This study corresponds to the first large-scale genetic analysis of inherited eye diseases (IED) in Argentina and describes the comprehensive genetic profile of a large cohort of patients. Medical records of 22 ophthalmology and genetics services throughout 13 Argentinian provinces were analyzed retrospectively. Patients with a clinical diagnosis of an ophthalmic genetic disease and a history of genetic testing were included. Medical, ophthalmological and family history was collected. A total of 773 patients from 637 families were included, with 98% having inherited retinal disease. The most common phenotype was retinitis pigmentosa (RP, 62%). Causative variants were detected in 379 (59%) patients.USH2A,RPGR, andABCA4were the most common disease-associated genes.USH2Awas the most frequent gene associated with RP,RDH12early-onset severe retinal dystrophy,ABCA4Stargardt disease,PROM1cone-rod dystrophy, andBEST1macular dystrophy. The most frequent variants wereRPGRc.1345 C > T, p.(Arg449*) andUSH2Ac.15089 C > A, p.(Ser5030*). The study revealed 156/448 (35%) previously unreported pathogenic/likely pathogenic variants and 8 possible founder mutations. We present the genetic landscape of IED in Argentina and the largest cohort in South America. This data will serve as a reference for future genetic studies, aid diagnosis, inform counseling, and assist in addressing the largely unmet need for clinical trials to be conducted in the region.

Hearing loss is a heterogeneous disorder. Identification of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants affecting 9 different non-GJB2 genes resulted novel: c.12829C > T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G > A, p.(Gly1167Glu) in COL4A3; c.1183C > T, p.(Pro395Ser) and c.1759C > T, p.(Pro587Ser) in COL4A5; c.580 + 2 T > C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939 T > C, p.(Phe647Leu), in MYO6; c.733C > T, p.(Gln245*) in MYO7A and c.242C > G, p.(Ser81*) in TMPRSS3 genes. To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.

Genetic variants in GJB2 and GJB6 genes are the most frequent causes of hereditary hearing loss among several deaf populations worldwide. Molecular diagnosis enables proper genetic counseling and medical prognosis to patients. In this study, we present an update of testing results in a cohort of Argentinean non-syndromic hearing-impaired individuals. A total of 48 different sequence variants were detected in genomic DNA from patients referred to our laboratory. They were manually curated and classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology ACMG/AMP standards and hearing-loss-gene-specific criteria of the ClinGen Hearing Loss Expert Panel. More than 50% of sequence variants were reclassified from their previous categorization in ClinVar. These results provide an accurately interpreted set of variants to be taken into account by clinicians and the scientific community, and hence, aid the precise genetic counseling to patients.

Waardenburg syndrome (WS) is a common genetic cause of syndromic hearing loss, accounting for 2–5% of congenital cases. It is characterized by hearing impairment and pigmentation abnormalities in the skin, hair, and eyes. Seven genes are associated with WS: PAX3, MITF, EDNRB, EDN3, SOX10, KITLG, and SNAI2. This study investigates the genetic causes of WS in three familial cases. Whole-exome sequencing (WES) was performed to identify single nucleotide variants (SNVs). Copy number variants (CNVs) were analyzed from the WES raw data and through multiplex ligation-dependent probe amplification (MLPA). The study identified one pathogenic SNV and two novel CNVs, corresponding to type I and type II WS patterns in the three families. The SNV, a nonsense variant (c.1198C>T p.Arg400*), was found in MITF and segregated in the affected father. The two CNVs were a deletion of exon 5 in PAX3 in a family with two affected members and a large novel deletion comprising seven genes, including SOX10, in a family with three affected members. These findings confirmed a WS diagnosis through genetic testing. The study emphasizes the importance of integrating multiple genetic testing approaches for accurate and reliable diagnosis, highlighting their role in improving patient management and providing tailored genetic counseling.

Hereditary hearing loss stands as the most prevalent sensory disorder, with over 124 non-syndromic genes and approximately 400 syndromic forms of deafness identified in humans. The clinical presentation of these conditions spans a spectrum, ranging from mild to profound hearing loss. The aim of this study was to identify the genetic cause of hearing loss in a family and functionally validate a novel variant identified in the MYO6 gene. After Whole Exome Sequencing analysis, the variant c.2775G>C p.Arg925Ser in MYO6 was detected in a family with postlingual non-syndromic hearing loss. By protein modeling a change in the electrostatic charge of the single alpha helix domain surface was revealed. Through a knockdown phenotype rescue assay in zebrafish, the detrimental effects of the identified variant on the auditory system was determined. These findings underscore the significance of a comprehensive approach, integrating both in silico and in vivo strategies, to ascertain the pathogenicity of this candidate variant. Such an approach has demonstrated its effectiveness in achieving an accurate genetic diagnosis and in promoting a more profound comprehension of the mechanisms that underlie the pathophysiology of hearing.