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PURPOSE OF REVIEW: To summarize indications, methods, and diagnostic yields for genetic testing for pediatric hearing loss. RECENT FINDINGS: Genetic testing has become a cornerstone of clinical care for children with sensorineural hearing loss. Recent studies have shown the efficacy of gene panels and exome sequencing for any child with sensorineural hearing loss. Recent findings have underscored the importance of a diagnosis in clinical care. Clinical trials for gene therapy for hearing loss have begun. SUMMARY: Genetic testing has become critical for personalized care for children with hearing loss. Recent studies have shown a 43% overall diagnostic yield for genetic testing for pediatric hearing loss, though the diagnostic yield may range from 10 to 60% depending on clinical features. Syndromic diagnoses comprise 25% of positive genetic tests for pediatric sensorineural hearing loss. While diagnostic yield is lower for children with unilateral or asymmetric sensorineural hearing loss, the likelihood of syndromic hearing loss finding is higher. An early and accurate genetic diagnosis is required for participating in clinical trials for gene therapy for hearing loss.
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OBJECTIVE: Atraumatic cerebrospinal fluid (CSF) rhinorrhea is uncommon in children and necessitates a multi-disciplinary evaluation for an etiology. Underlying osseous abnormality due to extensive or multifocal low flow vascular anomaly should be considered as a potential cause of spontaneous CSF leak. Treatment of multifocal low flow vascular anomalies may include medical and surgical approaches. In this series, we seek to determine the presenting signs and symptoms and medical and surgical treatment options for multifocal or extensive low flow vascular anomalies. METHODS: A retrospective case series at a quaternary care children's hospital was compiled. All children with CSF rhinorrhea diagnosed and treated for multifocal low flow vascular anomalies at our institution were included. A total of four patients were identified. RESULTS: All four patients had delay in initial diagnosis of underlying cause of meningitis and CSF rhinorrhea. Average age at diagnosis of multifocal low flow vascular anomaly was 7 years. This was on average 4 years after initial presentation for medical attention. Treatment approach was multidisciplinary and included medical management with sirolimus and bisphosphonates as well as surgical approaches to the skull base (lateral and anterior) to prevent CSF egress. CONCLUSION: Consideration of multifocal low flow vascular anomaly should be included in any pediatric patient presenting with CSF rhinorrhea.
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Rinorrea de Líquido Cefalorraquídeo , Hueso Temporal , Humanos , Rinorrea de Líquido Cefalorraquídeo/cirugía , Rinorrea de Líquido Cefalorraquídeo/diagnóstico , Rinorrea de Líquido Cefalorraquídeo/etiología , Niño , Estudios Retrospectivos , Femenino , Masculino , Hueso Temporal/anomalías , Hueso Temporal/diagnóstico por imagen , Preescolar , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/diagnóstico , Resultado del Tratamiento , AdolescenteRESUMEN
Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.
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Sordera , Mutación Missense , Linaje , Receptores de Superficie Celular , Estereocilios , Animales , Femenino , Humanos , Masculino , Sordera/genética , Secuenciación del Exoma , Genes Recesivos , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Modelos Moleculares , Receptores de Superficie Celular/genética , Estereocilios/metabolismo , Estereocilios/patología , Estereocilios/genéticaRESUMEN
Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modelling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.
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BACKGROUND: Mutations in TMPRSS3 are an important cause of autosomal recessive non-syndromic hearing loss. The hearing loss associated with mutations in TMPRSS3 is characterized by phenotypic heterogeneity, ranging from mild to profound hearing loss, and is generally progressive. Clinical presentation and natural history of TMPRSS3 mutations vary significantly based on the location and type of mutation in the gene. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to DFNB8/10. The heterogeneous presentation of TMPRSS3-associated disease makes it difficult to identify patients clinically. As the body of literature on TMPRSS3-associated deafness grows, there is need for better categorization of the hearing phenotypes associated with specific mutations in the gene. SUMMARY: In this review, we summarize TMPRSS3 genotype-phenotype relationships including a thorough description of the natural history of patients with TMPRSS3-associated hearing loss to lay the groundwork for the future of TMPRSS3 treatment using molecular therapy. KEY MESSAGES: TMPRSS3 mutation is a significant cause of genetic hearing loss. All patients with TMPRSS3 mutation display severe-to-profound prelingual (DFNB10) or a postlingual (DFNB8) progressive sensorineural hearing loss. Importantly, TMPRSS3 mutations have not been associated with middle ear or vestibular deficits. The c.916G>A (p.Ala306Thr) missense mutation is the most frequently reported mutation across populations and should be further explored as a target for molecular therapy.
