Nonsyndromic Hearing Loss Research Articles

Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: insights from transgenic mouse models

Mutations in various type II transmembrane serine protease (TMPRSS) family members are associated with non-syndromic hearing loss, with some mechanisms still unclear. For instance, the mechanism underlying profound hearing loss and tectorial membrane (TM) malformations in hepsin/TMPRSS1 knockout (KO) mice remains elusive. In this study, we confirmed significantly elevated hearing thresholds and abnormal TM morphology in hepsin KO mice, characterized by enlarged TM with gaps and detachment from the spiral limbus. Transgenic mouse lines were created to express either wild-type or a serine protease-dead mutant of human hepsin in the KO background. The Tg68;KO line, expressing moderate levels of wild-type human hepsin in the cochlea, showed partial restoration of hearing function. Conversely, the Tg5;KO or TgRS;KO lines, with undetectable hepsin or protease-dead hepsin, did not show such improvement. Histological analyses revealed that Tg68;KO mice, but not Tg5;KO or TgRS;KO mice, had a more compact TM structure, partially attached to the spiral limbus. These results indicate that hepsin expression levels correlate with improvements in hearing and TM morphology, and its protease activity is critical for these effects. Hepsin's role was further examined by studying its relationship with α-tectorin (TECTA) and β-tectorin (TECTB), non-collagenous proteins crucial for TM formation. Hepsin was co-expressed with TECTA and TECTB in the developing cochlear epithelium. Immunostaining showed decreased levels of TECTA and TECTB in hepsin KO TM, partially restored in Tg68;KO mice. These findings suggest that hepsin is essential for proper TM morphogenesis and auditory function, potentially by proteolytic processing/maturation of TECTA and TECTB and their incorporation into the TM.

Molecular and Clinical Characterization of a Cohort of Autosomal Recessive Sensorineural Hearing Loss in Egyptian Patients

Hearing loss (HL) is one of the most common health problems worldwide. Autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL) represents a large portion of congenital hereditary HL. Our study was conducted on 13 patients from 13 unrelated families. The majority of patients presented with congenital severe to profound bilateral sensorineural HL. All patients were subjected to detailed family history and three-generation pedigree analysis to exclude any environmental cause and to ensure an autosomal recessive mode of inheritance. Molecular analysis was performed using the whole exome sequencing (WES) technique for the recruited patients. Three variants in the MYO7A and OTOF genes were reported for the first time in patients with ARNSHL (one nonsense, one frameshift, and one splice variant). Ten previously reported variants were detected in seven genes (GJB2, MYO15A, BSND, OTOF, CDH23, SLC26A4, and TMIE). They varied between missense, nonsense, frameshift, and splice variants. This study expands the molecular spectrum of two types of autosomal recessive deafness (types 2 and 9).

A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non-Syndromic Hearing Loss.

Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.

A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice.

PTPRQ plays an important role in the development of inner ear hair cell stereocilia. While many autosomal recessive variants in PTPRQ have been identified as the pathogenic cause for nonsyndromic hearing loss (DFNB84A), so far only one autosomal dominant PTPRQ variant, c.6881G>A (p.Trp2294*), has been reported for late-onset, mild-to-severe hearing loss (DFNA73). By using targeted next-generation sequencing, this study identified a novel PTPRQ truncating pathogenic variant, c.3697del (p.Leu1233Phefs*11), from a Chinese Han family that co-segregated with autosomal dominant, postlingual, progressive hearing loss. A Ptprq-3700del knock-in mouse model was generated by CRISPR-Cas9 and characterized for its hearing function and inner ear morphology. While the homozygous knock-in mice exhibit profound hearing loss at all frequencies at the age of 3 weeks, the heterozygous mutant mice resemble the human patients in mild, progressive hearing loss from age 3 to 12 weeks, primarily affecting high frequencies. At this stage, the homozygous knock-in mice have a normal hair cell count but disorganized stereocilia. Cochlear proteosome analysis of the homozygous mutant mice revealed differentially expressed genes and pathways involved in oxidative phosphorylation, regulation of angiogenesis and synaptic vesicle cycling. Our study provides a valuable animal model for further functional studies of the pathogenic mechanisms underlying DFNA73.

The p. S178L mutation in Tbc1d24 disrupts endosome-mediated synaptic vesicle trafficking of cochlear hair cells and leads to hearing impairment in mice.

The ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle resupply to enable fast and sustained release rates. However, the molecular mechanisms of these physiological activities remain unelucidated. Previous studies showed that the RAB-specific GTPase-activating protein TBC1D24 controls the endosomal trafficking of the synaptic vesicles (SVs) in Drosophila and mammalian neurons, and mutations in TBC1D24 may lead to non-syndromic hearing loss or hearing loss associated with the DOORS syndrome in humans. In this study, we generated a knock-in mouse model for the p. S178L mutation in TBC1D24, which leads to autosomal dominant non-syndromic hearing loss (DFNA65). The p.S178L mutant mice show mild hearing loss and progressively declined wave I amplitude of the auditory brainstem responses. Despite the normal gross and cellular morphology of the cochlea, transmission electron microscopy reveals accumulation of endosome-like vacuoles and a lower-than-normal number of SVs directly associated with the ribbons in the IHCs. Consistently, patch clamp of the IHCs shows reduced exocytosis under prolonged stimulus. ARF6, a TBC1D24-interacting protein also involved in endosomal membrane trafficking, was underexpressed in the cochleae of the mutant mouse and has weakened in vitro interaction with the p.S178L mutant TBC1D24. Our results suggest an important role of TBC1D24 in maintaining endosomal-mediated vesicle recycling and sustained exocytosis of hair cell ribbon synapses.

Identification of a novel EYA4 likely pathogenic variant in a Chinese family with postlingual non-syndromic hearing loss and analysis of molecular epidemiology of EYA4 variants

BackgroundEYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life.MethodsIn this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations.ResultsWe identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family’s phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants.ConclusionsA novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.

Sensorineural Hearing Loss in Patients With the m.1555A>G Mutation in the MTRNR1 Gene.

Mutations in the MTRNR1 gene of mitochondrial DNA are associated with non-syndromic hearing loss and increased susceptibility to aminoglycoside ototoxicity. The aim of our study was to determine the clinical characteristics of sensorineural hearing loss caused by the m.1555A>G mutation in MTRNR1. An observational retrospective study of the m.1555A>G mutation was conducted in patients with suspected hereditary bilateral sensorineural hearing loss in the Department of Otolaryngology of the Marqués de Valdecilla University Hospital (Cantabria, Spain) and in 100 controls with normal hearing. The m.1555A>G mutation was found in 82 individuals from 20 different families and in none of the controls. Variable degrees of hearing loss were observed, ranging from normal hearing to profound deafness. Patients with a history of streptomycin administration exhibited significantly more pronounced hearing loss. The onset of hearing loss occurred from childhood to adulthood, with progression or stability over the years. No associated vestibular alterations or other clinical manifestations outside the ear were found. Two cochlear implant recipients showed significant improvement in speech comprehension. Patients with the m.1555A>G mutation in the MTRNR1 gene often develop bilateral, symmetric sensorineural hearing loss, predominantly affecting high frequencies, worsened by streptomycin administration. This mutation does not affect the vestibular function. The variability in the severity of hearing loss, the heterogeneity of phenotypic expression, and the presence of carrier individuals with normal hearing may indicate the existence of modifying factors, both environmental and genetic. Cochlear implantees showed a good response in terms of speech intelligibility. Genetic testing for this mutation is recommended in patients with a family history of hearing loss to prevent the use of aminoglycosides if the mutation is found. 4 Laryngoscope, 2024.

DMXL2 Is Required for Endocytosis and Recycling of Synaptic Vesicles in Auditory Hair Cells.

Ribbon synapses of inner hair cells (IHCs) are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles (SVs), however, remains elusive. This study showed that hair cell knock-out of murine Dmxl2, whose human homolog is responsible for nonsyndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave I amplitude of the auditory brainstem response. Membrane capacitance measurements of the IHCs revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of SVs and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the SVs.

Identification of novel likely pathogenic variant in CDH23 causing non-syndromic hearing loss, and a novel variant in OTOGL in an extended Iranian family

BackgroundSensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous group of disorders of the auditory system. SNHL can occur as a symptom in more than 400 syndromes, and mutations in more than 150 genes can lead to SNHL. Mutations in the GJB2 and GJB6 genes are among the most common causes of SNHL worldwide. Mutations in Cadherin 23 (CDH23) can cause Usher syndrome and/or non-syndromic hearing loss (NSHL).Material and methodsIn this study, the Whole Exome Sequencing (WES) was used to detect the cause of hearing loss in a large consanguineous Iranian family with two patients. All family members underwent a thorough Genotype–phenotype correlation assessment and co-segregation analysis to understand the inheritance pattern within the family. The candidate variants were further confirmed by Sanger sequencing. In addition, in silico analysis was performed to predict the functional impact of the variants; the interpretation of the variants was performed in accordance with the American College of Medical Genetics (ACMG) guidelines.ResultsWES results identified two novel variants, a homozygous missense variant in CDH23 (c.2961T > G) and a heterozygous splice site variant in OTOGL that was compatible with the autosomal recessive pattern of inheritance. Bioinformatics studies confirmed the pathogenic effects of novel variants. The c.2961T > G variant was classified as likely pathogenic.ConclusionsThe novel identified variant in the CDH23 was the cause of congenital profound progressive form of HL. Samples were not available from the second family to distinguish which variant is responsible for the molecular pathology of the disease. Further studies and functional examinations are suggested for investigating the role of OTOGL: c. 1863-1G > T in deafness.

