title: Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3.
abstract: BACKGROUND
  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, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family.
  
  
  METHODS
  Candidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  Mutations 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.
authors.affiliation: Bioscientia Center for Human Genetics, Konrad Adenauer-Str, 17, Ingelheim 55218, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberger
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mansour
authors.forename: Markus
authors.initials: M
authors.lastname: Nauck
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Christian
authors.initials: C
authors.lastname: Decker
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Hanno Jörn
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D018389:Codon, Nonsense; D005260:Female; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008297:Male; D008994:Monoacylglycerol Lipases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D052245:Usher Syndromes / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C552558:ABHD12 protein, human; D008994:Monoacylglycerol Lipases