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Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Serina Endopeptidasas/genética , Proteínas de la Membrana/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Mutación , Estudios de Asociación Genética , Fenotipo , Proteínas de Neoplasias/genéticaRESUMEN
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.
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Labio Leporino , Fisura del Paladar , Otolaringología , Apnea Obstructiva del Sueño , Tonsilectomía , Niño , Humanos , Síndrome de la Trisomía 13/complicaciones , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 13/cirugía , Síndrome de la Trisomía 18/complicaciones , Síndrome de la Trisomía 18/diagnóstico , Síndrome de la Trisomía 18/cirugía , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Tonsilectomía/métodos , Adenoidectomía/métodos , Apnea Obstructiva del Sueño/cirugía , Estudios RetrospectivosRESUMEN
OBJECTIVES: Idiopathic pain at the cochlear implant (CI) site outside of the immediate postoperative period is an uncommon occurrence but may necessitate device explantation. Our objective was to describe the clinical course for pediatric patients with CI site pain who ultimately required device explantation. STUDY DESIGN: Retrospective chart review. METHODS: We performed a retrospective database review of CIs performed at a tertiary referral center for pediatric cochlear implantation. We specifically evaluated pediatric patients who presented with pain at or near the CI device site and ultimately required explantation. RESULTS: Fifteen patients (16 CIs) had pain at or near the CI site requiring device explantation. Cultures taken during site exploration or device explantation identified bacteria in 86% and 81% of procedures, respectively. Propionibacterium acnes and Staphylococcus non-aureus were the most commonly identified organisms. CONCLUSIONS: The majority of patients with idiopathic pain in this cohort ultimately requiring CI explantation had chronic bacterial colonization. LEVEL OF EVIDENCE: 4 (Case series) Laryngoscope, 132:2044-2049, 2022.
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Implantación Coclear , Implantes Cocleares , Infecciones Estafilocócicas , Niño , Implantación Coclear/efectos adversos , Implantes Cocleares/efectos adversos , Remoción de Dispositivos , Humanos , Dolor , Estudios Retrospectivos , Staphylococcus aureusRESUMEN
Understanding genetic causes of hearing loss can determine the pattern and course of a patient's hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were GJB2 (20, 16%), TMPRSS3 (13, 10%), SLC26A4 (10, 8%), MYO7A (9, 7%), and MT-RNR1 (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.
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Implantación Coclear , Implantes Cocleares , Sordera , Pérdida Auditiva , Adulto , Niño , Estudios de Cohortes , Sordera/genética , Pérdida Auditiva/genética , Pérdida Auditiva/cirugía , Humanos , Proteínas de la Membrana/genética , Proteínas de Neoplasias , Serina Endopeptidasas/genéticaRESUMEN
Hearing loss affects an estimated 466 million people worldwide, with a substantial fraction due to genetic causes. Approximately 16% of genetic hearing loss is caused by pathogenic mutations in STRC, a gene that encodes the protein stereocilin. To develop gene therapy strategies for patients with STRC hearing loss, we generated a mouse model with a targeted deletion in the Strc gene. We devised a novel dual-vector approach to circumvent the size limitation of AAV vectors and drive expression of full-length STRC protein. To target outer hair cells, which are difficult to transduce, we used synthetic AAV9-PHP.B vectors for efficient dual-vector transduction. We report robust recovery of exogenous STRC expression in outer hair cells of Strc-deficient mice, recovery of hair bundle morphology, substantially improved cochlear amplification, and enhanced auditory sensitivity. The data raise the prospect that our strategy could benefit ~2.3 million patients worldwide affected by STRC mutations.
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Hearing loss (HL) is the most common sensory deficit in humans and is frequently accompanied by peripheral vestibular loss (PVL). While often overlooked, PVL is an important sensory dysfunction that may impair development of motor milestones in children and can have a significant negative impact on quality of life. In addition, many animal and in vitro models of deafness use vestibular hair cells as a proxy to study cochlear hair cells. The extent of vestibular end organ dysfunction associated with genetic pediatric hearing loss is not well-understood. We studied children with a known genetic cause of hearing loss who underwent routine preoperative vestibular testing prior to cochlear implantation between June 2014 and July 2020. Vestibular testing included videonystagmography, rotary chair, video head impulse testing, and/or vestibular evoked myogenic potentials. Etiology of HL was determined through history, physical examination, imaging, laboratory testing, and/or genetic testing. Forty-four children (21 female/23 male) met inclusion criteria; 24 had genetic non-syndromic and 20 had genetic syndromic forms of HL. Mean age at the time of testing was 2.8 ± 3.8 years (range 7 months-17 years). The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1). The most common forms of syndromic HL were Usher syndrome (4) and Waardenburg (4), followed by SCID/reticular dysgenesis (3), CHARGE (2), CAPOS (1), Coffin-Siris (1), Jervell and Lange-Nielsen (1), Noonan (1), peroxisome biogenesis disorder (1), Perrault (1), and Trisomy 21 (1). Overall, 23 patients (52%) had PVL. A larger proportion of children with syndromic forms of HL had PVL (12/20, 60%) compared with children with genetic non-syndromic HL (11/24, 46%), though without statistical significant (p = 0.3). The occurrence of PVL varied by affected gene. In conclusion, PVL is a common finding in children with syndromic and non-syndromic genetic HL undergoing vestibular evaluation prior to cochlear implantation. Improved understanding of the molecular physiology of vestibular hair cell dysfunction is important for clinical care as well as research involving vestibular hair cells in model organisms and in vitro models.