Identification of novel CDH23 variants linked to hearing loss in a Chinese family: A case report.

Deafness is associated with both environmental and genetic factors, with hereditary deafness often caused by mutations in deafness-related genes. Identifying and analyzing deafness-related genes will aid in early diagnosis and pave the way for treating inherited deafness through gene therapy in the future. A 15-month-old girl underwent audiological examination at the outpatient clinic of the hospital due to hearing loss and her brother was diagnosed with profound bilateral sensorineural hearing loss at the age of 3. The diagnosis was determined as extremely severe sensorineural hearing loss caused by genetic factors. Clinical data of the patient were collected, and peripheral blood samples were obtained from both the patient and her family members for DNA extraction and sequencing. By utilizing targeted capture next-generation sequencing to further screen for deafness-related genes, 2 novel variants in CDH23 were identified as the causative factors for the patient's deafness. This study identified 2 novel heterozygous mutations in a Chinese family. Both the proband and her sibling have non-syndromic hearing loss (NSHL) and carry distinct heterozygous mutations of cadherin-like 23 (CDH23). One mutation, CDH23:c.2651 A>G, originated from their mother and paternal family, affecting the exon23 domain of CDH23. The other mutation, CDH23:c.2113 G>T, was inherited from their paternal grandmother, impacting the exon19 domain of CDH23. These 2 novel mutations likely cause NSHL by affecting protein function. This finding suggests that identifying 2 novel mutations in CDH23 contributes to the genetic basis of NSHL.

A Village in the Southeastern Region of Iran Harboring the c.716T>A (p.Val239Asp) Mutation in SLC26A4.

After GJB2, SLC26A4 is the second most common contributor to autosomal recessive nonsyndromic hearing loss (ARNSHL) worldwide. In this study, we used Exome Sequencing (ES) to present a village with 31 individuals affected by hereditary hearing loss (HHL) in southeastern Iran near the border of Pakistan. The village harbored the known pathogenic missense SLC26A4 (NM_000441.2):c.716T>A (p.Val239Asp) mutation, which has a founder effect attributed to Pakistan, Iran's southeastern neighbor. Our findings, in addition to unraveling the molecular cause of non-syndromic hearing loss in these patients and further confirming the common ancestry and migration story between the people of this region and Pakistan, provide further insight into the genetic background of this region and highlight the importance of understanding the mutation spectrum of GJB2 and SLC26A4 in different regions to choose cost-effective strategies for molecular genetic testing.

Hearing loss secondary to variants in the OTOF gene

ObjectiveGenetic variants in the OTOF gene are responsible for non-syndromic hearing loss with an autosomal recessive inheritance pattern. The objective of our work was to evaluate the clinical characteristics of patients with biallelic pathogenic variants in OTOF and their evolution after treatment. MethodsA cohort of 124 patients with prelingual hearing loss, studied from 1996 to 2023, was included in this study. A genetic analysis was conducted to identify the type and frequency of variants in the OTOF gene and their relation to the clinical characteristics of the patients. ResultsThe homozygous p. Gln829* variant in the OTOF gene was detected in 3 probands (2.4 %) of a group of 124 individuals with prelingual hearing loss. Another 6 family members to a total of 9 individuals were finally included. All presented with severe/profound bilateral sensorineural hearing loss of congenital onset. Three of these individuals were diagnosed with auditory neuropathy spectrum disorder. One individual passed the OAE test during the screening program, and since he did not have risk factors for hearing loss that would warrant ABR testing, this led to a delay in his hearing loss diagnosis. Four individuals underwent cochlear implants (three bilateral) with good functional outcomes in three of them. However, in 17 familial cases with heterozygous variants, either no hearing loss was observed or it was within the expected range for their age. ConclusionsHearing loss secondary to the p.Gln829* variant of the OTOF gene is relatively rare in our medical area. Its presence in homozygosity is the cause of severe/profound bilateral prelingual sensorineural hearing loss, responsible for auditory neuropathy with a good response to cochlear implantation.

Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss.

Autosomal dominant hearing loss is represented by a large number of genetically determined forms. Over 50 genes associated with dominant nonsyndromic hearing impairments were described. Pathogenic variants in the CEACAM16 gene lead to the development of DFNA4B hearing loss. Currently, 8 pathogenic variants in this gene have been described. The objective of this study was to study the audiological and molecular genetic characteristics of a large family with CEACAM16-associated autosomal dominant nonsyndromic hearing loss. A detailed anamnesis was collected, and a comprehensive audiological examination was performed for 21 family members. Genetic testing was performed, including whole-genome sequencing for the proband's son and Sanger sequence analysis for the proband and for all available family members. In a large Russian family, including 5 generations, an autosomal dominant type of slowly progressing nonsyndromic late-onset hearing loss was observed. Eleven family members suffer from hearing impairment, which starts with tinnitus and threshold increase at high frequencies, since the age of 5-20 years. Hearing loss slowly progresses with age in each person and is similar to age-related hearing loss. We have detected the novel likely pathogenic variant с.419С>T (p.(Thr140Ile)) in exon 3 of the CEACAM16 gene, which segregates with late-onset nonsyndromic hearing loss in this family. The clinical data obtained in the examined family correspond with the phenotype in previously described cases. In general, the study widened the mutation spectrum of the gene, allowing to carry out medical genetic counseling and to answer the questions about the hearing impairment prognosis for future generations.

Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort.

Hearing loss is a common sensory disorder that impacts patients across the lifespan. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Yet, genetic testing is not routinely administered when hearing loss is diagnosed, particularly in adults. In this study, genetic testing was completed in patients with known hearing loss. A total of 104 patients who were evaluated for hearing loss were enrolled and received genetic testing. Of those 104 patients, 39 had available genetic testing, 20 had one missing allele, and 45 yielded no genetic diagnosis. Of the 39 cases with genetic testing data, 24 were simplex cases, and 15 were multiplex cases. A majority of patients presented with an autosomal recessive inheritance pattern (n = 32), 26 of whom presented with congenital hearing loss. 38% of cases were positive for GJB2 mutation with c.35delG being the most common pathogenic variant. These findings are consistent with previous literature suggesting GJB2 mutations are the most common causes of non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up, particularly as gene therapies are studied and become more widely available. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered a routine part of the hearing loss work-up.

Genetic analysis of TRIOBP and MYO15A variants in Iranian families with autosomal recessive non-syndromic hearing loss

BackgroundDeafness is a prevalent sensory and neurological disorder that impacts over 466 million individuals globally. Congenital deafness is the most prevalent birth defect, occurring in approximately 2–3 out of every 1000 births. It is recognized as a highly diverse condition. >50% of congenital deafness has genetic causes and the rest is due to environmental causes or both. With the development of next-generation sequencing and bioinformatics tools, whole-exome sequencing has been proposed as one of the effective methods for diagnosing genetics of hearing loss. MethodFive Iranian Autosomal recessive non-syndromic hearing loss (ARNSHL) families negative for GJB2 (NM_004004.6) gene mutations from Sistan and Baluchestan province were selected for further study by whole-exome sequencing analysis. The analysis procedure was performed using multiple bioinformatics tools and websites after filling the consent form and extracting DNA from whole blood using the salting out method. After detecting the variants in priority and confirming them in the probands by Sanger sequencing, other family members were studied to confirm the variant within the family. ResultsAfter analyzing the families recruited for this study, four known genes along with known and novel variants were discovered. Mutations found in the MYO15A, SLC26A4, TRIOBP and TECTA genes among which, the variants found in TRIOBP (NM_001039141.3, p.R283X) and MYO15A (NM_016239.4, p.P2880Rfs*19) were novel. Other known variants were TECTA (NM_005422.4, p.W1534X) and SLC26A4 (NM_000441.2, p.V239D). No genes or variants that might contribute to hearing loss have been identified within one of the families. ConclusionOur study's findings support previous research that has identified SLC26A4, MYO15A, and TECTA genes as common genetic factors following GJB2 in our population.

Novel GJB2 mutation c.188delT compound with c.235delC causing non-syndromic hearing loss in a Chinese family: A case report.

