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Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant pigmentary genodermatosis characterized by mixed hyperpigmented and hypopigmented macules on the dorsal aspects of hands and feet, often manifesting in infancy or early childhood. The condition exhibits full penetrance with considerable intra-familial phenotypic variability but distinctive acral distribution without systemic involvement. Clinical diagnosis is established by the characteristic mottled lesions and family history.
Genetic studies have unequivocally identified heterozygous pathogenic variants in the ADAR gene (HGNC:225) as the cause of DSH. Over 200 distinct ADAR1 variants—including missense, nonsense, splice-site, frameshift, and nonstop mutations—have been reported in more than 105 unrelated families, with segregation of these variants in over 100 affected relatives across diverse populations ([PMID:20186421]). The inheritance is autosomal dominant, and no biallelic or autosomal recessive pedigrees for DSH have been substantiated.
Variant spectrum in ADAR1 is broad, encompassing at least 93 unique heterozygous mutations in functional domains. Missense substitutions frequently cluster within the deaminase catalytic region (e.g., c.2879A>G (p.Tyr960Cys)) and dsRNA-binding motifs, while loss-of-function alleles (nonsense, frameshift) undergo nonsense-mediated decay. Founder or recurrent alleles (e.g., p.Arg1155Trp) have been observed across East Asian cohorts but without evidence of a single predominant hotspot.
Functional assays demonstrate that DSH arises via haploinsufficiency of the interferon-inducible p150 ADAR1 isoform. Truncating mutations (e.g., p.Q513X, p.Cys519ValfsTer5) result in mutant-specific mRNA decay and a ~50% reduction in ADAR1 expression in patient lymphocytes, while certain missense alleles exert dominant-negative effects on RNA editing activity ([PMID:16536805]). These findings align with aberrant RNA editing of melanocyte transcripts and dysregulated melanin deposition observed in skin biopsies.
No studies have disputed the ADAR1-DSH association, and all variants identified in DSH patients map to ADAR1 with consistent segregation and functional impact. The breadth of independent reports over two decades establishes a robust genotype-phenotype correlation without conflicting evidence.
In summary, ADAR1 is definitively associated with autosomal dominant DSH, with comprehensive genetic and experimental data supporting a haploinsufficiency mechanism. Genetic testing for ADAR1 variants enables accurate diagnosis, informs genetic counseling, and aids in differential diagnosis from other pigmentary disorders.
Key Take-home: Heterozygous ADAR1 mutations cause definitive autosomal dominant DSH via p150 isoform haploinsufficiency, underpinning clinical genetic testing and counseling.
Gene–Disease AssociationDefinitiveOver 200 ADAR1 variants in >105 unrelated DSH patients across multiple cohorts with consistent autosomal dominant segregation and functional concordance ([PMID:20186421]) Genetic EvidenceStrongCompilation of 203 pathogenic variants from 105 probands; segregation in >100 affected relatives ([PMID:20186421]) Functional EvidenceModerateADAR1 p150 haploinsufficiency demonstrated by mRNA decay and ~50% expression reduction in patients ([PMID:16536805]) |