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oai:repisalud.isciii.es:20.500.12105/225472024-11-28T20:18:32Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Cabanillas, Ruben author Dineiro, Marta author Cifuentes, Guadalupe A author Castillo, David author Pruneda, Patricia C author Alvarez, Rebeca author Sanchez-Duran, Noelia author Capin, Raquel author Plasencia, Ana author Viejo-Diaz, Monica author Garcia-Gonzalez, Noelia author Hernando, Ines author Llorente, Jose L author Reparaz-Andrade, Alfredo author Torreira-Banzas, Cristina author Rosell-Andreo, Jordi author Govea-Callizo, Nancy author Ramon Gomez-Martinez, Justo author Nunez-Batalla, Faustino author Garrote, Jose A author Mazon-Gutierrez, Angel author Costales, Maria author Isidoro-Garcia, Maria author Garcia-Berrocal, Belen author Ordonez, Gonzalo R author Cadinanos, Juan author 2018-07-09 Background: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. Methods: We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations. Results: The analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was > 99.5%, with a specificity > 99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n = 2], USH2A [n = 3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n = 3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n = 3] and Waardenburg [n = 2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n = 2]; partial CDH23 duplication; RDX exon 2 deletion). Conclusions: In the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50-60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes. Cabanillas R, Dineiro M, Cifuentes GA, Castillo D, Pruneda PC, Alvarez R, et al. Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients. BMC Med Genomics. 2018 Jul 09;11:58. 10.1186/s12920-018-0375-5 1755-8794 BMC Medical Genomics http://hdl.handle.net/20.500.13003/9217 29986705 L622972014 2-s2.0-85049990686 https://hdl.handle.net/20.500.12105/22547 437955700001 Hereditary Hearing loss Precision Diagnostics NGS Gene panel Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients