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Isolated congenital anosmia (ICA) is a rare disorder characterized by a lifelong inability to smell. Multiple independent studies have linked pathogenic variants in CNGA2 to ICA, with evidence spanning detailed case reports and multi‐patient studies. The initial report described a large Iranian family in which five affected members harbored a stop gain mutation, supporting an X‑linked inheritance pattern (PMID:28572688).
In this study, whole exome sequencing identified a pathogenic variant, c.577C>T (p.Arg193Ter), which segregated with the disease in affected family members. In addition, another study identified a similar stop mutation, c.634C>T (p.Arg212Ter), in two affected brothers with ICA, further reinforcing the association (PMID:25156905).
Segregation analysis across these investigations demonstrates that a total of seven affected relatives across distinct families exhibit hemizygosity for the CNGA2 mutations. This consistent pattern across family studies confirms the X‑linked mode of inheritance and strongly implicates CNGA2 in disease causation (PMID:28572688; PMID:25156905).
Functional assessments provide further support; CNGA2 knockout mice display congenital anosmia with abnormal olfactory system physiology. These experimental studies, along with recent candidate gene analyses in larger patient cohorts, are concordant with the human data, underscoring the gene’s critical role in olfaction (PMID:28572688).
Overall, the convergence of strong genetic evidence—delineated by clear segregation of stop gain mutations and corroborative genotype–phenotype correlations—with supportive functional studies places the gene‑disease association in the strong category. The evidence, including data from independent studies exceeding typical ClinGen scoring thresholds, establishes CNGA2 as a reliable diagnostic marker for ICA.
Key take‑home: Comprehensive testing for CNGA2 mutations can aid in the definitive diagnosis of isolated congenital anosmia and may guide clinical management and future therapeutic developments.
Gene–Disease AssociationStrongMultiple independent studies report CNGA2 stop gain mutations with segregation in at least 7 affected relatives across distinct families, supported by both clinical and experimental data (PMID:28572688; PMID:25156905). Genetic EvidenceStrongIdentification of two pathogenic stop mutations—c.577C>T (p.Arg193Ter) and c.634C>T (p.Arg212Ter)—in affected individuals, along with clear X‑linked segregation, firmly establishes the genetic link to ICA. Functional EvidenceModerateFunctional studies, including a CNGA2 knockout mouse model that recapitulates the anosmia phenotype, provide experimental support for the pathogenic role of CNGA2 in olfactory function. |