Congenital sensorineural hearing loss is a significant global health issue, primarily driven by genetic factors, such as mutations in the GJB2 gene. This report presents a Chinese girl with congenital deafness and a novel mutation of the GJB2 gene. A newborn Chinese girl exhibited signs of congenital deafness. Congenital deafness was confirmed through comprehensive newborn hearing screenings that included otologic, audiologic, and physical examinations. Genetic analysis revealed a compound heterozygous mutation involving c.188delT and c.235delC in the GJB2 gene, indicating a genetic basis for her hearing loss. The patient underwent cochlear implantation, which resulted in stable auditory outcomes. Despite follow-up difficulties, stable auditory outcomes were achieved post-cochlear implantation, highlighting the potential efficacy of this intervention in GJB2-related hearing loss. This case study enriches our understanding of GJB2 mutations and underscores the critical role of genetic testing in diagnosing congenital sensorineural hearing loss. It emphasizes the necessity for early intervention and sustained interdisciplinary care to enhance the quality of life for patients with genetic hearing impairment.

Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1.

Background: Mutations in Wolfram syndrome 1 (WFS1) cause Wolfram syndrome and autosomal dominant non-syndromic hearing loss DFNA6/14/38. To date, more than 300 pathogenic variants of WFS1 have been identified. Generally, the audiological phenotype of Wolfram syndrome or DFNA6/14/38 is characterized by low-frequency hearing loss; however, this phenotype is largely variable. Hence, there is a need to better understand the diversity in audiological and vestibular profiles associated with WFS1 variants, as this can have significant implications for diagnosis and management. This study aims to investigate the clinical characteristics, audiological phenotypes, and vestibular function in patients with DFNA6/14/38. Methods: Whole-exome or targeted deafness gene panel sequencing was performed to confirm the pathogenic variants in patients with genetic hearing loss. Results: We identified nine independent families with affected individuals who carried a heterozygous pathogenic variant of WFS1. The onset of hearing loss varied from the first to the fifth decade. On a pure-tone audiogram, hearing loss was symmetrical, and the severity ranged from mild to severe. Notably, either both low-frequency and high-frequency or all-frequency-specific hearing loss was observed. However, hearing loss was non-progressive in all types. In addition, vestibular impairment was identified in patients with DFNA6/14/38, indicating that impaired WFS1 may also affect the vestibular organs. Conclusions: Diverse audiological and vestibular profiles were observed in patients with pathogenic variants of WFS1. These findings highlight the importance of comprehensive audiological and vestibular assessments in patients with WFS1 mutations for accurate diagnosis and management.

Burden of rare genetic disorders in India: twenty-two years’ experience of a tertiary centre

BackgroundRare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India.ResultsOverall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study.ConclusionThe present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Genetic landscape of hearing loss in prelingual deaf patients of eastern Iran: Insights from exome sequencing analysis.

Hearing loss is one of the most prevalent genetic disorders in humans. Locus and allelic heterogeneity cause fundamental challenges in hearing loss genetic diagnosis and management of patients and their families. This study examined the genetic profile of patients with prelingual hearing loss who were referred to the Genetic Foundation of Khorasan Razavi spanning over a decade. Deleterious variants in GJB2 were evaluated through Sanger sequencing among 745 non-syndromic hearing loss patients. Furthermore, exome sequencing was applied in 250 patients with negative GJB2 sequencing results and 30 patients with syndromic hearing loss. The findings revealed a relatively low frequency of GJB2 variants among the studied patients. Exome sequencing successfully identified the genetic causes of hearing loss in 70% of the patients. Moreover, variants in 10 genes, namely SLC26A4, MYO15A, TMPRSS3, TMC1, OTOF, CDH23, PJVK, MYO7A, TECTA, and PCDH15, accounted for 66% of the positive exome sequencing findings in this study. At least three prevalent founder alleles in the hearing-impaired population of eastern Iran were identified. This study emphasizes the efficiency of exome sequencing as a powerful tool for determining the etiology of prelingual hearing loss in the eastern Iranian population.

First report of an Ivorian family with nonsyndromic hearing loss caused by GJB2 compound heterozygous variants.

The primary etiology of congenital hearing loss is attributed to genetic factors, with GJB2 identified as a pivotal gene across diverse ethnic groups. Additionally, nonsyndromic hearing loss is predominantly inherited in an autosomal recessive manner. We used Sanger sequencing to analyze GJB2 in 17 deaf children from 13 unrelated Ivory Coast families. One family had two children born with severe congenital deafness and exhibited pathogenic compound heterozygous variants. These variants included a nonsense substitution (c.132G>A or p.Trp44Ter) and a newly discovered duplication of 7 base pairs (c.205_211dupTTCCCCA or p.Ser72ProfsTer32). Segregation testing confirmed these variants, marking the first identification of GJB2 in an Ivorian family with congenital hearing loss.