recessive (AR) Inheritance

Core features under a simple model:

• Disease typically requires biallelic pathogenic variants in the same gene. The variants may be homozygous (the same variant on both copies) or compound heterozygous (different pathogenic variants, one on each copy), with the variants in trans where relevant.
• Males and females can be affected.
• Carrier parents are typically unaffected.
• A family may appear to "skip" generations because carriers are unaffected.

Conditions often used to teach AR concepts: cystic fibrosis, sickle cell disease, phenylketonuria, Tay-Sachs disease, spinal muscular atrophy, and GJB2-related hearing loss.

Important qualifications:

• Consanguinity increases the chance that both partners carry the same recessive variant.
• Carrier frequency differs by condition and population. Population labels are approximations, not individual risk estimates.
• Not all recessive disease is caused by two identical variants, and not every variant in a recessive gene is pathogenic.

Recurrence risk table for a simple AR model

This table describes a simplified model with full penetrance and relevant pathogenic variants in the same gene. It is a teaching model, not a substitute for family-specific counseling.

The last row models the unaffected partner as AA or Aa under full penetrance. If an affected partner is also possible, the general affected-child probability is P(partner Aa)/2 + P(partner aa). An unrelated partner is not automatically a noncarrier. If the partner's carrier probability is unknown, incorporate it rather than treating it as zero. For the same recessive condition, aa × AA produces no affected children and all carriers under the simple model; aa × Aa produces a 50% chance of an affected child and a 50% chance of a carrier.

Unaffected sibling of an affected child

For two confirmed carrier parents, the possible offspring genotypes are AA, Aa, aA, and aa. If the sibling is known to be unaffected, aa is excluded. Two of the three remaining outcomes are carriers:

Carrier probability = 2/3

That conditional probability belongs to the unaffected sibling, not to the already confirmed carrier parents. Confirmed carrier parents are carriers. This is the distinction that matters in pedigree questions.

For Aa × Aa, the outcomes are 25% affected, 50% unaffected carriers, and 25% unaffected noncarriers. Both carrier and noncarrier groups are unaffected under this model.

X-Linked Inheritance

X-linked inheritance is often taught as two tidy categories. Real conditions are more variable, and several commonly used examples need condition-specific explanations.

X-Linked Recessive (XLR)

Core features under a simple model:

• Males with a pathogenic variant on their single X chromosome are affected.
• Females with one pathogenic variant are carriers and are often unaffected, but can manifest symptoms due to skewed X-inactivation.
• A carrier mother has a 1/2 chance of transmitting the variant to each child. Sons who inherit it are affected; daughters who inherit it are carriers.
• An affected father does not transmit an X-linked variant to his sons.
• There is no father-to-son transmission of an X-linked variant.

Conditions often used to teach XLR concepts: hemophilia A and B, Duchenne and Becker muscular dystrophy, G6PD deficiency, and color vision deficiency.

Qualification: an affected father's son can still be affected through a maternal contribution or a different cause. The absence of father-to-son transmission applies to the X-linked variant, not to every possible explanation for a similar phenotype in the son.

X-Linked Dominant (XLD)

Core features under a simple model:

• A heterozygous mother has a 50% probability of transmitting the X-linked variant in each pregnancy.
• An affected father transmits the variant to all daughters and no sons under the usual XX/XY model. Whether an inheriting child manifests the condition depends on the disorder and other relevant factors.
• Expression can differ by sex, and male lethality can occur in specific conditions.

Qualification: daughters who inherit a paternal X-linked variant do not invariably have the same clinical outcome. State which parent carries which variant, and distinguish inheriting the variant from manifesting the disorder.

Conditions that do not fit a simple X-linked label

• Fragile X syndrome (FMR1). Inheritance depends on repeat size and parent of origin. Premutation carriers can have different risks than full-mutation carriers, and the phenotype differs by sex. Treating fragile X as a straightforward X-linked recessive or dominant condition obscures the counseling.
• MECP2 duplication syndrome. Inheritance is X-linked, but many mothers who carry the duplication are clinically unaffected heterozygotes. The condition is not a simple "all daughters of affected males are affected" example.
• Incontinentia pigmenti. The disorder is typically male-lethal, but affected males can survive in specific settings, including mosaicism or 47,XXY. Typical male lethality is not an exception-free rule.

The FMR1-related disorders and MECP2 duplication GeneReviews chapters are better starting points than a category label.

Mitochondrial Inheritance

Core features for mtDNA variants:

• Human mitochondrial DNA is ordinarily maternally inherited.
• A mother with a pathogenic mtDNA variant can transmit it to her children, but the outcome is not identical in every child.
• Heteroplasmy — the coexistence of variant and wild-type mtDNA — and tissue distribution influence severity. Higher variant levels are not a universal severity formula across people, tissues, variants, and disorders.
• An affected father does not ordinarily transmit an mtDNA variant to his children.

Conditions often used to teach mitochondrial concepts: MELAS, MERRF, Leber hereditary optic neuropathy, and single large-scale mtDNA deletion syndromes.

Important qualifications:

• Kearns-Sayre syndrome belongs among the single large-scale mtDNA deletion syndromes, which usually arise de novo. It is a poor unqualified example of a multigenerational maternal pedigree.
• Not all mitochondrial disease is mtDNA disease. Many mitochondrial disorders are caused by nuclear genes and follow Mendelian inheritance. A syndrome name alone does not establish maternal inheritance or heteroplasmy.
• A heteroplasmic mother's children are at risk, but transmission of a particular variant and clinical severity are not guaranteed to be identical in every child.

Y-Linked Inheritance

Under an explicit model, a variant on the Y chromosome is transmitted from an affected father to all sons and no daughters. Very few conditions are truly Y-linked.

Y-chromosome infertility is a reproductive-genetics example rather than a simple multigenerational pedigree: variants in the AZF regions can affect spermatogenesis, and the reproductive context matters. Do not imply that ordinary father-to-son transmission of an infertility phenotype is assured.

Pedigree Interpretation: A Framework

When a pedigree appears in a question, work through the information in a consistent order:

1. List affected people and their sex. Note ages and any known diagnoses.
2. Describe the transmission pattern. Vertical and horizontal patterns are clues, not proof.
3. Check for father-to-son transmission. Confirmed transmission of the same causal X-linked allele from father to son would exclude X-linked inheritance for that allele.
4. Look for consanguinity. A loop can raise AR risk, but it does not establish the diagnosis.
5. Consider penetrance, age at onset, mosaicism, and de novo variants. These are limits on a pedigree shortcut, not rare exceptions to ignore.
6. Calculate the probability the question asks for. Name whether you are estimating transmission, carrier status, or clinical disease.

A small family can fit more than one pattern. Visual resemblance alone does not establish that a child inherited the same causal allele from a parent.

Apply inheritance reasoning to your exam preparation

Use the current official ABGC or ABMGG outline to plan your coverage. For each inheritance pattern, practice identifying the relevant family information and calculating the outcome the question asks about.

Continue with pedigree practice and conditional risk, Bayesian risk, and the free Pedigree Workbook.

Selected sources: MedlinePlus inheritance risk assessment; GeneReviews on incontinentia pigmenti and primary mitochondrial disorders; NCI X-linked dominant inheritance. The risk table is an original teaching calculation under the stated model.

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