RÉSUMÉ
TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.
Sujet(s)
Études d'associations génétiques , Perte d'audition , Protéines membranaires , Serine endopeptidases , Humains , Femelle , Mâle , Serine endopeptidases/génétique , Adulte , Protéines membranaires/génétique , Perte d'audition/génétique , Enfant , Adulte d'âge moyen , Adolescent , Enfant d'âge préscolaire , Génotype , Études de cohortes , Phénotype , Mutation faux-sens , Études transversales , Jeune adulte , Études rétrospectives , Sujet âgé , Protéines tumoralesRÉSUMÉ
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆GFold) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆GFold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
Sujet(s)
Surdité , Perte d'audition , Humains , Protéome/génétique , Perte d'audition/génétique , Mutation faux-sens , Surdité/génétiqueRÉSUMÉ
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6,328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G Fold ) for all DVD missense variants. We find that 5,772 VUSs have a large, destabilizing ∆∆G Fold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3,456 VUSs are likely pathogenic at a probability of 99.0%. These VUSs affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
RÉSUMÉ
PURPOSE: De novo variants (DNVs) are a well-recognized cause of genetic disorders. The contribution of DNVs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNVs in HL-associated genes and assess their contribution to HL. METHODS: Targeted genomic enrichment and massively parallel sequencing were used for molecular testing of all exons and flanking intronic sequences of known HL-associated genes, with no exclusions on the basis of type of HL or clinical features. Segregation analysis was performed, and previous reports of DNVs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNVs in HL. RESULTS: DNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least â¼1% of probands for whom a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNVs of MITF were most common (21% of DNVs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNVs revealed gene-specific variability in contribution of DNV to the mutational spectrum of HL-associated genes. CONCLUSION: DNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL.
Sujet(s)
Surdité , Perte d'audition , Humains , Perte d'audition/génétique , Séquençage nucléotidique à haut débit , Mutation , Exons , Protéines et peptides de signalisation intercellulaireRÉSUMÉ
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.
Sujet(s)
Implantation cochléaire , Implants cochléaires , Surdité , Perte d'audition , Adulte , Enfant , Études de cohortes , Surdité/génétique , Perte d'audition/génétique , Perte d'audition/chirurgie , Humains , Protéines membranaires/génétique , Protéines tumorales , Serine endopeptidases/génétiqueRÉSUMÉ
Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.
Sujet(s)
Fréquence d'allèle , Perte d'audition/génétique , Myosines/génétique , Adolescent , Adulte , Enfant , Enfant d'âge préscolaire , Femelle , Gènes récessifs , Perte d'audition/ethnologie , Perte d'audition/anatomopathologie , Humains , Nourrisson , Juif/génétique , Mâle , Mutation , Pedigree , Épissage des ARNRÉSUMÉ
We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.
Sujet(s)
Protéines de la matrice extracellulaire/génétique , Génotype , Surdité neurosensorielle/génétique , Canaux potassiques KNCQ/génétique , Protéines membranaires/génétique , Mutation , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Asiatiques , Audiométrie , Études cas-témoins , Enfant , Enfant d'âge préscolaire , Femelle , Protéines liées au GPI/génétique , Expression des gènes , Études d'associations génétiques , Surdité neurosensorielle/diagnostic , Surdité neurosensorielle/ethnologie , Surdité neurosensorielle/physiopathologie , Humains , Nourrisson , Nouveau-né , Japon , Mâle , Adulte d'âge moyen , Pedigree , Phénotype , États-Unis ,RÉSUMÉ
Background: Usher syndrome is the most common hereditary syndrome combining deafness and blindness. In the 2017 National Child Count of Children and Youth who are Deaf-Blind, Usher syndrome represented 329 of 10,000 children, but there were also at least 70 other etiologies of deaf-blindness documented. The purpose of this study was to analyze the work-up and ultimate diagnoses of 21 consecutive families who presented to the Genetic Eye-Ear Clinic (GEEC) at the University of Iowa. Our hypothesis was that most families referred to the GEEC would have initial and final diagnoses of Usher syndrome.Materials and Methods: Patients were identified through an IRB approved retrospective chart review of referrals to the GEEC between 2012 and 2019. Details about each patient's history, exam, and clinical and genetic work-up were recorded.Results: From 2012 to 2019, 21 families (25 patients) were referred to the collaborative GEEC. Overall molecular diagnostic rate in this cohort was 14/21 (67%). Evaluation resulted in a change of diagnosis in 11/21 (52%) families. Ultimately, there were eleven unique diagnoses including hereditary, non-hereditary, and independent causes of combined visual impairment and hearing loss. The most common diagnosis was Usher syndrome, which represented 6/21 (29%) families.Conclusions: Providing a correct diagnosis for patients with visual impairment and hearing loss can be challenging for clinicians and their patients, but it can greatly improve clinical care and outcomes. We recommend an algorithm that includes multidisciplinary collaboration, careful clinical evaluation, strategic molecular testing, and consideration of a broad differential diagnosis.
