Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% ...of diagnosed cases. While large deletions involving the gene
STRC
are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss.
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, ...especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.
Copy number variants (CNVs) are a well-recognized cause of genetic disease; however, methods for their identification are often gene-specific, excluded as 'routine' in screens of genetically ...heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. We aimed to incorporate a method for CNV identification as part of our standard analysis pipeline and to determine the contribution of CNVs to genetic hearing loss.
We used targeted genomic enrichment and massively parallel sequencing to isolate and sequence all exons of all genes known to cause NSHL. We completed testing on 686 patients with hearing loss with no exclusions based on type of hearing loss or any other clinical features. For analysis we used an integrated method for detection of single nucleotide changes, indels and CNVs. CNVs were identified using a previously published method that utilizes median read-depth ratios and a sliding-window approach.
Of 686 patients tested, 15.2% (104) carried at least one CNV within a known deafness gene. Of the 38.9% (267) of individuals for whom we were able to determine a genetic cause of hearing loss, a CNV was implicated in 18.7% (50). We identified CNVs in 16 different genes including 7 genes for which no CNVs have been previously reported. CNVs of STRC were most common (73% of CNVs identified) followed by CNVs of OTOA (13% of CNVs identified).
CNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.
Early intervention for newborns who are deaf or hard-of-hearing leads to improved language, communication, and social-emotional outcomes. Universal physiologic newborn hearing screening has been ...widely implemented across the United States with the goal of identifying newborns who are deaf or hard-of-hearing, thereby reducing time to diagnosis and intervention. The current physiologic newborn hearing screen is generally successful in accomplishing its goals but improvements could be made. In the past ten years, genetic testing has emerged as the most important etiological diagnostic test for evaluation of children with deafness and congenital cytomegalovirus has been recognized as a major cause of childhood deafness that may be treatable. A comprehensive newborn hearing screen that includes physiologic, genetic, and cytomegalovirus testing would have multiple benefits, including (1) identifying newborns with deafness missed by the current physiologic screen, (2) providing etiologic information, and (3) possibly decreasing the number of children lost to follow up. We present a framework for integrating limited genetic testing and cytomegalovirus screening into the current physiologic newborn hearing screening. We identify needed areas of research and include an overview of genome sequencing, which we believe will become available over the next decade as a complement to universal physiologic newborn hearing screening.
The past fifteen years has seen a dramatic improvement in our understanding of hearing and hearing loss. Scientists have worked to identify dozens of genes involved in hearing loss and elucidate the ...complex molecular machinery responsible for hearing. At the same time, there have been rapid advances in clinical diagnostic tools including imaging and genetic tests. What this means is that for the first time, for the majority of children with hearing loss, we are able to obtain a diagnosis.
Objective
The survival rate of patients with trisomy 13 and trisomy 18 has increased dramatically over the past two decades. We sought to comprehensively describe the otolaryngologic clinical ...characteristics and procedures required for these patients at our institution.
Methods
We performed algorithmic identification of patients with a diagnosis of trisomy 13 and trisomy 18 for whom the otolaryngology service provided inpatient or outpatient care at our institution between the dates of February 1997 and March 2021.
Results
Of the 47 patients studied, 18 patients had a diagnosis of trisomy 13, and 29 had a diagnosis of trisomy 18. Complete trisomy was present in 44% (8/18) of trisomy 13 patients and 55% (16/29) of trisomy 18 patients. 81% of patients were living at the time of the study. About 94% (44/47) of patients required consultation with another specialty in addition to Otolaryngology. Overall, the most common diagnoses among this cohort were gastroesophageal reflux disease (47%), dysphagia (40%), otitis media (38%), and obstructive sleep apnea (34%). Nearly three‐quarters (74%) of patients studied required an otolaryngologic procedure. The most common surgical procedure was tonsillectomy and/or adenoidectomy. Patients with trisomy 18 were significantly more likely to have external auditory canal stenosis and obstructive sleep apnea whereas patients with trisomy 13 were more likely to have cleft lip and palate.
Conclusions
Patients with a diagnosis of trisomy 13 or 18 often require multidisciplinary management and the range of required care spans the breadth of otolaryngology.
Level of Evidence
4 Laryngoscope, 133:1501–1506, 2023
The survival rate of patients with trisomy 13 and trisomy 18 has increased dramatically over the past two decades. We reviewed all patients diagnosed with trisomy 13 and trisomy 18 and evaluated by the Otolaryngology service at our institution. We identified the most common diagnoses and procedures performed by our specialty.
To evaluate the use of new genetic sequencing techniques for comprehensive genetic testing for hearing loss.
Articles were identified from PubMed and Google Scholar databases using pertinent search ...terms.
Literature search identified 30 studies as candidates that met search criteria. Three studies were excluded, and 8 studies were found to be case reports. Twenty studies were included for review analysis, including 7 studies that evaluated controls and 16 studies that evaluated patients with unknown causes of hearing loss; 3 studies evaluated both controls and patients.
In the 20 studies included in the review analysis, 426 control samples and 603 patients with unknown causes of hearing loss underwent comprehensive genetic diagnosis for hearing loss using massively parallel sequencing. Control analysis showed a sensitivity and specificity >99%, sufficient for clinical use of these tests. The overall diagnostic rate was 41% (range, 10%-83%) and varied based on several factors, including inheritance and prescreening prior to comprehensive testing. There were significant differences in platforms available with regard to the number and type of genes included and whether copy number variations were examined. Based on these results, comprehensive genetic testing should form the cornerstone of a tiered approach to clinical evaluation of patients with hearing loss along with history, physical examination, and audiometry and can determine further testing that may be required, if any.
Comprehensive genetic testing has become the new standard of care for genetic testing for patients with sensorineural hearing loss.
Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large ...multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39 %). Pathogenic variants were found in 49 genes and included missense variants (49 %), large copy number changes (18 %), small insertions and deletions (18 %), nonsense variants (8 %), splice-site alterations (6 %), and promoter variants (<1 %). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.
The assessment of competitive movement demands in team sports has traditionally relied upon global positioning system (GPS) analyses presented as fixed-time epochs (e.g., 5-40 min). More recently, ...presenting game data as a rolling average has become prevalent due to concerns over a loss of sampling resolution associated with the windowing of data over fixed periods. Accordingly, this study compared rolling average (ROLL) and fixed-time (FIXED) epochs for quantifying the peak movement demands of international rugby union match-play as a function of playing position. Elite players from three different squads (n = 119) were monitored using 10 Hz GPS during 36 matches played in the 2014-2017 seasons. Players categorised broadly as forwards and backs, and then by positional sub-group (FR: front row, SR: second row, BR: back row, HB: half back, MF: midfield, B3: back three) were monitored during match-play for peak values of high-speed running (>5 m·s-1; HSR) and relative distance covered (m·min-1) over 60-300 s using two types of sample-epoch (ROLL, FIXED). Irrespective of the method used, as the epoch length increased, values for the intensity of running actions decreased (e.g., For the backs using the ROLL method, distance covered decreased from 177.4 ± 20.6 m·min-1 in the 60 s epoch to 107.5 ± 13.3 m·min-1 for the 300 s epoch). For the team as a whole, and irrespective of position, estimates of fixed effects indicated significant between-method differences across all time-points for both relative distance covered and HSR. Movement demands were underestimated consistently by FIXED versus ROLL with differences being most pronounced using 60 s epochs (95% CI HSR: -6.05 to -4.70 m·min-1, 95% CI distance: -18.45 to -16.43 m·min-1). For all HSR time epochs except one, all backs groups increased more (p < 0.01) from FIXED to ROLL than the forward groups. Linear mixed modelling of ROLL data highlighted that for HSR (except 60 s epoch), SR was the only group not significantly different to FR. For relative distance covered all other position groups were greater than the FR (p < 0.05). The FIXED method underestimated both relative distance (~11%) and HSR values (up to ~20%) compared to the ROLL method. These differences were exaggerated for the HSR variable in the backs position who covered the greatest HSR distance; highlighting important consideration for those implementing the FIXED method of analysis. The data provides coaches with a worst-case scenario reference on the running demands required for periods of 60-300 s in length. This information offers novel insight into game demands and can be used to inform the design of training games to increase specificity of preparation for the most demanding phases of matches.
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