Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients

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 p...

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Detalles Bibliográficos
Autores: Cabanillas, Ruben, Dineiro, Marta, Cifuentes, Guadalupe A., Castillo, David, Pruneda, Patricia C., Alvarez, Rebeca, Sanchez-Duran, Noelia, Capin, Raquel, Plasencia, Ana, Viejo-Diaz, Monica, Garcia-Gonzalez, Noelia, Hernando, Ines, Llorente, Jose L., Reparaz-Andrade, Alfredo, Torreira-Banzas, Cristina, Rosell-Andreo, Jordi, Govea-Callizo, Nancy, Ramon Gomez-Martinez, Justo, Nunez-Batalla, Faustino, Garrote, Jose A., Mazon-Gutierrez, Angel, Costales, Maria, Isidoro-Garcia, Maria, Garcia-Berrocal, Belen, Ordonez, Gonzalo R., Cadinanos, Juan
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/9217
Acceso en línea:https://hdl.handle.net/20.500.13003/9217
Access Level:acceso abierto
Palabra clave:Middle Aged
Infant
Phenotype
Male
Infant, Newborn
Female
INDEL Mutation
Young Adult
Child
Spain
Adult
Hearing Loss
Humans
Child, Preschool
Adolescent
Genomics
High-Throughput Nucleotide Sequencing
España
Pérdida Auditiva
Recién Nacido
Femenino
Lactante
Adolescente
Masculino
Mutación INDEL
Genómica
Preescolar
Humanos
Persona de Mediana Edad
Adulto Joven
Fenotipo
Secuenciación de Nucleótidos de Alto Rendimiento
Niño
Adulto
Hereditary
Hearing loss
Precision
Diagnostics
NGS
Gene panel
Descripción
Sumario: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.

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