Sujet(s)
Cécité/diagnostic , Surdité/diagnostic , Marqueurs génétiques , Mutation , Syndromes d'Usher/diagnostic , Adolescent , Adulte , Cécité/génétique , Enfant , Enfant d'âge préscolaire , Surdité/génétique , Diagnostic différentiel , Femelle , Études de suivi , Prédisposition génétique à une maladie , Génotype , Humains , Nourrisson , Mâle , Adulte d'âge moyen , Pronostic , Études rétrospectives , Syndromes d'Usher/génétiqueRÉSUMÉ
Single-cell RNA sequencing is a powerful tool by which to characterize the transcriptional profile of low-abundance cell types, but its application to the inner ear has been hampered by the bony labyrinth, tissue sparsity, and difficulty dissociating the ultra-rare cells of the membranous cochlea. Herein, we present a method to isolate individual inner hair cells (IHCs), outer hair cells (OHCs), and Deiters' cells (DCs) from the murine cochlea at any post-natal time point. We harvested more than 200 murine IHCs, OHCs, and DCs from post-natal days 15 (p15) to 228 (p228) and leveraged both short- and long-read single-cell RNA sequencing to profile transcript abundance and structure. Our results provide insights into the expression profiles of these cells and document an unappreciated complexity in isoform variety in deafness-associated genes. This refined view of transcription in the organ of Corti improves our understanding of the biology of hearing and deafness.
Sujet(s)
Surdité/génétique , Organe spiral/métabolisme , Transcriptome , Animaux , Femelle , Analyse de profil d'expression de gènes , Mâle , Souris , Organe spiral/croissance et développement , Analyse sur cellule uniqueRÉSUMÉ
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.
Sujet(s)
Surdité/génétique , Mutation/génétique , Bases de données génétiques , Fréquence d'allèle/génétique , Génomique/méthodes , Perte d'audition/génétique , HumainsRÉSUMÉ
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.
Sujet(s)
Surdité/sang , Surdité/diagnostic , Dépistage génétique/méthodes , Biobanques , Surdité/génétique , Dépistage sur goutte de sang séché , Tests hématologiques , HumainsRÉSUMÉ
OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Sujet(s)
Encéphalopathies/génétique , Encéphalopathies/métabolisme , dGTPases/génétique , dGTPases/métabolisme , Protéines associées aux microtubules/génétique , Protéines associées aux microtubules/métabolisme , Protéines mitochondriales/génétique , Protéines mitochondriales/métabolisme , Mutation , Adolescent , Enfant , Enfant d'âge préscolaire , Études de cohortes , Analyse de mutations d'ADN , Dynamines , Femelle , Protéines à homéodomaine , Humains , Nourrisson , Mâle , Modèles moléculaires , Phénotype , Protéine homéotique associée à la petite taille , Fratrie , Vésicules synaptiques/métabolisme , Jeune adulteRÉSUMÉ
A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment.
Sujet(s)
Consanguinité , Surdité neurosensorielle/épidémiologie , Surdité neurosensorielle/génétique , Connexine-26 , Connexines/génétique , Prestations des soins de santé , Dépistage génétique , Humains , Iran/épidémiologie , Protéines de transport membranaire/génétique , Mutation , Myosine-VIIa , Myosines/génétique , Transporteurs de sulfateRÉSUMÉ
OBJECTIVE: Copy number variations (CNVs), a major cause of genetic hearing loss, most frequently involve the STRC gene, located on chr15q15.3 and causally related to autosomal recessive non-syndromic hearing loss (ARNSHL) at the DFNB16 locus. The interpretation of STRC sequence data can be challenging due to the existence of a virtually identical pseudogene, pSTRC, that promotes complex genomic rearrangements in this genomic region. Targeted genomic enrichment with massively parallel sequencing (TGE+MPS) has emerged as the preferred method by which to provide comprehensive genetic testing for hearing loss. We aimed to identify CNVs in the STRC region using established and validated bioinformatics methods. METHODS: We used TGE+MPS to identify the genetic cause of hearing loss. The CNV results were confirmed with customized array comparative genomic hybridization (array CGH). RESULTS: Three probands with progressive mild to moderate hearing loss were found among 40 subjects with ARNSHL to segregate homozygous STRC deletions and gene to pseudogene conversion. Array CGH showed that the deletions/conversions span multiple genes outside of the exons captured by TGE+MPS. CONCLUSION: These data further validate the necessity to integrate the detection of both simple variant changes and complex genomic rearrangements in the clinical diagnosis of genetic hearing loss.
