A Case of Class I 17p13.3 Microduplication Syndrome with Unilateral Hearing Loss.

17p13 is a chromosomal region characterized by genomic instability due to high gene density leading to multiple deletion and duplication events. 17p13.3 microduplication syndrome is a rare condition, reported only in 40 cases worldwide, which is found in the Miller-Dieker chromosomal region, presenting a wide range of phenotypic manifestations. Usually, the duplicated area is de novo and varies in size from 1.8 to 4.0 Mbp. Critical genes for this region are PAFAH1B1 (#601545), YWHAE (#605066), and CRK (#164762). 17p13.3 microduplication syndrome can be categorized into two classes (Class I and Class II) based on the genes that are present in the duplicated area, which lead to different phenotypes. In this report, we present a new case of Class I 17p13.3 microduplication syndrome that presents with unilateral sensorineural hearing loss. Oligonucleotide and SNP array comparative genomic hybridization (a-CGH) analysis revealed a duplication of approximately 121 Kbp on chromosome 17p13.3, which includes YWHAE and CRK genes. Whole-exome sequencing (WES) analysis confirmed the duplication. Our patient has common clinical symptoms of Class I 17p13.3 microduplication syndrome, and in addition, she has unilateral sensorineural hearing loss. Interestingly, WES analysis did not detect any mutations in genes that are associated with hearing loss. The above findings lead us to propose that hearing loss is a manifestation of 17p13.3 duplication syndrome.

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss.

OBJECTIVE: Unilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features. STUDY DESIGN: Retrospective analysis of a prospectively recruited cohort. SETTING: Tertiary referral center. METHODS: We enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next-generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies. RESULTS: Causative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild-to-moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole-genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses. CONCLUSION: Genetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children.

Comparison of the prevalence and features of inner ear malformations in congenital unilateral and bilateral hearing loss.

OBJECTIVES: The aim of the study was to clarify differences in the prevalence and features of bony malformations in inner ear between congenital unilateral sensorineural hearing loss (USNHL) and congenital bilateral sensorineural hearing loss (BSNHL). METHODS: We conducted a retrospective study of 378 consecutive infants referred from routine newborn hearing screening in the past 18 years. Clinical background, audiological data, and temporal bone computed tomography (CT) findings were analyzed. The prevalence of malformations between USNHL and BSNHL groups were compared using the Chi-square test. RESULTS: The proportion of family history of hearing loss was significantly higher in infants with BSNHL than in those with USNHL (26/107 [24.3%] vs. 4/105 [3.7%]; p = 0.0001). Temporal bone CT scanning revealed significantly a higher prevalence of inner ear malformations in infants with USNHL than in those with BSNHL (93/109 [85.3%] vs. 4/107 [3.7%]; p < 0.0001). The most frequent anomaly in USNHL was cochlear nerve canal stenosis (69.7%), followed by cochlear malformations (20.2%), and narrow internal auditory canal (17.4%). Four infants with BSNHL accompanied by inner ear anomaly had complications such as Down's syndrome, developmental delay, or epilepsy. CONCLUSIONS: The prevalence of bony malformations in inner ear and/or IAC was markedly higher in infants with congenital USNHL than in infants with BSNHL. Temporal bone CT scanning may help to clarify the etiology of congenital hearing loss, especially in USNHL.

A rare case of Waardenburg syndrome with unilateral hearing loss caused by nonsense variant c.772C>T (p.Arg259*) in the MITF gene in Yakut patient from the Eastern Siberia (Sakha Republic, Russia).

Waardenburg syndrome (WS) is an orphan genetic disease with autosomal dominant pattern of inheritance characterised by varying degrees of hearing loss accompanied by skin, hair and iris pigmentation abnormalities. Four types of WS differing in phenotypic characteristics are now described. We performed a Sanger sequencing of coding regions of genes PAX3, MITF, SOX10 and SNAI2 in the patient with WS from a Yakut family living in the Sakha Republic. No changes were found in the PAX3, SOX10 and SNAI2 coding regions while a previously reported heterozygous transition c.772C>T (p.Arg259*) in exon 8 of the MITF gene was found in this patient. This patient presents rare phenotype of WS type 2: congenital unilateral hearing loss, unilateral heterochromia of irises, and absence of skin/hair depigmentation and dystopia canthorum. Audiological variability in WS type 2, caused by the c.772C>T (p.Arg259*) variant in the MITF gene, outlines the importance of molecular analysis and careful genotype-phenotype comparisons in order to optimally inform patients about the risk of hearing loss. The results of this study confirm the association of pathogenic variants in the MITF gene with WS type 2 and expanded data on the variability of audiological features of the WS.

Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss.

Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.

Unilateral Sensorineural Hearing Loss: Medical Context and Etiology.

OBJECTIVE: Unilateral sensorineural hearing loss (USNHL) is known to impact on school performance and social skills during childhood, but the etiologies remain unclear. The aim of this study was to assess various etiologies and to study the clinical contexts in this population. METHODS: The study is a retrospective review. Characteristics of hearing loss (HL), audiometric parameters, imaging, and genetic and medical contexts were analyzed. RESULTS: Eighty children were included. USNHL was profound in 68%, could be progressive in 19%, and become bilateral in 7.5% of cases. Inner ear malformations were identified in 41% of cases; cochlear nerve deficiency (CND) was frequent (33%). Cytomegalovirus (CMV) infection and genetic syndromes were confirmed in 10 and 6% of cases, respectively. CONCLUSION: Long-term hearing follow-up remains useful in USNHL as it can become bilateral. Looking to etiology, MRI should be the gold standard, as CND is frequently observed and screening for CMV infection should be systematic. Genetic etiologies appear to be different compared to bilateral HL. Further genetic research in this domain is needed.

Concomitant imaging and genetic findings in children with unilateral sensorineural hearing loss.

OBJECTIVE: To describe the concomitant imaging and genetic findings in children diagnosed with non-syndromic unilateral sensorineural hearing loss. METHODS: A retrospective cohort study was conducted of 60 children diagnosed between January 2005 and December 2015 in a tertiary-level paediatric institution. RESULTS: Average age at diagnosis was 4.3 years. All children were considered non-syndromic. Hearing loss was categorised as mild (17 children), moderate (17 children), severe (7 children) or profound (19 children). Imaging was performed in 43 children (71.66 per cent). Nineteen patients (44.2 per cent) had positive computed tomography or magnetic resonance imaging findings. Genetic testing was performed in 51 children (85 per cent). Sixteen children (31 per cent) tested positive to connexin 26 (GJB2); 1 patient (2 per cent) had a homozygous mutation of GJB2 and 15 were heterozygous carriers. Amongst children who tested positive as heterozygous carriers of a GJB2 mutation, there was a high rate of positive imaging findings (47 per cent compared to 37.2 per cent in the total cohort). A genetic abnormality was confirmed in 50 per cent of children with positive imaging findings who underwent genetic testing. CONCLUSION: Rates of concomitant imaging and genetic findings suggest that both investigations are of value in the study of these patients.

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review.

OBJECTIVE: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. METHODS: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. RESULTS: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. CONCLUSION: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-ß1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

Molecular Etiology of Hereditary Single-Side Deafness: Its Association With Pigmentary Disorders and Waardenburg Syndrome.

Unilateral sensorineural hearing loss (USNHL)/single-side deafness (SSD) is a frequently encountered disability in children. The etiology of a substantial portion of USNHL/SSD still remains unknown, and genetic causes have not been clearly elucidated. In this study, the authors evaluated the heritability of USNHL/SSD.The authors sequentially recruited 50 unrelated children with SSD. For an etiologic diagnosis, we performed a rigorous review on the phenotypes of family members of all children and conducted, if necessary, molecular genetic tests including targeted exome sequencing of 129 deafness genes.Among the 50 SSD children cohort, the authors identify 4 (8%) unrelated SSD probands from 4 families (SH136, SB173, SB177, and SB199) with another hearing impaired family members. Notably, all 4 probands in our cohort with a familial history of SSD also have pigmentary abnormalities such as brown freckles or premature gray hair within first degree relatives, which may indicate that genes whose products are involved with pigmentary disorder could be candidates for heritable SSD. Indeed, SH136 and SB199 turned out to segregate a mutation in MITF and PAX3, respectively, leading to a molecular diagnosis of Waardenburg syndrome (WS).We report, for the first time in the literature, a significant heritability of pediatric SSD. There is a strong association between the heritability of USNHL/SSD and the pigmentary abnormality, shedding a new light on the understanding of the molecular basis of heritable USNHL/SSD. In case of children with congenital SSD, it would be mandatory to rigorously screen pigmentary abnormalities. WS should also be included in the differential diagnosis of children with USNHL/SSD, especially in a familial form.

Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology.

AIM: The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. METHODS: The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. RESULTS: Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA-positive children were carriers of mutations of Cx26. CONCLUSION: Congenital CMV infection is a high risk factor in hearing impairment among children.

Etiology of unilateral hearing loss in a national hereditary deafness repository.

PURPOSE: The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository. MATERIALS AND METHODS: This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment. Candidate deafness genes were screened by single-stranded conformation polymorphism, and mutations were confirmed with sequencing. RESULTS: Thirty-four subjects (19 males, 15 females) with unilateral HL were identified, ranging in age from 2 months to 36 years. The mean age at diagnosis was 7 years, and the left ear was affected in 62% of the cases. The racial distribution of our sample was 62% white, 23% African American, and 15% Hispanic. Imaging results were available in 47%, and most (69%) were considered normal. Nineteen percent had enlarged vestibular aqueducts, 2 had ipsilateral Mondini dysplasia, and 1 had a common cavity deformity. Twenty subjects (59%) had a family history of HL, with 26% specifically reporting familial unilateral HL. Mutational screening revealed sequence variants in the GJB2 (connexin 26), GJB3 (connexin 31), TECTA, and COCH genes. Two novel mutations were detected in COCH and TECTA. CONCLUSIONS: Sequence variants in known deafness genes were detected in more than one-third of our study population, suggesting that gene/gene or gene/environmental interactions may indeed play a role in the etiology of some cases of unilateral deafness. Further prospective studies including congenital cytomegalovirus screening at birth and molecular screening of deafness genes in children with congenital unilateral HL will be required to establish the etiology of unilateral deafness with certainty.

Congenital deafness in Jack Russell terriers: prevalence and association with phenotype.

Congenital hereditary sensorineural deafness is the most common form of deafness in dogs. The objectives of this study were to determine a reliable measure of the prevalence of deafness in Jack Russell terriers, an affected breed, and associations between deafness and phenotypic characteristics. Brainstem auditory evoked response recordings and phenotypic parameters (coat color, coat texture, sex, eye color, sire and dam hearing status) were recorded for 1009 Jack Russell terriers. The prevalence of unilateral and bilateral deafness was 3.57% and 0.50%, respectively, lower by a factor of three to four than in earlier reports based on smaller and closely related kindreds. Significant association with deafness was identified with white coat color and parental hearing status, but not with sex or coat type. Lack of significant sex or coat type associations and the significant association with white coat color are consistent with previous reports. In conclusion the prevalence of deafness in Jack Russell terriers is lower than initially reported. Deafness was associated with white coat color and parental hearing status. The association with parental hearing status supports this form of deafness being a heritable trait in the breed and the association with white coat color supports an inheritance linked to pigmentation genes.

[Analysis of positive rate of common genetic mutations in 1448 cases with different hearing phenotype].

OBJECTIVE: To analyze the positive rate of common genetic mutations in Chinese non-syndromic sensorineural hearing loss groups with different hearing phenotype. METHOD: One thousand four hundred and forty-eight subjects with hearing test results received at least one of three genetic testings including: mutations in coding region of GJB2 and SLC26A4 with sequencing analysis and mitochondrial DNA C1494T/A1555G with microarray detection. Of 1448 subjects, 1333 have bilateral sensorineural hearing loss, 65 have unilateral hearing loss and 50 have normal hearing threshold even though they have high frequency hearing loss or family history. The informed consent of each subject was achieved. RESULT: Mutation positive rate of GJB2, SLC26A4 and mtDNA C1494T/ A1555G of 1448 subjects were 19.23%, 27.55%, 0.1% and 1.72% respectively. The positive rate of GJB2 and SLC26A4 mutations in bilateral hearing loss group (20.22%, 29.17%) was statistically significantly higher than unilateral group (0, 0) (P < 0.01). In bilateral hearing loss group, the positive rate of GJB2 mutations was highest in the profound group (24.67%), and then severe (22.33%), moderate (14.33%) and mild group (6.58%) (P < 0.01). The positive rate of SLC26A4 mutations was highest in the severe group (48.67%), and then profound (28.42%), moderate (21.16%) and mild (8.93%) (P < 0.01). CONCLUSION: The positive rate of GJB2 and SLC26A4 mutations is high in the groups with bilateral profound and severe sensorineural hearing loss, whose genetic testing should be put emphasis on. However, the genetic testing should be performed in patients with mild to moderate hearing impairment as well if necessary.

