Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees

International audience

A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family

International audience

Non-Syndromic Hearing Impairment in India: High Allelic Heterogeneity among Mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE

Mutations in the autosomal genes TMPRSS3, TMC1, USHIC, CDH23 and TMIE are known to cause hereditary hearing loss. To study the contribution of these genes to autosomal recessive, non-syndromic hearing loss (ARNSHL) in India, we examined 374 families with the disorder to identify potential mutations. We found four mutations in TMPRSS3, eight in TMC1, ten in USHIC, eight in CDH23 and three in TMIE. Of the 33 potentially pathogenic variants identified in these genes, 23 were new and the remaining have been previously reported. Collectively, mutations in these five genes contribute to about one-tenth of ARNSHL among the families examined. New mutations detected in this study extend the allelic heterogeneity of the genes and provide several additional variants for structure-function correlation studies. These findings have implications for early DNA-based detection of deafness and genetic counseling of affected families in the Indian subcontinent.

Chromosome imbalances in syndromic hearing loss

The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.

Non-organic hearing loss: new and confirmed findings

Although non-organic hearing losses are relatively rare, it is important to identify suspicious findings early to be able to administer specific tests, such as objective measurements and specific counseling. In this retrospective study, we searched for findings that were specific ti or typical for non-organic hearing losses. Patient records from a 6 year period (2003-2008) from the University ENT Department of Bern, Switzerland, were reviewed. In this period, 40 subjects were diagnosed with a non-organic hearing loss (22 children, ages 7-16, mean 10.6 years; 18 adults, ages 19-57, mean 39.7 years; 25 females and 15 males). Pure tone audiograms in children and adults showed predominantly sensorineural and frequency-independent hearing losses, mostly in the range of 40-60 dB. In all cases, objective measurements (otoacoustic emissions and/or auditory-evoked potentials) indicated normal or substantially better hearing thresholds than those found in pure tone audiometry. In nine subjects (22.5%; 2 children, 7 adults), hearing aids had been fitted before the first presentation at our center. Six children (27%) had a history of middle ear problems with a transient hearing loss and 11 (50%) knew a person with a hearing loss. Two new and hitherto unreported findings emerged from the analysis: it was observed that a small air-bone gap of 5-20 dB was typical for non-organic hearing losses and that speech audiometry might show considerably poorer results than expected from pure tone audiometry.

Novel OTOF mutations in Brazilian patients with auditory neuropathy

The OTOF gene encoding otoferlin is associated with auditory neuropathy (AN), a type of non-syndromic deafness. We investigated the contribution of OTOF mutations to AN and to non-syndromic recessive deafness in Brazil. A test for the Q829X mutation was carried out on a sample of 342 unrelated individuals with non-syndromic hearing loss, but none presented this mutation. We selected 48 cases suggestive of autosomal recessive inheritance, plus four familial and seven isolated cases of AN, for genotyping of five microsatellite markers linked to the OTOF gene. The haplotype analysis showed compatibility with linkage in 11 families (including the four families with AN). Samples of the 11 probands from these families and from seven isolated cases of AN were selected for an exon-by-exon screening for mutations in the OTOF gene. Ten different pathogenic variants were detected, among which six are novel. Among the 52 pedigrees with autosomal recessive inheritance (including four familial cases of AN), mutations were identified in 4 (7.7%). Among the 11 probands with AN, seven had at least one pathogenic mutation in the OTOF gene. Mutations in the OTOF gene are frequent causes of AN in Brazil and our results confirm that they are spread worldwide. Journal of Human Genetics (2009) 54, 382-385; doi: 10.1038/jhg.2009.45; published online 22 May 2009

Perfil audiológico e genético de pacientes com perda auditiva sensorioneural não sindrônica atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu-Universidade Estadual Paulista

Pós-graduação em Bases Gerais da Cirurgia - FMB

Role of the Mitochondrial Mutations, m. 827A > G and the Novel m. 7462C > T, in the Origin of Hearing Loss

Samples from 30 deaf probands exhibiting features suggestive of syndromic mitochondrial deafness or from families with maternal transmission of deafness were selected for investigation of mutations in the mitochondrial genes MT-RNR1 and MT-TS1. Patients with mutation m. 1555A>G had been previously excluded from this sample. In the MT-RNR1 gene, five probands presented the m. 827A>G sequence variant, of uncertain pathogenicity. This change was also detected in 66 subjects of an unaffected control sample of 306 Brazilian individuals from various ethnic backgrounds. Given its high frequency, we consider it unlikely to have a pathogenic role on hereditary deafness. As to the MT-TS1 gene, one proband presented the previously known pathogenic m. 7472insC mutation and three probands presented a novel variant, m. 7462C>T, which was absent from the same control sample of 306 individuals. Because of its absence in control samples and association with a family history of hearing impairment, we suggest it might be a novel pathogenic mutation.

"Genome-Wide Linkage in a Highly Consanguineous Pedigree Reveals Two Novel Loci on Chromosome 7 for Non-Syndromic Familial Premature Ovarian Failure"

Background: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10–15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. Methodology/Principal Findings: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LODmax of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations. Conclusions/Significance: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function.

TAP deficiency syndrome: chronic rhinosinusitis and conductive hearing loss

Nose-ear-throat manifestations of immunodeficiency disorders represent a diagnostic challenge for clinicians as these diseases often constitute the initial sign for connective disorders or autoimmune disease. The history of chronic rhinosinusitis and conductive hearing loss is often non specific. Therefore attention to an HLA class I deficiency must be considered if the disease has not been diagnosed on routine examination. One of the syndromes is due to a defective TAP complex, the peptide transporter complex associated with antigen presentation. Herein, we report two sisters with TAP-deficiency. The treatment of choice for TAP-deficient patients is conservative.

