Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.

Autor: Neuhaus C; Bioscientia Center for Human GeneticsIngelheimGermany., Eisenberger T; Bioscientia Center for Human GeneticsIngelheimGermany., Decker C; Bioscientia Center for Human GeneticsIngelheimGermany., Nagl S; Bioscientia Center for Human GeneticsIngelheimGermany., Blank C; Bioscientia Center for Human GeneticsIngelheimGermany., Pfister M; HNO-Praxis SarnenSarnenSwitzerland.; Molecular Genetics, THRCDepartment of OtolaryngologyUniversity of TübingenTübingenGermany., Kennerknecht I; Institute of Human GeneticsWestfälische Wilhelms-UniversitätMünsterGermany., Müller-Hofstede C; Institute of Human GeneticsWestfälische Wilhelms-UniversitätMünsterGermany., Charbel Issa P; Department of OphthalmologyUniversity of BonnBonnGermany.; Center for Rare Diseases Bonn (ZSEB)University of BonnBonnGermany.; Oxford Eye HospitalUniversity of OxfordOxfordUK., Heller R; Institute of Human GeneticsUniversity Hospital of CologneCologneGermany., Beck B; Institute of Human GeneticsUniversity Hospital of CologneCologneGermany., Rüther K; Sankt Gertrauden-KrankenhausBerlinGermany., Mitter D; Institute of Human GeneticsUniversity of Leipzig Hospitals and ClinicsLeipzigGermany., Rohrschneider K; Department of OphthalmologyUniversity of HeidelbergHeidelbergGermany., Steinhauer U; CölbeCölbeGermany., Korbmacher HM; Department of OrthodonticsGiessen and Marburg University Hospital, Marburg CampusMarburgGermany., Huhle D; Praxis für Humangenetik LeipzigLeipzigGermany., Elsayed SM; Medical Genetics CenterCairoEgypt.; Children's HospitalAin Shams UniversityCairoEgypt., Taha HM; Children's HospitalAin Shams UniversityCairoEgypt., Baig SM; Human Molecular Genetics LaboratoryHealth Biotechnology DivisionNational Institute for Biotechnology and Genetic Engineering (NIBGE)FaisalabadPakistan., Stöhr H; Department of Human GeneticsUniversity Medical Center RegensburgRegensburgGermany., Preising M; Department of OphthalmologyJustus-Liebig-University GiessenGiessenGermany., Markus S; MVZ Dr. Staber und Kollegen GmbHRegensburgGermany., Moeller F; Department of Cell and Matrix BiologyInstitute of Zoology, Johannes GutenbergUniversity of MainzMainzGermany., Lorenz B; Department of OphthalmologyJustus-Liebig-University GiessenGiessenGermany., Nagel-Wolfrum K; Department of Cell and Matrix BiologyInstitute of Zoology, Johannes GutenbergUniversity of MainzMainzGermany., Khan AO; Division of Pediatric OphthalmologyKing Khaled Eye Specialist HospitalRiyadhSaudi Arabia.; Eye InstituteCleveland ClinicAbu DhabiUAE., Bolz HJ; Bioscientia Center for Human GeneticsIngelheimGermany.; Institute of Human GeneticsUniversity Hospital of CologneCologneGermany.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2017 Jul 06; Vol. 5 (5), pp. 531-552. Date of Electronic Publication: 2017 Jul 06 (Print Publication: 2017).
DOI: 10.1002/mgg3.312
Abstrakt: Background: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP).
Methods: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome.
Results: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3 , genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome.
Conclusion: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje