Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene.

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

"Something is just not right with my hearing": early experiences of adults living with hearing loss.

OBJECTIVE: To understand the psychosocial process of how adults experience hearing loss; specifically, their readiness to accept that they may have hearing loss, and the challenges and coping strategies associated with it. DESIGN: A grounded theory methodology guided the research. A patient-orientated research approach informed the study. Thirty-nine individual interviews and six focus groups were completed. STUDY SAMPLE: Participants included 68 individuals aged 50 years and older with self-reported hearing loss living in Newfoundland and Labrador. RESULTS: The theoretical construct, 'Realising that something is just not quite right with my hearing' captured individuals' experiences as they gradually awakened to the fact that they had hearing loss. Three categories describe the process: (1) Rationalising suspicions, (2) Managing the invisible and (3) Reaching a turning point. CONCLUSIONS: Many individuals do not recognise hearing loss in its early stages, although they may be already experiencing its negative effects. It is important to identify motivators to engage individuals as early as possible in their hearing health. Taking a proactive approach to hearing health can help mitigate the potential negative outcomes of hearing loss.

Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss.

BACKGROUND: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade. METHODS: Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss. RESULTS: In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688*), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs*6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome. CONCLUSION: These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.

Characterising and justifying sample size sufficiency in interview-based studies: systematic analysis of qualitative health research over a 15-year period.

BACKGROUND: Choosing a suitable sample size in qualitative research is an area of conceptual debate and practical uncertainty. That sample size principles, guidelines and tools have been developed to enable researchers to set, and justify the acceptability of, their sample size is an indication that the issue constitutes an important marker of the quality of qualitative research. Nevertheless, research shows that sample size sufficiency reporting is often poor, if not absent, across a range of disciplinary fields. METHODS: A systematic analysis of single-interview-per-participant designs within three health-related journals from the disciplines of psychology, sociology and medicine, over a 15-year period, was conducted to examine whether and how sample sizes were justified and how sample size was characterised and discussed by authors. Data pertinent to sample size were extracted and analysed using qualitative and quantitative analytic techniques. RESULTS: Our findings demonstrate that provision of sample size justifications in qualitative health research is limited; is not contingent on the number of interviews; and relates to the journal of publication. Defence of sample size was most frequently supported across all three journals with reference to the principle of saturation and to pragmatic considerations. Qualitative sample sizes were predominantly - and often without justification - characterised as insufficient (i.e., 'small') and discussed in the context of study limitations. Sample size insufficiency was seen to threaten the validity and generalizability of studies' results, with the latter being frequently conceived in nomothetic terms. CONCLUSIONS: We recommend, firstly, that qualitative health researchers be more transparent about evaluations of their sample size sufficiency, situating these within broader and more encompassing assessments of data adequacy. Secondly, we invite researchers critically to consider how saturation parameters found in prior methodological studies and sample size community norms might best inform, and apply to, their own project and encourage that data adequacy is best appraised with reference to features that are intrinsic to the study at hand. Finally, those reviewing papers have a vital role in supporting and encouraging transparent study-specific reporting.

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect.

Genetic isolates provide unprecedented opportunities to identify pathogenic mutations and explore the full natural history of clinically heterogeneous phenotypes such as hearing loss. We noticed a unique audioprofile, characterized by prelingual and rapid deterioration of hearing thresholds at frequencies >0.5 kHz in several adults from unrelated families from the island population of Newfoundland. Targeted serial Sanger sequencing of probands for deafness alleles (n = 23) that we previously identified in this founder population was negative. Whole exome sequencing in four members of the largest family (R2010) identified a CLDN14 (DFNB29) variant [c.488C>T; p. (Ala163Val)], likely pathogenic, sensorineural hearing loss, autosomal recessive. Although not associated with deafness or disease, CLDN14 p.(Ala163Val) has been previously reported as a variant of uncertain significance (VUS). Targeted sequencing of 169 deafness probands identified one homozygote and one heterozygous carrier. Genealogical studies, cascade sequencing and haplotype analysis across four unrelated families showed all subjects with the unique audioprofile (n = 12) were also homozygous for p.(Ala163Val) and shared a 1.4 Mb DFNB29-associated haplotype on chromosome 21. Most significantly, sequencing 175 population controls revealed 1% of the population are heterozygous for CLDN14 p.(Ala163Val), consistent with a major founder effect in Newfoundland. The youngest CLDN14 [c.488C>T; p.(Ala163Val)] homozygote passed newborn screening and had normal hearing thresholds up to 3 years of age, which then deteriorated to a precipitous loss >1 kHz during the first decade. Our study suggests that genetic testing may be necessary to identify at-risk children in time to prevent speech, language and developmental delay.

