The molecular genetic diagnosis of prelingual sensorineural hearing impairment (HI) is essential for genetic counseling and patient management. Effective diagnosis requires a knowledge of the genetic architecture of HI, which is often lacking. We established a cohort of 450 unrelated patients with familial (at least two affected relatives) severe-to-profound bilateral prelingual HI in five countries with high consanguinity rates: Tunisia, Jordan, Algeria, Morocco, and Mauritania (the TJAMM cohort). Recessive and dominant inheritance were observed in 92% and 8% of cases, respectively; 14% were syndromic. Genome analysis detected 211 different mutations (36% not reported before) in 49 deafness genes, and fully resolved 90% of cases of autosomal recessive isolated deafness (DFNB forms), 89% of the mutations being homozygous. The deafness genes involved were similar in different countries, but their mutations, except a few in GJB2 and LRTOMT, differed considerably, suggesting an overrepresentation of private mutations. Biallelic missense mutations in MYO7A, CDH23, PCDH15, USH1C cause either DFNB forms or Usher syndrome type 1 (USH1) (USH1/DFNB genes). Such mutations were overrepresented (13% of patients), highlighting the importance of distinguishing between these two mutation classes. We hypothesized that current difficulties might stem from the misclassification of certain mutations. By studying the 65 USH1/DFNB missense mutations reported to cause DFNB in the homozygous state, we identified some that, when associated with a loss-of-function mutation, resulted in USH1, a characteristic pattern of some recessive hypomorphic mutations. This reappraised classification of USH1/DFNB mutations has the potential to improve molecular diagnosis and patient management significantly.

ObjectiveThis current cross-sectional study aimed to investigate the demographic characteristics and molecular epidemiology of patients with Usher syndrome in the Turkish population.MethodsPatients who were followed up with a preliminary diagnosis of Usher syndrome from various regions of the country were included in the study. After a review of patients' medical histories, all underwent ophthalmological and otorhinolaryngological examinations. Mutations reported in previous studies in MYO7A, PCDH15, USH1C, CDH23, and USH2A were investigated using Sanger sequencing.ResultsFourteen (29.2%) patients had Usher syndrome type 1 and 16 (33.3%) had type 2. Eighteen (37.5%) patients could not be typed. We detected mutations in MYO7A (c.1343 + 1 G > A) in seven patients (six heterozygous and one homozygous) from seven families clinically compatible with Usher syndrome type 2 (rather than Usher syndrome type 1, as was expected based on previous studies).ConclusionsOur preliminary findings suggest that the proportions of patients with Usher syndrome type 1 and Usher syndrome type 2 in the Turkish population were almost equal, and none of our patients was clinically compatible with Usher syndrome type 3. Although previous studies reported that mutations in MYO7A rarely caused Usher syndrome type 2, in the Turkish population, MYO7A alleles may be hypomorphic and manifest as a milder phenotype in Usher syndrome compared with other populations.

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions leading to visual impairment and blindness with over 280 associated genes identified so far. This study aims to provide an initial characterization of the clinical and genetic landscape of IRDs in the United States with a cohort from Kentucky and contribute to the existing knowledge from studies in other regions. This single-academic center retrospective analysis was conducted on patients seen at the University of Kentucky Ophthalmic Genetic Services from January 2019 to March 2022 with a diagnosis of or concern for unspecified IRD and who underwent subsequent genetic testing with an IRD panel. The study included 366 subjects with a pre-genetic testing IRD diagnosis, with an age range from 9 to 87 years old and mean age of 42.11 years. The most common pre-genetic diagnoses were retinitis pigmentosa (RP) in 116 subjects (31.69%), referral for ‘concern for unspecified IRD’ in 107 subjects (29.23%), and macular dystrophy in 31 subjects (8.46%). The diagnostic yield of genetic testing for rod-cone dystrophy (RCD) cases was 83.89%. The five most common genetic testing confirmed diagnoses were RP, Usher syndrome type 2 (USH2A), Stargardt disease (STGD), Bardet-Biedl syndrome (BBS), and Usher syndrome type 1 (USH1). A total of 46 individual genes had pathogenic variants. The three most frequently pathogenic genes were RHO, USH2A, and ABCA4, with 5 pathogenic variants within RHO, 20 within USH2A, and 17 within ABCA4. Five novel variants were identified across the WFS1, ARSG, USH2A, ADGRV1, and PCDH15 genes. This study characterizes the genetic landscape of IRDs in a Kentucky cohort, with pathogenic variants in 46 genes, including five novel variants. These novel variants highlight the need for continued research to identify more population-specific variants. The findings highlight the value of genetic testing and contribute to advancing IRD research and care. ClinicalTrials.gov registration number: NCT06177977. First posted date: 12/20/2023. The online version contains supplementary material available at 10.1186/s12920-025-02186-5.

The aim of this study was to describe a patient with a rare co-occurrence of Usher syndrome type 1C and renal disease, suspected to be secondary to Alport syndrome. This was a case report and literature review of cases with Usher syndrome and renal failure. Clinical examination, color fundus photography, visual field tests, electroretinography, and whole-exome sequencing were used to diagnose and document the patient's clinical presentation. An 18-year-old female patient with a known history of congenital hearing loss and chronic renal failure presented with progressive night and peripheral visual impairment, suspicious for an inherited retinal disease. Visual field testing, fundus examination, and electroretinography findings supported the diagnosis of Usher syndrome. Whole-exome sequencing identified a novel homozygous frameshift variant (c.238del) in USH1C gene. Whole-exome sequencing also identified a homozygous COL4A3 variant of unknown significance, which may be responsible for concomitant Alport syndrome. By presenting this rare case of co-occurring Usher syndrome Type 1 and renal failure, the authors highlight the importance of conducting further investigations that could reveal an additional underlying etiology when these entities are present.

Advancements in genetic testing have led to Usher syndrome now being diagnosed at a much earlier age than in the past, enabling the provision of early intervention and support to children and families. Despite these developments, anecdotal reports suggest there are substantial gaps in the services and supports provided to parents of children with Usher syndrome. The current study investigated the support needs of parents of children with Usher syndrome Type 1 when their child was aged 0 to 5 years. Purposive sampling was used, and six semi-structured interviews were conducted with Australian parents of children with Usher syndrome, Type 1. Data was analysed using modified reflexive thematic analysis. Four key themes were identified as being central to the support needs of parents of children with Usher syndrome aged 0 to 5 years. (1) Social Needs referred to parents' need for various sources of social support, (2) Informational Needs described the lack of information parents received regarding Usher syndrome from treating professionals, (3) Practical Needs included supports needed to assist parents in managing the day-to-day tasks of caring for a child with a disability, and (4) Emotional Needs represented the emotional support (both formal and informal) that parents needed to be a positive support to their child. Findings provide rich information for relevant support groups, policy makers, individual healthcare professionals, and professional governing bodies regarding the education of stakeholders and the development and implementation of best-practice treatment guidelines.