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In a single three-generation family with mild Liebenberg syndrome, whole-genome sequencing identified a heterozygous 8.5 kb deletion encompassing the non-coding exon and promoter of MACROH2A1. This deletion segregated with a partial arm-to-leg transformation in three affected individuals under an autosomal dominant model (3 probands)[PMID:30711920]. CRISPR-Cas9–engineered mice harboring the orthologous deletion demonstrated ectopic Pitx1 expression in forelimbs and recapitulated the upper limb phenotype by disrupting promoter insulation of the Pen enhancer (functional model)[PMID:30711920].
These data establish promoter loss of MACROH2A1 as a novel mechanism for brachydactyly–elbow wrist dysplasia syndrome and support inclusion of regulatory element analysis in diagnostic workflows. Key take-home: screening of non-coding exons of MACROH2A1 can yield diagnoses in unresolved cases of Liebenberg syndrome.
Gene–Disease AssociationLimitedSingle family with three affected individuals; heterozygous promoter deletion with segregation and functional model Genetic EvidenceLimitedOne family (3 probands), autosomal dominant segregation in 2 relatives supports association Functional EvidenceStrongCRISPR-Cas9 mouse model recapitulates phenotype through loss of promoter insulation |