Autosomal Recessive Inheritance

Autosomal recessive (AR) inheritance requires two pathogenic alleles (one from each parent) for disease expression. Carriers (heterozygotes) are typically unaffected, and affected individuals usually have unaffected parents who are both carriers. The recurrence risk for carrier parents is 25% per pregnancy.

For the carrier-frequency math (Hardy-Weinberg, partner-screen Bayesian updates, consanguinity corrections, worked pedigree examples), see Autosomal Recessive Risk Assessment.

• Horizontal pedigree pattern: Affected individuals appear in a single generation (siblings), not in every generation. Parents are typically unaffected carriers.
• Carrier frequency: Heterozygous carriers are far more common than affected homozygotes. For a disease with frequency 1/10,000, carrier frequency is approximately 1/50 (using Hardy-Weinberg: 2pq).
• Consanguinity: Mating between related individuals increases the probability of homozygosity for rare recessive alleles. The closer the relationship, the greater the risk. First cousins share 1/8 of their genes.
• Pseudodominance: An AR condition mimics a dominant pattern when a homozygous affected individual mates with a carrier, producing affected children in successive generations. More likely in small populations or with consanguinity.
• Compound heterozygosity: An affected individual carries two different pathogenic variants in the same gene (one from each parent). Common in cystic fibrosis: many patients have F508del on one allele and a different variant on the other.
• Founder effect: Certain AR conditions are enriched in specific populations because a small founding group carried the allele (e.g., Tay-Sachs in Ashkenazi Jewish populations, sickle cell disease in populations from malaria-endemic regions).
• Genetic heterogeneity: The same phenotype can result from variants in different genes (locus heterogeneity). For example, hearing loss can be caused by variants in GJB2, SLC26A4, and many other genes.

• Cystic fibrosis (CFTR): Most common lethal AR disorder in Northern European populations; carrier frequency ~1/25; newborn screening available
• Sickle cell disease (HBB): AR with carrier advantage (heterozygote advantage against malaria); carrier frequency ~1/12 in African Americans
• Phenylketonuria (PAH): Classic AR metabolic disorder; treatable with dietary phenylalanine restriction; detected by newborn screening
• Tay-Sachs disease (HEXA): AR lysosomal storage disorder; carrier screening reduced incidence by >90% in Ashkenazi Jewish populations