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

Orphanet Journal of Rare Diseases

Hanno Jörn Bolz¹  Carsten Bergmann⁵  Inga Ebermann¹  Claudia Dafinger¹  Christian Decker²  Peter Nürnberg³  Gudrun Nürnberg³  Markus Nauck²  Ahmad Mansour⁶  Rima Slim⁴  Tobias Eisenberger² 

[1] Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany;Bioscientia Center for Human Genetics, Konrad Adenauer-Str. 17, Ingelheim 55218, Germany;Cologne Center for Genomics, University of Cologne, Cologne, Germany;Department of Obstetrics and Gynecology, McGill University Health Center, Montreal, Canada;Center for Clinical Research, University Hospital of Freiburg, Freiburg, Germany;Department of Ophthalmology, American University of Beirut, Beirut, Lebanon

关键词: PHARC;    ABHD12;    Retinitis pigmentosa;    Deafness;    Usher syndrome;   

Others  :  864245
DOI  :  10.1186/1750-1172-7-59

 received in 2012-06-11, accepted in 2012-08-29,  发布年份 2012

【 摘 要 】

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.

Conclusion

Mutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (

p

olyneuropathy,

h

earing loss,

a

taxia,

r

etinitis pigmentosa, and early-onset

c

ataract). 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.

【 授权许可】

   
2012 Eisenberger et al.; licensee BioMed Central Ltd.

【 图 表 】

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