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BACKGROUND: Dizziness after concussion is primarily attributed to effects on the brain, but traumatic inner ear disorders can also contribute. Benign paroxysmal positional vertigo (BPPV) is a common vestibular disorder that can result from minor head trauma and can be easily diagnosed and rapidly treated in an office setting. The role of BPPV in pediatric postconcussive dizziness has not been well-studied. PURPOSE: To evaluate the prevalence and clinical features of BPPV in a group of pediatric patients with concussion and prolonged dizziness after concussion. STUDY DESIGN: Case-control study. LEVEL OF EVIDENCE: Level 3. METHODS: Retrospective review of 102 patients seen within the past 3 years in a pediatric multidisciplinary concussion clinic for evaluation of postconcussive dizziness. RESULTS: BPPV was diagnosed in 29.4% (30/102) of patients with postconcussion syndrome and dizziness. All patients with BPPV were treated with repositioning maneuvers, except for 5 patients who had spontaneous resolution of symptoms. Patients were evaluated at an average of 18.8 weeks (SD, 16.4 weeks) after the injury. BPPV was diagnosed at similar rates regardless of gender or age group (children vs adolescents). The mean Post-Concussion Symptom Scale (PCSS) score did not differ significantly between patients with (58.3 [SD, 22.5]) or without BPPV (55.8 [SD, 29.4]; P = 0.39). The PCSS "balance problems or dizziness" subscore also did not differ between patients with (3.3 [SD, 1.7]) or without BPPV (2.8 [SD, 1.6]; P = 0.13). CONCLUSION: BPPV is fairly common in pediatric concussion, occurring in one-third of the patients studied. BPPV is often not diagnosed and treated until many weeks after the injury. Increased awareness of the evaluation and management of BPPV among pediatric concussion providers may help expedite resolution of dizziness and hasten overall recovery in affected patients. CLINICAL RELEVANCE: BPPV is a treatable cause of dizziness caused by minor head injuries and is more common than previously reported in pediatric patients with concussion. Improved awareness of BPPV by concussion providers may expedite recovery.
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Vértigo Posicional Paroxístico Benigno/etiología , Conmoción Encefálica/complicaciones , Adolescente , Vértigo Posicional Paroxístico Benigno/diagnóstico , Vértigo Posicional Paroxístico Benigno/terapia , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Posicionamiento del Paciente , Estudios Retrospectivos , Adulto JovenRESUMEN
In the original version of this Article, several individuals were erroneously acknowledged in the acknowledgements, they have been removed. The Acknowledgement section in the PDF and HTML versions of the Article has now been corrected to the following.
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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.
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Sordera/diagnóstico , Pruebas Auditivas/métodos , Tamizaje Neonatal/métodos , Sordera/genética , Femenino , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/genética , Humanos , Lactante , Recién Nacido , Masculino , Estados UnidosRESUMEN
BACKGROUND: Adult-type rhabdomyoma (ATR) is a rare mesenchymal tumor of skeletal muscle differentiation. Extracardiac ATR occurs most commonly in the head and neck, but do so in a heterogeneous fashion, arising at numerous different locations within this region. METHODS: At our institution, we encountered a patient who was diagnosed clinically with parathyroid adenoma based on signs and symptoms of hyperparathyroidism and suggestive radiologic findings. A parathyroidectomy with intraoperative consultation was performed. RESULTS: The frozen section diagnosis was ambiguous and a diagnosis of ATR was only made on permanent section. CONCLUSION: Awareness of this tumor can prevent incorrect diagnosis and overtreatment intraoperatively. Herein, we describe the clinical history, pathologic findings, and review histologic features of rhabdomyomas.