Technology-assisted self-testing and management of oral anticoagulation therapy: a qualitative patient-focused study.

BACKGROUND: Oral anticoagulation therapy requires regular blood testing to ensure therapeutic levels are maintained and excessive bleeding/clotting is avoided. Technology-assisted self-testing and management is seen as one of the key areas in which quality of care can be improved whilst reducing costs. Nevertheless, levels of patient engagement in self-testing and management remain low. To date, little research emphasis has been placed on understanding the patients' perspectives for low engagement. The typical approach adopted by healthcare providers is to provide patient education programmes, with the expectation that individual patients will change their behaviour and adopt new self-care strategies. However, if levels of patient engagement are to be increased, healthcare providers must also develop a better understanding of how their clinical service provision is perceived by patients and make adaptations. OBJECTIVE: To explore patient views, needs and expectations of an anticoagulation service and the self-testing and management services provided. METHODS: Interviews were conducted with 17 patients who currently engage in international normalised ratio (INR) self-testing and management. Thematic coding and analysis were carried out on the interview transcripts. RESULTS: Four high-level themes emerged from interviews: (i) role of clinic, (ii) motivations for self-testing, (iii) managing INR and (iv) trust. The clinic was seen as adding value in terms of specifying testing frequency, dosage profiles and calibrating equipment. Prompt communication from clinic to patient was also valued, although more personalised/real-time communication would help avoid feelings of isolation. Patients felt more in control as self-tester/managers and often took decisions about treatment adjustments themselves. However, some also manipulated their own test results to avoid 'unnecessary' interventions. CONCLUSIONS AND RECOMMENDATIONS: More personalised/real-time communication, pragmatic and collaborative patient-clinician partnerships and recognition of expert patient knowledge and expertise are needed if increased levels of engagement with self-testing and management service provision is to be realised.

Perceived economic burden associated with an inherited cardiac condition: a qualitative inquiry with families affected by arrhythmogenic right ventricular cardiomyopathy.

PURPOSE: Significant gaps remain in the literature on the economic burden of genetic illness. We explored perceived economic burden associated with one inherited cardiac condition, arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: Semistructured interviews were held with individuals from families affected by ARVC. Data on the perceived financial and economic impacts of ARVC were used to identify emerging categories and themes using the method of constant comparison. RESULTS: Data analysis revealed four themes that described participants' perceptions of the economic impact ARVC had on them and their families: (i) economic impact during childhood, (ii) impact on current and future employment, (iii) impact on current and future financial well-being, and (iv) no perceived economic impact. CONCLUSIONS: This study is the first to explore the economic burden of ARVC from the perspective of affected families. It revealed a number of perceived burdens, from employment and career choices to worry about insurance for self and children, decreased household spending, and the need for childhood employment. Findings highlight potential areas of discussion for genetic counseling sessions, as well as areas for future research.Genet Med 18 6, 584-592.

Relationships between sleep apnea, cardiovascular disease risk factors, and aortic pulse wave velocity over 18 years: the Wisconsin Sleep Cohort.

