Search

Introduction: The definition of a molecular diagnosis for patients affected by hereditary hearing loss (HHL) is significantly hampered by the extreme clinical and genetic heterogeneity that characterise the condition. In particular, peculiar and understudied cases are those of non-syndromic mimics (NSM), meaning patients with particularly mild forms of syndromic HHL or initially presenting isolated deafness and delayed onset of other clinical signs. Material and methods: In the last 18 months, a cohort of 73 apparently non-syndromic Italian HHL patients has been enrolled in the study. All the individuals were negative at GJB2 and STRC genetic tests and underwent whole-exome sequencing, aiming to define a molecular diagnosis and eventually identify NSMs. Results: A molecular diagnosis was provided for 36/73 patients (49.3%), and 12 of them could be classified as NSMs. In detail, two groups of patients could be highlighted: (1) patients presenting subtle additional signs that were missed during the first clinical evaluation and (2) patients whose molecular diagnosis suggests the future development of additional clinical features. In Group 1, two patients were identified, and they carried pathogenic variants within the MITF and GATA3 genes, which are associated with Waardenburg and Barakat syndromes, respectively. As regards Group 2, ten patients were detected, and the involved genes were CDH23 (one patient), USH2A (six patients) and ADGRV1 (three patients). Thus, these results suggest that Usher syndrome type 2 accounts for the vast majority of NSMs (75%). Moreover, these considerations further confirm our previous findings regarding the high prevalence of Usher syndrome type 2 carriers in the Italian population (1: 70). Conclusions: Identifying patients within Group 1 of NSMs highlights the importance of a critical re-evaluation of the diagnostic criteria of each condition and provides crucial insight into the clinical characteristics of very mild forms of syndromic deafness. On the other hand, the clinical condition of Group 2 NSM patients will be evaluated by a multi-disciplinary team in order to provide personalised follow-up and specific preventive strategies. [ABSTRACT FROM AUTHOR]