Genotype phenotype correlations for hearing impairment: Approaches to management

Hoefsloot, Lies H.; Feenstra, Ilse; Kunst, Henricus P. M.; Kremer, Hannie

doi:10.1111/cge.12339

Cited by 25 publications

(28 citation statements)

References 25 publications

(41 reference statements)

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“…This patient had an incomplete partition of the cochlea and mutations in SLC26A4. 35 We did not find other cases with an identifiable phenotype such as progressive HI with a downsloping audiogram caused by TMPRSS3 mutations, 7,36 and the stable HI with a cookie-bite audiogram configuration caused by mutations in TECTA. 7 This is most likely due to the fact that these genes are generally pretested in patients with these identifiable phenotypes.…”

Section: Discussionmentioning

confidence: 60%

“…This is in agreement with the previously published studies on the involvement of HI genes in other populations. [6][7][8][9][32][33][34]36,[38][39][40] The diagnostic yield of WES targeting a panel of HI-related genes is generally higher than that of single gene testing. Therefore, we recommend to reduce prescreening of single genes to a minimum.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Some exceptions are known, for example, mutations in GJB2 followed by mutations in STRC and MYO15A are the most common causes for arNSHI worldwide. [6][7][8][9] Since many genes contribute to hereditary HI, targeting all or a selection of protein-coding exons in a single experiment, as in WES, might currently be the best option for a comprehensive genetic analysis of HI individuals. The implementation of WES in a diagnostic setting has been much slower than in scientific research due to the relatively low sensitivity of this method in detection of genetic variation in some exonic regions, for example, extremely GC-rich regions, as compared with Sanger sequencing.…”

Section: Introductionmentioning

confidence: 99%

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The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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“…The condition is clinically and genetically extremely heterogeneous, with more than 160 loci identified today. Autosomal dominant NSHI (ADNSHI) shows great variation in age of onset, rate of progression, severity and frequencies affected in contrast to autosomal recessive NSHI (ARNSHI) that is usually congenital/prelingual and non-progressive [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

et al. 2015

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Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXФ). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment.

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“…Besides, 70% of the inherited cases of HL are non-syndromic (nsHL), meaning the symptom is presented isolated. The rest are syndromic accompanied by other signs, as in Usher syndrome (Hoefsloot et al 2014).…”

Section: Etiologymentioning

confidence: 99%

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

García¹

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Gracias también a todo mi grupillo de Philly que tan rápida y cálidamente me recibieron en su cuadrilla. En especial a Berta y Álvaro, por allanarme tanto el camino; y a Alba y Vicky, que desde el primer minuto os desvivisteis por que aprovechara al máximo mi estancia. Many thanks to Dr. Hakonarson and all the CAG members for allowing me the opportunity to learn from such a proficient and nice team during those six months. No me olvido tampoco del resto de amigos que, sólo con interesarse por mi trabajo o darme apoyo moral, también me ayudado durante estos años. Y, por supuesto, gracias a mi familia. A mis abuelos, porque sé que muchas de mis capacidades las he heredado de ellos, y porque sé la enorme ilusión que les habría hecho ser partícipes de este momento. En especial, a mi abuelo Jesús, quien sembró mi interés por la investigación y a quien le hubiese entusiasmado saber que finalmente desarrollé su profesión platónica. A Adrián, mil gracias (y me quedo corta). Es una gran suerte poder compartir las ilusiones e inquietudes del gremio con mi compañero de vida y de vocación. Gracias por sacarme de tantos apuros, porque literalmente sin ti me habría estancado. Gracias por escucharme cuando he necesitado desahogarme, por animarme y aconsejarme, y por disfrutar con mis éxitos. Gracias, en suma, por ser mi cómplice en todo. Gracias, de manera muy profunda, a mis padres, a quienes dedico esta tesis. Por innumerables motivos que, a fin de cuentas y de forma desvirtuada, se reducen a una esencia: por apoyarme siempre en todo, por las oportunidades que me habéis dado, por educarme como lo habéis hecho, y por vuestro desmedido cariño. Porque si he llegado hasta aquí, ha sido por vosotros, y porque si soy quien soy, es por vosotros. Gracias papá, gracias mamá, por ser como sois. Finalmente, mi más sincera gratitud a todos los pacientes y sus familiares que han participado en los estudios. Al fin y al cabo, todo esto es por vosotros. Gracias por vuestra confianza. Quiero creer que nuestro empeño, si no el de otros, acabará traduciéndose en una solución.

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Genotype phenotype correlations for hearing impairment: Approaches to management

Cited by 25 publications

References 25 publications

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

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