PURPOSE: The purpose of this study is to determine if apnea-hypopnea index (AHI) severity predicts future aortic pulse wave velocity (PWV) in the Wisconsin Sleep Cohort. METHODS: Applanation tonometry was used to derive carotid-to-femoral PWV a mean of 18 years (standard deviation 4) after overnight polysomnography. Multivariable regression models were created to describe prospective associations between baseline AHI and future PWV. RESULTS: The 618 adults were mean 65 (7) years old (55 % male) with a mean body mass index of 31 (7) kg/m(2) at the tonometry visit. Mean baseline AHI was 4.6 (9.7) events/h. In multiple linear regression models adjusted for age (ß = 0.13/year, standard error [SE] = 0.01, p < 0.001) and sex, higher log10AHI (ß = 0.43/events/h, SE = 0.18, p = 0.02) was associated with PWV. After adjustment for waist circumference (ß = 0.01/cm, SE = 0.01, p = 0.05) and height, the association between baseline log10AHI and future PWV was not statistically significant (p = 0.11), although the association with age persisted unchanged. Addition of covariates such as smoking status (current smoker ß = 0.66, SE = 0.22, p = 0.002), diabetes mellitus status (ß = 2.89, SE = 0.59, p < 0.001), and systolic blood pressure (BP, ß = 0.03/mmHg, SE = 0.01, p < 0.001) did not change the association. AHI did not interact with age or smoking status to predict PWV. A secondary analysis of nocturnal oxygen saturation parameters in 517 participants, 9 (2) years prior also did not show any significant relationships with future PWV. CONCLUSIONS: The prospective association between AHI and PWV is confounded by body size and influenced by smoking, diabetes mellitus, and BP. Weight management, BP control, and smoking cessation may help prevent arterial stiffening associated with obstructive sleep apnea.

The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified. METHODS AND RESULTS: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls. CONCLUSION: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.

Minimal nocturnal oxygen saturation predicts future subclinical carotid atherosclerosis: the Wisconsin sleep cohort.

Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO2 ) and cardiovascular disease (CVD) risk factors with carotid intima-media thickness (IMT) and plaques. We used data on 689 Wisconsin sleep cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (SD) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B-mode ultrasound. Bilateral common, bifurcation and internal carotid artery segments were evaluated for plaque score. Participants (8) were aged 56 years (55% male); 32% had hypertension and mean body mass index (BMI) was 31 (7) kg m(2). Mean and minimum nocturnal SaO2 were 95% (2) and 86% (7), respectively. Mean percentage sleep time with SaO2 < 90% was 2% (8). Both mean (odds ratio [OR]: 0.60 lower plaque count per 5% higher mean SaO2, 95% confidence interval [CI]: 0.38-0.96, P = 0.033) and minimum SaO2 (OR: 0.88 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.80-0.97, P = 0.013) predicted carotid plaque score after adjusting for age, sex and BMI. Minimum SaO2 predicted future plaque score after adding adjustment for traditional CVD risk factors (OR: 0.90 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.81-0.99, P = 0.038). Mean SaO2 was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO2 is an independent predictor of future carotid plaque burden. Other nocturnal SaO2 parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors.

Obstructive sleep apnea is associated with future subclinical carotid artery disease: thirteen-year follow-up from the Wisconsin sleep cohort.

OBJECTIVE: To determine the longitudinal associations between obstructive sleep apnea, carotid artery intima-media thickness (IMT), and plaque. APPROACH AND RESULTS: This is a population-based, prospective cohort study conducted from July, 1989, to November, 2012, on 790 randomly selected Wisconsin residents who completed a mean of 3.5 (range, 1-6) polysomnograms during the study period. Obstructive sleep apnea was characterized by the apnea-hypopnea index (AHI, events/h). Common carotid artery IMT and plaque were assessed by B-mode ultrasound. The mean (SD) time from the first polysomnograms to carotid ultrasound was 13.5 (3.6) years. Multivariable regression models were created to estimate the independent associations of baseline and cumulative obstructive sleep apnea exposure with subsequent carotid IMT and plaque. At baseline, the mean age of participants was 47.6 (7.7) years (55% men, 97% white). AHI was 4.4 (9.0) events/h (range, 0-97); 7% had AHI >15 events/h. Carotid IMT was 0.755 (0.161) mm; 63% had plaque. Adjusting for age, sex, body mass index, systolic blood pressure, smoking, and use of lipid-lowering, antihypertensive, and antidiabetic medications, baseline AHI independently predicted future carotid IMT (ß=0.027 mm/unit log10[AHI+1]; P=0.049), plaque presence (odds ratio, 1.55 [95% confidence intervals, 1.02-2.35]; P=0.041) and plaque score (odds ratio, 1.30 [1.05-1.61]; P=0.018). In cumulative risk factor-adjusted models, AHI independently predicted future carotid plaque presence (P=0.012) and score (P=0.039), but not IMT (P=0.608). CONCLUSIONS: Prevalent obstructive sleep apnea is independently associated with increased carotid IMT and plaque more than a decade later, indicating increased future cardiovascular disease risk.

Obstructive sleep apnea during REM sleep and hypertension. results of the Wisconsin Sleep Cohort.

RATIONALE: Obstructive sleep apnea (OSA) is associated with hypertension. OBJECTIVES: We aimed to quantify the independent association of OSA during REM sleep with prevalent and incident hypertension. METHODS: We included adults enrolled in the longitudinal community-based Wisconsin Sleep Cohort Study with at least 30 minutes of REM sleep obtained from overnight in-laboratory polysomnography. Studies were repeated at 4-year intervals to quantify OSA. Repeated measures logistic regression models were fitted to explore the association between REM sleep OSA and prevalent hypertension in the entire cohort (n = 4,385 sleep studies on 1,451 individuals) and additionally in a subset with ambulatory blood pressure data (n = 1,085 sleep studies on 742 individuals). Conditional logistic regression models were fitted to longitudinally explore the association between REM OSA and development of hypertension. All models controlled for OSA events during non-REM sleep, either by statistical adjustment or by stratification. MEASUREMENTS AND MAIN RESULTS: Fully adjusted models demonstrated significant dose-relationships between REM apnea-hypopnea index (AHI) and prevalent hypertension. The higher relative odds of prevalent hypertension were most evident with REM AHI greater than or equal to 15. In individuals with non-REM AHI less than or equal to 5, a twofold increase in REM AHI was associated with 24% higher odds of hypertension (odds ratio, 1.24; 95% confidence interval, 1.08-1.41). Longitudinal analysis revealed a significant association between REM AHI categories and the development of hypertension (P trend = 0.017). Non-REM AHI was not a significant predictor of hypertension in any of the models. CONCLUSIONS: Our findings indicate that REM OSA is cross-sectionally and longitudinally associated with hypertension. This is clinically relevant because treatment of OSA is often limited to the first half of the sleep period leaving most of REM sleep untreated.

HEADROOM APPROACH TO DEVICE DEVELOPMENT: CURRENT AND FUTURE DIRECTIONS.

OBJECTIVES: The headroom approach to medical device development relies on the estimation of a value-based price ceiling at different stages of the development cycle. Such price-ceilings delineate the commercial opportunities for new products in many healthcare systems. We apply a simple model to obtain critical business information as the product proceeds along a development pathway, and indicate some future directions for the development of the approach. METHODS: Health economic modelling in the supply-side development cycle for new products. RESULTS: The headroom can be used: initially as a 'reality check' on the viability of the device in the healthcare market; to support product development decisions using a real options approach; and to contribute to a pricing policy which respects uncertainties in the reimbursement outlook. CONCLUSIONS: The headroom provides a unifying thread for business decisions along the development cycle for a new product. Over the course of the cycle attitudes to uncertainty will evolve, based on the timing and manner in which new information accrues. Within this framework the developmental value of new information can justify the costs of clinical trials and other evidence-gathering activities. Headroom can function as a simple shared tool to parties in commercial negotiations around individual products or groups of products. The development of similar approaches in other contexts holds promise for more rational planning of service provision.

Association between asthma and risk of developing obstructive sleep apnea.

IMPORTANCE: Obstructive sleep apnea (OSA) is more common among patients with asthma; whether asthma is associated with the development of OSA is unknown. OBJECTIVE: To examine the prospective relationship of asthma with incident OSA. DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective epidemiologic study (the Wisconsin Sleep Cohort Study) beginning in 1988. Adult participants were recruited from a random sample of Wisconsin state employees to attend overnight polysomnography studies at 4-year intervals. Asthma and covariate information were assessed during polysomnography studies through March 2013. Eligible participants were identified as free of OSA (apnea-hypopnea index [AHI] of <5 events/h and not treated) by 2 baseline polysomnography studies. There were 1105 4-year follow-up intervals provided by 547 participants (52% women; mean [SD] baseline age, 50 [8] years). EXPOSURES: Questionnaire-assessed presence and duration of self-reported physician-diagnosed asthma. MAIN OUTCOMES AND MEASURES: The associations of presence and duration of asthma with 4-year incidences of both OSA (AHI of ≥5 or positive airway pressure treatment) and OSA concomitant with habitual daytime sleepiness were estimated using repeated-measures Poisson regression, adjusting for confounders. RESULTS: Twenty-two of 81 participants (27% [95% CI, 17%-37%]) with asthma experienced incident OSA over their first observed 4-year follow-up interval compared with 75 of 466 participants (16% [95% CI, 13%-19%]) without asthma. Using all 4-year intervals, participants with asthma experienced 45 cases of incident OSA during 167 4-year intervals (27% [95% CI, 20%-34%]) and participants without asthma experienced 160 cases of incident OSA during 938 4-year intervals (17% [95% CI, 15%-19%]); the corresponding adjusted relative risk (RR) was 1.39 (95% CI, 1.06-1.82), controlling for sex, age, baseline and change in body mass index, and other factors. Asthma was also associated with new-onset OSA with habitual sleepiness (RR, 2.72 [95% CI, 1.26-5.89], P = .045). Asthma duration was related to both incident OSA (RR, 1.07 per 5-year increment in asthma duration [95% CI, 1.02-1.13], P = .01) and incident OSA with habitual sleepiness (RR, 1.18 [95% CI, 1.07-1.31], P = .02). CONCLUSIONS AND RELEVANCE: Asthma was associated with an increased risk of new-onset OSA. Studies investigating the mechanisms underlying this association and the value of periodic OSA evaluation in patients with asthma are warranted.

Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.

AIMS: Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland. METHODS AND RESULTS: Bidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry. CONCLUSION: Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation.

APOE-ε4 is not associated with pure-tone hearing thresholds, visual acuity or cognition, cross-sectionally or over 3 years of follow up in the Canadian Longitudinal Study on Aging.

INTRODUCTION: Hearing loss and diminished visual acuity are associated with poorer cognition, but the underlying mechanisms are not understood. The apolipoprotein (APOE) ε4 allelic variant may drive the associations. We tested whether APOE-ε4 allele count (0, 1, or 2) was associated with declines in memory, executive function, pure-tone hearing threshold averages, and pinhole-corrected visual acuity among participants in the Canadian Longitudinal Study on Aging (CLSA). METHODS: Multivariable linear mixed regression models were utilized to assess associations between APOE-ε4 allele count and each of the outcome variables. For each main effects model, interactions between APOE-ε4 and sex and age group (45-54-, 55-64-, 65-74-, and 75-85 years) respectively, were analyzed. RESULTS: Significant associations were not observed in main effects models. Models including APOE-ε4 * age (but not APOE-ε4 * sex) interaction terms better fit the data compared to main effects models. In age group-stratified models, however, there were minimal differences in effect estimates according to allele count. CONCLUSION: APOE-ε4 allele count does not appear to be a common cause of sensory-cognitive associations in this large cohort.

A novel deletion in SMPX causes a rare form of X-linked progressive hearing loss in two families due to a founder effect.

X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.

Increased prevalence of sleep-disordered breathing in adults.

Sleep-disordered breathing is a common disorder with a range of harmful sequelae. Obesity is a strong causal factor for sleep-disordered breathing, and because of the ongoing obesity epidemic, previous estimates of sleep-disordered breathing prevalence require updating. We estimated the prevalence of sleep-disordered breathing in the United States for the periods of 1988-1994 and 2007-2010 using data from the Wisconsin Sleep Cohort Study, an ongoing community-based study that was established in 1988 with participants randomly selected from an employed population of Wisconsin adults. A total of 1,520 participants who were 30-70 years of age had baseline polysomnography studies to assess the presence of sleep-disordered breathing. Participants were invited for repeat studies at 4-year intervals. The prevalence of sleep-disordered breathing was modeled as a function of age, sex, and body mass index, and estimates were extrapolated to US body mass index distributions estimated using data from the National Health and Nutrition Examination Survey. The current prevalence estimates of moderate to severe sleep-disordered breathing (apnea-hypopnea index, measured as events/hour, ≥15) are 10% (95% confidence interval (CI): 7, 12) among 30-49-year-old men; 17% (95% CI: 15, 21) among 50-70-year-old men; 3% (95% CI: 2, 4) among 30-49-year-old women; and 9% (95% CI: 7, 11) among 50-70 year-old women. These estimated prevalence rates represent substantial increases over the last 2 decades (relative increases of between 14% and 55% depending on the subgroup).