RESUMEN
RATIONALE AND PATIENT CONCERNS: Congenital hearing loss is often caused by an inner ear malformation, in such cases, the presence of other anomalies, such as microtia, and venous anomalies of the temporal bone and laryngomalacia makes it challenging to perform cochlear implantation surgery. DIAGNOSES: This study reports the case of a 28-month-old girl with congenital profound hearing loss, laryngomalacia, and malformed inner ear, who received cochlear implantation surgery. The bony structure, vessels and nerves were first assessed through magnetic resonance imaging and computed tomography before exploring the genetic basis of the condition using trio-based whole exome sequencing. Perioperative evaluation and management of the airway was then performed by experienced anesthesiologist, with the surgical challenges as well as problems encountered fully evaluated. INTERVENTIONS: Cochlear implantation was eventually performed using a trans-mastoid approach under uneventful general anesthesia. OUTCOMES: Due to the small size of the cochlea, a short electrode FLEX24 was inserted through the cochleostomy. LESSONS: Considering the high risk of facial nerve injury and limited access to the cochlea when patients present significant bony and venous anomalies, cochlear implantation in such patients require careful preoperative evaluation and thoughtful planning. In these cases, airway assessment, magnetic resonance venography, magnetic resonance arteriography, and magnetic resonance imaging and computed tomography can be useful to minimize the risks. Intraoperative facial nerve monitoring is also recommended to assist in the safe location of facial nerve.
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Implantación Coclear , Implantes Cocleares , Microtia Congénita , Pérdida Auditiva Sensorineural , Laringomalacia , Malformaciones Vasculares , Preescolar , Femenino , Humanos , Cóclea/anomalías , Cóclea/patología , Cóclea/cirugía , Implantación Coclear/métodos , Microtia Congénita/cirugía , Pérdida Auditiva Sensorineural/cirugía , Laringomalacia/cirugía , Hueso Temporal/diagnóstico por imagen , Hueso Temporal/cirugía , Hueso Temporal/patología , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/cirugía , Malformaciones Vasculares/patologíaRESUMEN
BACKGROUND: Myhre syndrome is a rare multisystem genetic disorder that is caused by de novo heterozygous gain-of-function variants in SMAD4. Patients with Myhre syndrome exhibit several phenotypes at different ages such as small size, autism, developmental delay, left-sided heart defects, and hearing loss and often have a characteristic facial appearance. The early clinical diagnosis of Myhre syndrome remains a major challenge, particularly in the first year of life. METHODS: A Chinese male infant with syndactyly of fingers, hypertelorism, short palpebral fissures, and short philtrum was enrolled into the ENT department of the Chinese PLA General Hospital. Whole exome sequencing analysis was used to detect the disease-causing variant. A literature review of Myhre syndrome was also performed. RESULTS: A recurrent de novo missense variant c.1498A > G p.I500V(p. Ile500Val) in SMAD4 was detected confirming the clinical diagnosis of Myhre syndrome at the age of 38 days. The infant appears to be the youngest reported case of Myhre syndrome. At 23-month follow-up, the affected infant has dysmorphic facial features, growth retardation, and previously undescribed complete syndactyly. Review the literatures noted several common features in Myhre syndrome patients including hearing loss (72.7%), characteristic facial features (26.0%-54.5%), finger and toe abnormalities (3.9%-48.1%), short stature (45.5%), and respiratory (30.0%) and cardiovascular problems (65.0%). CONCLUSIONS: Clinicians should have a low threshold to perform genetic testing on patients with features suggesting Myhre syndrome even in the first year of life. Although some individuals with Myhre syndrome have normal hearing, early onset or progressive hearing loss usually occur in one or both ears in most patients, with remarkable phenotypic heterogeneity. Syndactyly may be minor such as typical 2-3 toe involvement, or more complicated as was observed in our patient.
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Sordera , Pérdida Auditiva , Discapacidad Intelectual , Sindactilia , Humanos , Masculino , Trastornos del Crecimiento/genética , Discapacidad Intelectual/genética , Recién NacidoRESUMEN
Pathogenic variants in MYO15A are known to cause autosomal recessive nonsyndromic hearing loss (ARNSHL), DFNB3. We have previously reported on one ARNSHL family including two affected siblings and identified MYO15A c.5964+3G > A and c.8375 T > C (p.Val2792Ala) as the possible deafness-causing variants. Eight year follow up identified one new affected individual in this family, who also showed congenital, severe to profound sensorineural hearing loss. By whole exome sequencing, we identified a new splice-site variant c.5531+1G > C (maternal allele), in a compound heterozygote with previously identified missense variant c.8375 T > C (p.Val2792Ala) (paternal allele) in MYO15A as the disease-causing variants. The new affected individual underwent unilateral cochlear implantation at the age of 1 year, and 5 year follow-up showed satisfactory speech and language outcomes. Our results further indicate that MYO15A-associated hearing loss is good candidates for cochlear implantation, which is in accordance with previous report. In light of our findings and review of the literatures, 58 splice-site variants in MYO15A are correlated with a severe deafness phenotype, composed of 46 canonical splice-site variants and 12 non-canonical splice-site variants.