Sujet(s)
Surdité/génétique , Protéines membranaires/génétique , Adulte , Enfant , Hybridation génomique comparative/méthodes , Variations de nombre de copies de segment d'ADN , Femelle , Dépistage génétique/méthodes , Séquençage nucléotidique à haut débit/méthodes , Humains , Protéines et peptides de signalisation intercellulaire , MâleRÉSUMÉ
Whole exome sequencing (WES) has revolutionized the way we think about and diagnose epileptic encephalopathies. Multiple recent review articles discuss the benefits of WES and suggest various algorithms to follow for determining the etiology of epileptic encephalopathies. Incorporation of WES in these algorithms is leading to the discovery of new genetic diagnoses of early onset epileptic encephalopathies (EOEEs) at a rapid rate; however, WES is not yet a universally utilized diagnostic tool. Clinical WES may be underutilized due to provider discomfort in ordering the test or perceived costliness. At our hospital WES is not routinely performed for patients with EOEE due to limited insurance reimbursement. In fact for any patient with noncommercial insurance (Medicaid) the institution does not allow sending out WES as this is not "established"/"proven to be highly useful and cost effective"/"approved test" in patients with epilepsy. Recently, we performed WES on four patients from three families and identified novel mutations in known epilepsy genes in all four cases. These patients had State Medicaid as their insurance carrier and were followed up for several years for EOEE while being worked up using the traditional/approved testing methods. Following a recently proposed diagnostic pathway, we analyzed the cost savings (US dollars) that could be accrued if WES was performed earlier in the diagnostic odyssey. This is the first publication that addresses the dollar cost of traditional testing in EOEE as performed in these four cases versus WES and the potential cost savings.
Sujet(s)
Encéphalopathies/diagnostic , Encéphalopathies/économie , Tests diagnostiques courants/économie , Épilepsie/diagnostic , Épilepsie/économie , Âge de début , Encéphalopathies/complications , Enfant , Enfant d'âge préscolaire , Épilepsie/complications , Exome , Femelle , Dépistage génétique/méthodes , Génomique , Génotype , Coûts des soins de santé , Humains , Nourrisson , Assurance maladie , Mâle , Medicaid (USA) , Phénotype , Analyse de séquence d'ADN , Délai jusqu'au traitement , États-UnisRÉSUMÉ
We describe the presentation and workup of two brothers with early-onset epileptic encephalopathy who became seizure-free on a ketogenic diet. Extensive testing culminated in whole exome sequencing, which led to the diagnosis of phosphatidyl inositol glycan biosynthesis class A protein (PIGA) deficiency. This familial case highlights the importance of genetic testing for early-onset epileptic encephalopathies and underscores the potential value of a ketogenic diet in the treatment of this condition.
Sujet(s)
Régime cétogène , Épilepsie/diétothérapie , Épilepsie/étiologie , Protéines membranaires/déficit , Diagnostic différentiel , Épilepsie/diagnostic , Épilepsie/génétique , Techniques de génotypage , Humains , Nourrisson , Mâle , Protéines membranaires/génétique , Mutation , Pedigree , Fratrie , Résultat thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Dépistage génétique , Perte d'audition/génétique , Adolescent , Enfant , Enfant d'âge préscolaire , Femelle , Hétérogénéité génétique , Perte d'audition/diagnostic , Humains , Nourrisson , MâleRÉSUMÉ
The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
Sujet(s)
Maladies du rein/diagnostic , Maladies du rein/génétique , Glomérule rénal , Microangiopathies thrombotiques/diagnostic , Microangiopathies thrombotiques/génétique , Adolescent , Enfant , Enfant d'âge préscolaire , Complément C3 , Femelle , Dépistage génétique/méthodes , Humains , Maladies du rein/immunologie , MâleRÉSUMÉ
OBJECTIVE: To present audiometric data in 3 dimensions by considering age as an addition dimension. METHODS: Audioprofile surfaces (APSs) were fitted to a set of audiograms by plotting each measurement of an audiogram as an independent point in 3 dimensions with the x, y, and z axes representing frequency, hearing loss in dB, and age, respectively. RESULTS: Using the Java-based APS viewer as a standalone application, APSs were pre-computed for 34 loci. By selecting APSs for the appropriate genetic locus, a clinician can compare this APS-generated average surface to a specific patient's audiogram. CONCLUSION: Audioprofile surfaces provide an easily interpreted visual representation of a person's hearing acuity relative to others with the same genetic cause of hearing loss. Audioprofile surfaces will support the generation and testing of sophisticated hypotheses to further refine our understanding of the biology of hearing.
Sujet(s)
Audiométrie tonale/tendances , Seuil auditif/physiologie , Surdité neurosensorielle/diagnostic , Ouïe/physiologie , Logiciel , Surdité neurosensorielle/physiopathologie , Humains , Adulte d'âge moyenRÉSUMÉ
OBJECTIVE: We present 2 patients who were identified with mutations in the GPR98 gene that causes Usher syndrome type 2 (USH2). METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were used to identify the genetic causes of hearing loss. RESULTS: We identified causative mutations in the GPR98 gene in 1 family (2 siblings). The patients had moderate sloping hearing loss, and no progression was observed over a period of 10 years. Fundus examinations were normal. However, electroretinograms revealed impaired responses in both patients. CONCLUSION: Early diagnosis of Usher syndrome has many advantages for patients and their families. This study supports the use of comprehensive genetic diagnosis for Usher syndrome, especially prior to the onset of visual symptoms, to provide the highest chance of diagnostic success in early life stages.