The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands
EUROPEAN JOURNAL OF HUMAN GENETICS
Authors: Seco, Celia Zazo; Wesdorp, Mieke; Feenstra, Ilse; Pfundt, Rolph; Hehir-Kwa, Jayne Y.; Lelieveld, Stefan H.; Castelein, Steven; Gilissen, Christian; de Wijs, Ilse J.; Admiraal, Ronald J. C.; Pennings, Ronald J. E.; Kunst, Henricus P. M.; van de Kamp, Jiddeke M.; Tamminga, Saskia; Houweling, Arjan C.; Plomp, Astrid S.; Maas, Saskia M.; Gans, Pia A. M. de Koning; Kant, Sarina G.; de Geus, Christa M.; Frints, Suzanna G. M.; Vanhoutte, Els K.; van Dooren, Marieke F.; van den Boogaard, Marie-Jose H.; Scheffer, Hans; Nelen, Marcel; Kremer, Hannie; Hoefsloot, Lies; Schraders, Margit; Yntema, Helger G.
Abstract
Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.
Lights and Shadows in the Genetics of Syndromic and Non-Syndromic Hearing Loss in the Italian Population
GENES
Authors: Morgan, Anna; Lenarduzzi, Stefania; Spedicati, Beatrice; Cattaruzzi, Elisabetta; Murru, Flora Maria; Pelliccione, Giulia; Mazza, Daniela; Zollino, Marcella; Graziano, Claudio; Ambrosetti, Umberto; Seri, Marco; Faletra, Flavio; Girotto, Giorgia
Abstract
Hearing loss (HL), both syndromic (SHL) and non-syndromic (NSHL), is the most common sensory disorder, affecting similar to 460 million people worldwide. More than 50% of the congenital/childhood cases are attributable to genetic causes, highlighting the importance of genetic testing in this class of disorders. Here we applied a multi-step strategy for the molecular diagnosis of HL in 125 patients, which included: (1) an accurate clinical evaluation, (2) the analysis of GJB2, GJB6, and MT-RNR1 genes, (3) the evaluation STRC-CATSPER2 and OTOA deletions via Multiplex Ligation Probe Amplification (MLPA), (4) Whole Exome Sequencing (WES) in patients negative to steps 2 and 3. Our approach led to the characterization of 50% of the NSHL cases, confirming both the relevant role of the GJB2 (20% of cases) and STRC deletions (6% of cases), and the high genetic heterogeneity of NSHL. Moreover, due to the genetic findings, 4% of apparent NSHL patients have been re-diagnosed as SHL. Finally, WES characterized 86% of SHL patients, supporting the role of already know disease-genes. Overall, our approach proved to be efficient in identifying the molecular cause of HL, providing essential information for the patients' future management.
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