Relatedness, Consanguinity, and Coefficient of Inbreeding

Consanguinity is the mating of individuals with a recent common ancestor. It increases the probability that offspring will be homozygous by descent for any allele present in that ancestor, raising the empiric risk of autosomal recessive disease in aggregate by unmasking rare variants. Two coefficients describe the genetics:

• Coefficient of relationship (r): the proportion of alleles two relatives share IBD.
• Coefficient of inbreeding (F): the probability that an individual's two alleles at a randomly chosen locus are identical by descent. For the child of two relatives, F = r/2. F is a genome-wide property, not a disease-specific risk.

Autozygosity is homozygosity by descent: the molecular consequence of inbreeding, visible as runs of homozygosity (ROH) on SNP microarray.

1. Identify the common ancestor(s).
2. Trace all paths from parent 1 up to the common ancestor and back down to parent 2.
3. For each path: F = (1/2)^n, where n = number of links (meioses) in the path.
4. If the common ancestor is themselves inbred, multiply by (1 + F_ancestor).
5. Sum F across all independent paths.

F is NOT a disease risk. It is the probability of autozygosity (homozygosity by descent) at any random locus across the genome. Do not use F (or F × q) to counsel the risk that a consanguineous couple will have a child affected with a specific AR disorder. That is a population-genetics approximation, not a clinical risk figure.

For counseling, use whichever framework actually fits the question:

• Risk of a specific AR disorder with a known pedigree carrier: use standard Mendelian / Bayesian risk based on the actual carrier probabilities of the related parents (treat consanguinity as a structural feature of the pedigree, not as a multiplier on q). Apply F only when justified by the path through a known carrier ancestor.
• Overall risk of any serious AR / birth defect outcome in the offspring of consanguineous parents: use empiric risk estimates (see below). These are derived from cohort data and already incorporate the autozygosity contribution averaged across real disease loci.
• Diagnostic interpretation in an affected child: F predicts the genome-wide fraction in ROH (autozygosity mapping). A homozygous variant inside a large ROH in an affected child of consanguineous parents is strongly supportive of pathogenicity.

• Baseline risk of a major birth defect or early-childhood genetic disease in an outbred population is ~2–3%.
• First-cousin offspring: ~1.7–2% absolute increase, total ~4–6%.
• Incestuous unions (parent-offspring, full sibs): 30–50% of offspring affected by major anomalies or severe disease.
• Risk depends on family history, population background carrier frequencies, and degree of consanguinity.

• Take a detailed three-generation pedigree and ask explicitly about consanguinity; patients often underreport.
• Document the degree of consanguinity and any recurring or undiagnosed disease in the family.
• Offer expanded carrier screening with NGS panels; they catch rare variants that ethnicity-based panels miss.
• In an affected child of consanguineous parents, consider homozygosity mapping (ROH on CMA); a homozygous variant inside a large ROH is strongly supportive of pathogenicity.
• Discuss prenatal diagnosis and PGT when a causative variant is identified.

Consanguinity is common in many regions (Middle East, South Asia, North Africa) where first-cousin marriage rates can exceed 20%. Counseling should be nonjudgmental and respect cultural values while conveying accurate risk information. The elevated risk is real but moderate; most offspring of first cousins are unaffected. Present risk in context; emphasize informed decision-making, not advocacy.