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Sordera , Pérdida Auditiva , Humanos , Linaje , Miosinas/genética , Sordera/genética , Pérdida Auditiva/genética , Fenotipo , Familia , GenotipoRESUMEN
Non-syndromic hearing loss (NSHL) is a common neurosensory disease with an extreme genetic heterogeneity which has been linked to variants in over 120 genes. The LOXHD1 gene (DFNB77), encoding lipoxygenase homology domain 1, is a rare hearing loss gene found in several populations. To evaluate the importance of LOXHD1 variants in Chinese patients with NSHL, we performed genetic analysis on LOXHD1 in 2,901 sporadic Chinese patients to identify the aspect and frequency of LOXHD1 causative variants. Next-generation sequencing using a custom gene panel of HL was conducted on 2,641 unrelated patients and whole-exome sequencing on the remaining 260 patients. A total of 33 likely causative variants were identified in 21 patients, including 20 novel variants and 13 previously reported pathogenic variants. Each of the 20 novel variants was evaluated according to ACMG criteria. These findings showed that causative variants in LOXHD1 were found in about 0.72% (21/2,901) of Chinese NSHL patients. This study is by far the largest number of novel variants identified in this gene expanding the range of pathogenic variants in LOXHD1, and suggests that variants in this gene occur relatively commonly in Chinese NSHL patients. This extensive investigation of LOXHD1 in Chinese NSHL patients proposed six recurrent LOXHD1 variants. These findings may assist in both molecular diagnosis and genetic counseling.
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Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.
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Anomalías del Ojo , Enfermedades Hereditarias del Ojo , Segmento Anterior del Ojo/anomalías , Preescolar , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Enfermedades Hereditarias del Ojo/genética , Factores de Transcripción Forkhead/genética , Humanos , MasculinoRESUMEN
BACKGROUND: Germline variants in PTPN11 are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients with PTPN11 pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence of PTPN11-related NSML or NS in patients with congenital SNHL and explored the expression of PTPN11 and the underlying mechanisms in the auditory system. METHODS: A total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients with PTPN11 variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish with Ptpn11 knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes. RESULTS: Ten NSML/NS probands were diagnosed via the identification of pathogenic variants of PTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded by Ptpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown of ptpn11a and overexpression of mutant PTPN11 were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom in PTPN11-associated NSML or NS. Other features may be mild, especially in children. CONCLUSION: Screening for PTPN11 in patients with congenital hearing loss and variant-based diagnoses are recommended.
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Pérdida Auditiva Sensorineural/congénito , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adolescente , Animales , Pueblo Asiatico/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Técnicas de Silenciamiento del Gen , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/epidemiología , Humanos , Incidencia , Lactante , Masculino , Ratones , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Transducción de Señal , Proteínas Wnt/metabolismo , Pez Cebra , beta Catenina/metabolismoRESUMEN
Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the POU class 4 transcription factor 3 (POU4F3) are known to cause autosomal dominant nonsyndromic hearing loss linked to the loci of DFNA15. In this study, we describe a pathogenic missense mutation in POU4F3 in a four-generation Chinese family (6126) with midfrequency, progressive, and postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 129 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified POU4F3 c.602T>C (p.Leu201Pro) as the disease-causing variant. This variant cosegregated with hearing loss in other family members but was not detected in 580 normal controls or the ExAC database and could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. We conclude that POU4F3 c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss in this family. Routine examination of POU4F3 is necessary for the genetic diagnosis of midfrequency hearing loss.
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Pueblo Asiatico/genética , Pérdida Auditiva Sensorineural/genética , Proteínas de Homeodominio/genética , Mutación Missense/genética , Factor de Transcripción Brn-3C/genética , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Familia , Femenino , Proteínas de Homeodominio/química , Humanos , Persona de Mediana Edad , Linaje , Factor de Transcripción Brn-3C/químicaRESUMEN
Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) - a protein that functions in the Jak/ STAT pathway- are associated with ADNSHL Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. ConclusionIFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.
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Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Receptores de Citocinas/genética , Receptores de Interferón/genética , Animales , Técnicas de Silenciamiento del Gen , Ligamiento Genético , Pérdida Auditiva Sensorineural/fisiopatología , Heterocigoto , Humanos , Janus Quinasa 1/genética , Ratones , Morfolinas , Mutación Missense/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Secuenciación del Exoma , Pez Cebra/genéticaRESUMEN
Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Mutations in the TMPRSS3 (transmembrane protease, serine 3) gene cause prelingual (DFNB10) or postlingual (DFNB8) deafness. In our previous study, three pathogenic mutations in TMPRSS3 were identified in one Chinese family. To evaluate the importance of TMPRSS3 mutations in recessive deafness among the Chinese, we screened 150 autosomal recessive nonsyndromic hearing loss (ARNSHL) families and identified 6 that carried seven causative TMPRSS3 mutations, including five novel mutations (c.809T>A, c.1151T>G, c.1204G>A, c.1244T>C, and c.1250G>A) and two previously reported mutations (c.323-6G>A and c.916G>A). Each of the five novel mutations was classified as severe, by both age of onset and severity of hearing loss. Together with our previous study, six families were found to share one pathogenic mutation (c.916G>A, p.Ala306Thr). To determine whether this mutation arose from a common ancestor, we analyzed six short tandem repeat (STR) markers spanning the TMPRSS3 gene. In four families, we observed linkage disequilibrium between p.Ala306Thr and STR markers. Our results indicate that mutations in TMPRSS3 account for about 4.6% (7/151) of Chinese ARNSHL cases lacking mutations in SLC26A4 or GJB2 and that the recurrent TMPRSS3 mutation p.Ala306Thr is likely to be a founder mutation.
