An Italian family with two siblings affected by nonsyndromic sensorineural hearing loss (NSHL) and showing a recessive pattern of transmission was selected for whole-exome next-generation sequencing (NGS). Genomic capture and NGS on a HiSeq 2000 sequencer (Illumina) of the proband lead to the identification of a novel missense mutation within PRPS1. Mutations in this gene, which codes for the phosphoribosylpyrophosphate synthetase 1 (PRS-I) enzyme, were previously demonstrated to cause X-linked syndromic conditions associated with hearing impairment (e.g. Arts syndrome and Charcot-Marie-Tooth disease-5), and, most recently, NSHL in 4 families (DFNX1 locus). The identified mutation segregates with prelingual, bilateral, profound NSHL in the proband’s family. A subsequent screening of the entire PRPS1 gene by Sanger sequencing in 13 additional unrelated probands from NSHL families showing a likely X-linked inheritance pattern led to the discovery of a second missense mutation segregating with pre-lingual hearing impairment. The two novel variants were absent in a cohort of 126 Italian audiologically-tested, normal-hearing controls. Both amino-acid substitutions are predicted to cause a destabilization of the enzyme structure. The impact of both PRPS1 mutations on the function of PRS-I is currently under analysis by measuring the enzyme activity in the patients’ emolysates compared to controls. In conclusion, we provide evidence of the usefulness of whole-exome NGS for the genetic diagnosis of NSHL and we highlight the recurrence of PRPS1 mutations, suggesting that it may represent a major locus for X-linked NSHL to be prioritised in genetic screenings.

Exome sequencing identifies PRPS1 as a major locus for X-linked nonsyndromic hearing loss in the Italian population / M. Robusto, J. Zhang, R. Asselta, J. Liang, X. Liu, P. Primignani, P. Castorina, S. Caccia, U. Ambrosetti, Y. Yin, J. Wang, S. Duga, G. Soldà. ((Intervento presentato al convegno European Human Genetics Conference (ESHG Conference) tenutosi a Nurnberg, Germany nel 2012.

Exome sequencing identifies PRPS1 as a major locus for X-linked nonsyndromic hearing loss in the Italian population

M. Robusto
Primo
;
R. Asselta;S. Caccia;U. Ambrosetti;S. Duga
Penultimo
;
G. Soldà
Ultimo
2012

Abstract

An Italian family with two siblings affected by nonsyndromic sensorineural hearing loss (NSHL) and showing a recessive pattern of transmission was selected for whole-exome next-generation sequencing (NGS). Genomic capture and NGS on a HiSeq 2000 sequencer (Illumina) of the proband lead to the identification of a novel missense mutation within PRPS1. Mutations in this gene, which codes for the phosphoribosylpyrophosphate synthetase 1 (PRS-I) enzyme, were previously demonstrated to cause X-linked syndromic conditions associated with hearing impairment (e.g. Arts syndrome and Charcot-Marie-Tooth disease-5), and, most recently, NSHL in 4 families (DFNX1 locus). The identified mutation segregates with prelingual, bilateral, profound NSHL in the proband’s family. A subsequent screening of the entire PRPS1 gene by Sanger sequencing in 13 additional unrelated probands from NSHL families showing a likely X-linked inheritance pattern led to the discovery of a second missense mutation segregating with pre-lingual hearing impairment. The two novel variants were absent in a cohort of 126 Italian audiologically-tested, normal-hearing controls. Both amino-acid substitutions are predicted to cause a destabilization of the enzyme structure. The impact of both PRPS1 mutations on the function of PRS-I is currently under analysis by measuring the enzyme activity in the patients’ emolysates compared to controls. In conclusion, we provide evidence of the usefulness of whole-exome NGS for the genetic diagnosis of NSHL and we highlight the recurrence of PRPS1 mutations, suggesting that it may represent a major locus for X-linked NSHL to be prioritised in genetic screenings.
Settore BIO/13 - Biologia Applicata
Settore BIO/11 - Biologia Molecolare
Settore MED/32 - Audiologia
European Society of Human Genetics
Exome sequencing identifies PRPS1 as a major locus for X-linked nonsyndromic hearing loss in the Italian population / M. Robusto, J. Zhang, R. Asselta, J. Liang, X. Liu, P. Primignani, P. Castorina, S. Caccia, U. Ambrosetti, Y. Yin, J. Wang, S. Duga, G. Soldà. ((Intervento presentato al convegno European Human Genetics Conference (ESHG Conference) tenutosi a Nurnberg, Germany nel 2012.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/198906
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