FAMILY CHARACTERISTICS, STATE PROGRAM EFFECTIVENESS, AND REPORT OF INADEQUATE CARE AMONG FAMILIES OF YOUNG CHILDREN WITH HEARING LOSS

Approximately 1.6 per 1,000 newborns in the U.S. are born with hearing loss. Congenital hearing loss poses a risk to their speech, language, cognitive, and social-emotional development. Early detection and intervention can improve outcomes. Every state has an Early Hearing Detection and Intervention program (EHDI) to promote and track screening, audiological assessments and linkage to early intervention. However, a large percentage of children are “lost to system (LTS),” meaning that they did not receive recommended care or that it was not reported. This study used data from the 2009-2010 National Survey of Children with Special Health Care Needs and data from the 2011 EHDI Hearing Screening and Follow-Up Survey to examine how 1) family characteristics; 2) EHDI program effectiveness, as determined by LTS percentages; and 3) the family conditions of education and poverty are related to parental report of inadequate care. The sample comprised 684 children between the ages of 0 and 5 years with hearing loss. The results indicated that living in states with less effective EHDI programs was associated with an increased likelihood of not receiving early intervention services (EIS) and of reporting poor family-centered communication. Sibling classification was associated with both receipt of EIS and report of unmet need. Single mothers were less likely to report increased difficulties accessing care. Poor and less educated families, assessed separately, who lived in states with less effective EHDI programs, were more likely to report non-receipt of EIS and less likely to report unmet need as compared to similar families living in states with more effective programs. Poor families living in states with less effective programs were more likely to report less coordinated care than were poor families living in states with more effective programs. This study supports the conclusion that both family characteristics and the effectiveness of state programs affect quality of care outcomes. It appears that less effective state programs affect disadvantaged families’ service receipt report more than that of advantaged families. These findings are important because they may provide insights into the development of targeted efforts to improve the system of care for children with hearing loss.

A cross-sectional survey of 5-year-old children with non-syndromic unilateral cleft lip and palate:the Cleft Care UK study. Part 1: background and methodology

OBJECTIVES: We describe the methodology for a major study investigating the impact of reconfigured cleft care in the United Kingdom (UK) 15 years after an initial survey, detailed in the Clinical Standards Advisory Group (CSAG) report in 1998, had informed government recommendations on centralization. SETTING AND SAMPLE POPULATION: This is a UK multicentre cross-sectional study of 5-year-olds born with non-syndromic unilateral cleft lip and palate. Children born between 1 April 2005 and 31 March 2007 were seen in cleft centre audit clinics. MATERIALS AND METHODS: Consent was obtained for the collection of routine clinical measures (speech recordings, hearing, photographs, models, oral health, psychosocial factors) and anthropometric measures (height, weight, head circumference). The methodology for each clinical measure followed those of the earlier survey as closely as possible. RESULTS: We identified 359 eligible children and recruited 268 (74.7%) to the study. Eleven separate records for each child were collected at the audit clinics. In total, 2666 (90.4%) were collected from a potential 2948 records. The response rates for the self-reported questionnaires, completed at home, were 52.6% for the Health and Lifestyle Questionnaire and 52.2% for the Satisfaction with Service Questionnaire. CONCLUSIONS: Response rates and measures were similar to those achieved in the previous survey. There are practical, administrative and methodological challenges in repeating cross-sectional surveys 15 years apart and producing comparable data.

Binang gurri: turning a deaf ear to indigenous hearing loss

Objective: This paper asks whether Indigenous health policies might be improved if governments listened to Indigenous voices, both Australian and those who drafted the Declaration on the Rights of Indigenous Peoples, 2007. Methods: A fundamental tenet of the Declaration, which Australia endorsed in 2009, is respect for Indigenous knowledge and voice. The author analyses legal, cultural and historical sources for evidence of this respect. The metaphorical and empirical framework of the analysis is the epidemic of otitis media among Indigenous children. Results: A survey of Indigenous advice about health clearly demonstrates that access to their land and respect for the diversity of Indigenous cultures should inform health policies. Despite, however, claiming to consult Indigenous peoples, policy-makers have not been listening. In many Indigenous languages not listening, or ‘bad ears’, has connotations of disrespect. Conclusions: By turning a deaf ear to Indigenous knowledge governments are undermining any respect Indigenous peoples may have for them and their policies. A new approach is needed. Implications: The Declaration on the Rights of Indigenous Peoples can provide federal, state and territory governments with benchmarks against which health policy can be developed and implemented. Authentic consultation could restore Indigenous confidence in government policies.

Hearing loss and a supportive tactile signal in a navigation system : effects on driving behavior and eye movements

An on-road study was conducted to evaluate a complementary tactile navigation signal on driving behaviour and eye movements for drivers with hearing loss (HL) compared to drivers with normal hearing (NH). 32 participants (16 HL and 16 NH) performed two preprogrammed navigation tasks. In one, participants received only visual information, while the other also included a vibration in the seat to guide them in the correct direction. SMI glasses were used for eye tracking, recording the point of gaze within the scene. Analysis was performed on predefined regions. A questionnaire examined participant's experience of the navigation systems. Hearing loss was associated with lower speed, higher satisfaction with the tactile signal and more glances in the rear view mirror. Additionally, tactile support led to less time spent viewing the navigation display.