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Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación , Proteínas de Neoplasias/genética , Serina Endopeptidasas/genética , Adulto , Edad de Inicio , Niño , Preescolar , China , Análisis Mutacional de ADN , Femenino , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Recién Nacido , Masculino , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfsâ12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfsâ12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfsâ12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.
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Pueblo Asiatico/genética , Genes Recesivos , Predisposición Genética a la Enfermedad , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Mutación/genética , Proteínas de Neoplasias/genética , Serina Endopeptidasas/genética , Anciano , Secuencia de Aminoácidos , Audiometría , Secuencia de Bases , Niño , Implantes Cocleares , Secuencia Conservada , Análisis Mutacional de ADN , Sordera/genética , Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Linaje , FenotipoRESUMEN
Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the transmembrane channel-like gene1 (TMC1) are known to cause autosomal dominant and recessive forms of nonsyndromic hearing loss linked to the loci of DFNA36 and DFNB7/11, respectively. We characterized a six-generation Chinese family (5315) with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 82 known deafness genes, next-generation sequencing and bioinformatic analysis, we identified TMC1 c.1714G>A (p. D572N) as the disease-causing mutation. This mutation co-segregated with hearing loss in other family members and was not detected in 308 normal controls. In order to determine the prevalence of TMC1 c.1714G>A in Chinese ADNSHL families, we used DNA samples from 67 ADNSHL families with sloping audiogram and identified two families carry this mutation. To determine whether it arose from a common ancestor, we analyzed nine STR markers. Our results indicated that TMC1 c.1714G>A (p.D572N) account for about 4.4% (3/68) of ADNSHL in the Chinese population.
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Biología Computacional/métodos , Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Pueblo Asiatico , Audiometría , Secuencia de Bases , Estudios de Casos y Controles , Niño , Análisis Mutacional de ADN , Femenino , Expresión Génica , Genes Dominantes , Sitios Genéticos , Marcadores Genéticos , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/patología , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Datos de Secuencia Molecular , LinajeRESUMEN
Mutations in PTPRQ are associated with deafness in humans due to defects of stereocilia in hair cells. Using whole exome sequencing, we identified responsible gene of family 1572 with autosomal recessively non-syndromic hearing loss (ARNSHL). We also used DNA from 74 familial patients with ARNSHL and 656 ethnically matched control chromosomes to perform extended variant analysis. We identified two novel compound heterozygous missense mutations, c. 3125 A>G p.D1042G (maternal allele) and c.5981 A>G p.E1994G (paternal allele), in the PTPRQ gene, as the cause of recessively inherited sensorineural hearing loss in family 1572. Both variants co-segregated with hearing loss phenotype in family 1572, but were absent in 74 familial patients. Heterozygosity for c. 3125 A>G was identified in two samples from unaffected Chinese individuals (656 chromosomes). Therefore, the hearing loss in this family was caused by two novel compound heterozygous mutations in PTPRQ.
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Pueblo Asiatico/genética , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva/genética , Mutación/genética , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Exoma/genética , Familia , Femenino , Heterocigoto , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Mutantes/química , Linaje , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/química , Adulto JovenRESUMEN
Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29-55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.
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Heterocigoto , Mutación , Miosinas/genética , Síndromes de Usher/genética , Secuencia de Aminoácidos , Animales , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Miosina VIIa , Miosinas/química , Linaje , Homología de Secuencia de AminoácidoRESUMEN
CONCLUSION: In the current study, hair cells of vestibular terminal organs in rats were completely eliminated with trans-scala vestibuli injection of neomycin, and then the Math1 gene was transferred. It was shown that type I vestibular hair cells were regenerated and synapses were formed. OBJECTIVES: The objective of this study was to identify the cell type of the regenerated vestibular hair cells and relative innervation and synaptic linkage after hair cells of vestibular terminal organs in rats were completely eliminated. METHODS: Neomycin injection was used to eliminate all the vestibular terminal organs, and then the animals were treated with an injection of Ad-Math1-EGFP in the scala vestibuli of the cochlea. RESULTS: Math1 gene transfer into the inner ear induced type I hair cell regeneration and synaptic formation. However, neither the number nor the appearance of the hair cells was normal.