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Adenoma/diagnóstico , Neoplasias de las Paratiroides/diagnóstico , Rabdomioma/diagnóstico , Anciano de 80 o más Años , Diagnóstico Diferencial , Humanos , Masculino , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía , Rabdomioma/cirugíaRESUMEN
Cochlear implantation, a surgical method to bypass cochlear hair cells and directly stimulate the spiral ganglion, is the standard treatment for severe-to-profound hearing loss. Changes in cochlear implant electrode array design and surgical approach now allow for preservation of acoustic hearing in the implanted ear. Electrocochleography (ECochG) was performed in eight hearing preservation subjects to assess hair cell and neural function and elucidate underlying genetic hearing loss. Three subjects had pathogenic variants in TMPRSS3 and five had pathogenic variants in genes known to affect the cochlear sensory partition. The mechanism by which variants in TMPRSS3 cause genetic hearing loss is unknown. We used a 500-Hz tone burst to record ECochG responses from an intracochlear electrode. Responses consist of a cochlear microphonic (hair cell) and an auditory nerve neurophonic. Cochlear microphonics did not differ between groups. Auditory nerve neurophonics were smaller, on average, in subjects with TMPRSS3 deafness. Results of this proof-of-concept study provide evidence that pathogenic variants in TMPRSS3 may impact function of the spiral ganglion. While ECochG as a clinical and research tool has been around for decades, this study illustrates a new application of ECochG in the study of genetic hearing and deafness in vivo.
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Cóclea/metabolismo , Cóclea/fisiopatología , Sordera/metabolismo , Sordera/fisiopatología , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Serina Endopeptidasas/metabolismo , Ganglio Espiral de la Cóclea/metabolismo , Ganglio Espiral de la Cóclea/fisiopatología , Estimulación Acústica/métodos , Adolescente , Adulto , Audiometría de Respuesta Evocada/métodos , Niño , Implantación Coclear/métodos , Implantes Cocleares , Nervio Coclear/metabolismo , Nervio Coclear/fisiología , Femenino , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/fisiología , Audición/fisiología , Pérdida Auditiva/metabolismo , Pérdida Auditiva/fisiopatología , Humanos , Masculino , Proteínas de la Membrana/fisiología , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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Sordera/genética , Mutación/genética , Bases de Datos Genéticas , Frecuencia de los Genes/genética , Genómica/métodos , Pérdida Auditiva/genética , HumanosRESUMEN
Comprehensive genetic testing has become integral in the evaluation of children with deafness, but the amount of blood required to obtain DNA can be prohibitive in newborns. Dried blood spots (DBSs) are routinely collected and would provide an alternative source of DNA. Our objective was to evaluate the use of DBSs for comprehensive genetic testing for deafness. DNA derived from fresh and archived DBS samples was compared with DNA from whole blood. We performed next-generation sequencing of all known deafness genes in 4 DBS samples: 2 positive controls, an unknown sample, and a negative control. The DBS-derived DNA was of sufficient quantity and quality for clinical testing. In the 2 positive control samples, pathogenic variants were identified; in the negative control, no pathogenic variants were found; and in the unknown sample, homozygous deletion of the OTOA gene was identified as the cause of deafness. This pilot study shows that comprehensive genetic testing for deafness is feasible with fresh and/or archived DBSs.
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Sordera/sangre , Sordera/diagnóstico , Pruebas Genéticas/métodos , Bancos de Muestras Biológicas , Sordera/genética , Pruebas con Sangre Seca , Pruebas Hematológicas , HumanosRESUMEN
BACKGROUND: Cochlear implantation is an effective habilitation modality for adults with significant hearing loss. However, post-implant performance is variable. A portion of this variance in outcome can be attributed to clinical factors. Recent physiological studies suggest that the health of the spiral ganglion also impacts post-operative cochlear implant outcomes. The goal of this study was to determine whether genetic factors affecting spiral ganglion neurons may be associated with cochlear implant performance. METHODS: Adults with post-lingual deafness who underwent cochlear implantation at the University of Iowa were studied. Pre-implantation evaluation included comprehensive genetic testing for genetic diagnosis. A novel score of genetic variants affecting genes with functional effects in the spiral ganglion was calculated. A Z-scored average of up to three post-operative speech perception tests (CNC, HINT, and AzBio) was used to assess outcome. RESULTS: Genetically determined spiral ganglion health affects cochlear implant outcomes, and when considered in conjunction with clinically determined etiology of deafness, accounts for 18.3% of the variance in postoperative speech recognition outcomes. Cochlear implant recipients with deleterious genetic variants that affect the cochlear sensory organ perform significantly better on tests of speech perception than recipients with deleterious genetic variants that affect the spiral ganglion. CONCLUSION: Etiological diagnosis of deafness including genetic testing is the single largest predictor of postoperative speech outcomes in adult cochlear implant recipients. A detailed understanding of the genetic underpinning of hearing loss will better inform pre-implant counseling. The method presented here should serve as a guide for further research into the molecular physiology of the peripheral auditory system and cochlear implants.