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

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.

Paediatric Cochlear Implantation in Patients with Waardenburg Syndrome.

Objective: To analyse the benefit of cochlear implantation in young deaf children with Waardenburg syndrome (WS) compared to a reference group of young deaf children without additional disabilities.

Method: A retrospective study was conducted on children with WS who underwent cochlear implantation at the age of 2 years or younger. The post-operative results for speech perception (phonetically balanced standard Dutch consonant-vocal-consonant word lists) and language comprehension (the Reynell Developmental Language Scales, RDLS), expressed as a language quotient (LQ), were compared between the WS group and the reference group by using multiple linear regression analysis.

AGORA, a data- and biobank for birth defects and childhood cancer.

Background: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG.

Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells.

Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.

Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.

Objective: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox).

Study Design: Double-blind follow-up study.

Setting: University hospital.

Similar phenotypes caused by mutations in OTOG and OTOGL.

Objectives: Recently, OTOG and OTOGL were identified as human deafness genes. Currently, only four families are known to have autosomal recessive hearing loss based on mutations in these genes. Because the two genes code for proteins (otogelin and otogelin-like) that are strikingly similar in structure and localization in the inner ear, this study is focused on characterizing and comparing the hearing loss caused by mutations in these genes.

Incidental findings on cone beam computed tomography scans in cleft lip and palate patients.

Objectives: Cone beam computed tomography (CBCT) is frequently used in treatment planning for alveolar bone grafting (ABG) and orthognathic surgery in patients with cleft lip and palate (CLP). CBCT images may depict coincident findings. The aim of this study was to assess the prevalence of incidental findings on CBCT scans in CLP patients.

Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment.

Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.

Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans.

Congenital aural atresia (CAA) can occur as an isolated congenital malformation or in the context of a number of monogenic and chromosomal syndromes. CAA is frequently seen in individuals with an 18q deletion, which is characterized by intellectual disability, reduced white-matter myelination, foot deformities, and distinctive facial features. Previous work has indicated that a critical region for CAA is located in 18q22.

Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations.

In the present study, genotype-phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.

Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment.

In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes.

Proximal symphalangism, hyperopia, conductive hearing impairment, and the NOG gene: 2 new mutations.

Objectives: To report on 2 families with proximal symphalangism syndrome and 2 new NOG gene mutations and to report on the outcomes of exploratory tympanotomy.

Study Design: Retrospective chart study.

Setting: Tertiary referral center.

Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion.

Causes of permanent childhood hearing impairment.

Introduction: The causes of Permanent Childhood Hearing Impairment (PCHI) are often quoted as being hereditary in 50%, acquired in 25%, and unknown in 25% of cases. Interest in the causes of PCHI has grown recently due to increasing diagnostic possibilities. We investigated the evidence for the reported distribution of these causes.

Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction.

We identified overlapping homozygous regions within the DFNB84 locus in a nonconsanguineous Dutch family and a consanguineous Moroccan family with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). The critical region of 3.17 Mb harbored the PTPRQ gene and mouse models with homozygous mutations in the orthologous gene display severe hearing loss.

Mutations in TPRN cause a progressive form of autosomal-recessive nonsyndromic hearing loss.

We performed genome-wide homozygosity mapping in a large consanguineous family from Morocco and mapped the autosomal-recessive nonsyndromic hearing loss (ARNSHL) in this family to the DFNB79 locus on chromosome 9q34. By sequencing of 62 positional candidate genes of the critical region, we identified a causative homozygous 11 bp deletion, c.42_52del, in the TPRN gene in all seven affected individuals.

Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment.

We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb.

[Psychosocial adjustment in children with a cleft lip and/or palate].

Objective: To gain insight into the psychosocial health of children aged 9 to 12 years with a cleft lip and/or palate; to determine the relation between their health and the nature and severity of the cleft as well as other individual characteristics.

Design: Descriptive, cross-sectional study.

Method: Questionnaires completed by parents, teachers and children were used to obtain information about the psychosocial health, nature and severity of the cleft lip and/or palate, and individual characteristics of 80 children.

Results of sonotubometry in testing eustachian tube ventilatory function in children with cleft palate.

Objectives: In previous studies, an updated sonotubometry setup was tested in healthy adults and children to test its validity and reproducibility in the assessment of the ventilatory function of the eustachian tube (ET). The results were promising, but further investigations were needed to confirm the discriminative potential of this sonotubometry setup. Our objective in the present study was to test the discriminative potential of an updated sonotubometry setup in children with cleft palate.

Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome.

CHARGE syndrome is a multiple congenital anomaly syndrome caused by mutations in the CHD7 gene. Mutations in this gene are found in 60-70% of patients suspected of having CHARGE syndrome. However, if only typical CHARGE patients are taken into account, mutations in the CHD7 gene are found in over 90% of cases.

Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability.

CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features.

CHARGE syndrome: relations between behavioral characteristics and medical conditions.

The behaviors and medical problems in 27 persons with CHARGE syndrome were studied, because it was hypothesized that their behavior might be partly dependent on the heterogeneous medical status. With the exception of more tics, cardiac surgery was associated with positive behaviors: less withdrawn behavior, better mood, and a more easy temperament. Tube feeding was also related to positive behavior, since participants with a history of tube feeding showed less intense behavior.

Vestibular deterioration precedes hearing deterioration in the P51S COCH mutation (DFNA9): an analysis in 74 mutation carriers.

Objectives: To analyze cochleovestibular impairment features in P51S COCH mutation carriers (n = 22) in a new, large Dutch family and to compare the results to those obtained in previously identified similar mutation carriers (n = 52). To evaluate age-related features between progressive hearing and vestibular impairment of all mutation carriers (n = 74).

Study Design: Family study.