Abstract
BackgroundUsher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family.MethodsCandidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing.ResultsUsing a capture array targeting the three identified homozygosity-by-descent regions on chromosomes 1q43-q44, 20p13-p12.2 and 20p11.23-q12, we identified a homozygous nonsense mutation, p.Arg65X, in ABHD12 segregating with the phenotype.ConclusionMutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract). After the identification of the ABHD12 mutation in this family, one patient underwent neurological examination which revealed ataxia, but no polyneuropathy. ABHD12 is not known to be related to the USH protein interactome. The phenotype of our patient represents a variant of PHARC, an entity that should be taken into account as differential diagnosis for USH3. Our study demonstrates the potential of comprehensive genetic analysis for improving the clinical diagnosis.
Highlights
Usher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP)
Usher syndrome (USH) is an autosomal recessive disorder manifesting in about 10% of children with congenital sensorineural hearing impairment, characterized by additional retinitis pigmentosa (RP)
Our study aimed at identifying the causative mutation – and potentially the second USH type 3 (USH3) gene – in this family by homozygosity mapping and targeted next-generation sequencing (NGS)
Summary
Usher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, clinically diagnosed as USH type 3 (USH3). Usher syndrome (USH) is an autosomal recessive disorder manifesting in about 10% of children with congenital sensorineural hearing impairment, characterized by additional retinitis pigmentosa (RP). Our study aimed at identifying the causative mutation – and potentially the second USH3 gene – in this family by homozygosity mapping and targeted next-generation sequencing (NGS). After the identification of a homozygous truncating mutation in a known disease gene, ABHD12, one patient was re-examined and found to display ataxia, reversing the diagnosis to a neurodegenerative disease, PHARC, that is characterized by polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract
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