Screening of SLC26A4, FOXI1 and KCNJ10 genes in unilateral hearing impairment with ipsilateral enlarged vestibular aqueduct.

OBJECTIVE: To investigate the implication of SLC26A4, FOXI and KCNJ10 genes in unilateral hearing impairment associated with ipsilateral inner ear malformation (Enlargement of the vestibular aqueduct and/or Mondini dysplasia). METHODS: We have gathered 25 patients presenting unilateral hearing impairment and ipsilateral enlarged vestibular aqueduct. For each of the patients, we have analyzed SLC26A4, FOXI1 and KCNJ10 genes sequences. RESULTS: The analysis of SLC26A4 revealed only eight heterozygous SLC26A4 sequence variants, three of them being novel (p.Met147Ile, p.Asn538Asn and p.Leu627Arg). None of the patients carried a second mutation on the other allele. Moreover, the SLC26A4 locus was excluded by segregation analysis in two families. No mutations were present in FOXI1 and KCNJ10 genes. CONCLUSIONS: Together, these data suggest that SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct compared with their implication in Pendred syndrome and non-syndromic bilateral enlarged vestibular aqueduct.

Haploinsufficiency of 16.4 Mb from chromosome 22pter-q11.21 in a girl with unilateral conductive hearing loss.

We present the postnatal diagnosis of a de novo der(18)t(18;22)(p11.32;q11.21)pat, resulting in an unbalanced 45,XX,der (18)t(18;22) karyotype in a girl with conductive hearing loss on the left and ptosis of the right upper eye-lid. Unilateral ptosis was also observed in the patient's 2 years and 8 months younger sister, who grows noticeably faster and appears to be a much quicker learner. After speech therapy the patient was eventually placed in normal school. The haploinsufficient 16.4-Mb region on chromosome 22pter-->q11.21 contains 10 genes as well as many predicted genes, pseudogenes, and retrotransposed sequences with unknown functions. This observation may prove useful for prenatal diagnosis and genetic counselling of chromosome 22q11.1 gains and losses.

Response of the flat cochlear epithelium to forced expression of Atoh1.

Following hair cell elimination in severely traumatized cochleae, differentiated supporting cells are often replaced by a simple epithelium with cuboidal or flat appearance. Atoh1 (previously Math1) is a basic helix-loop-helix transcription factor critical to hair cell differentiation during mammalian embryogenesis. Forced expression of Atoh1 in the differentiated supporting cell population can induce transdifferentiation leading to hair cell regeneration. Here, we examined the outcome of adenovirus mediated over-expression of Atoh1 in the non-sensory cells of the flat epithelium. We determined that seven days after unilateral elimination of hair cells with neomycin, differentiated supporting cells are absent, replaced by a flat epithelium. Nerve processes were also missing from the auditory epithelium, with the exception of infrequent looping nerve processes above the habenula perforata. We then inoculated an adenovirus vector with Atoh1 insert into the scala media of the deafened cochlea. The inoculation resulted in upregulation of Atoh1 in the flat epithelium. However, two months after the inoculation, Atoh1-treated ears did not exhibit clear signs of hair cell regeneration. Combined with previous data on induction of supporting cell to hair cell transdifferentiation by forced expression of Atoh1, these results suggest that the presence of differentiated supporting cells in the organ of Corti is necessary for transdifferentiation to occur.

Causation of permanent unilateral and mild bilateral hearing loss in children.

Children with permanent unilateral or mild bilateral hearing loss have been a focus of concern by audiologists, educators, and physicians for at least 2 decades. These children are known to be at risk for psychoeducational difficulties. However, despite this concern, little has been learned about the causative factors of these hearing losses and how those factors might be contributing to child development. This review of known causes of permanent unilateral and mild bilateral hearing loss in children is meant to draw attention to the importance of the search for etiologic factors. That is, the identification of the hearing loss should not signal the end of the diagnostic process but, rather, the beginning of a search for causation. With the combined efforts of audiologists, otolaryngologists, pediatricians, geneticists, and other medical professionals, we may enhance our understanding of the primary causes of unilateral and mild bilateral hearing loss and, perhaps, create links between causative factors and psychosocial and psychoeducational outcomes.