Genetic landscape of Usher syndromes

Abstract

AbstractUsher syndrome (USH) refers to recessively inherited disorders that associate hearing loss (HL) and retinitis pigmentosa (RP). Three clinical subtypes are defined with respect to the degree of HL, the age of RP onset and the occurrence of vestibular areflexia. Ten genes, that when mutated lead the development of the disease, have been identified: six (MYO7A, USH1C, CDH23, PCDH15, USH1G and CIB2) are involved in Usher type 1, the most disabling form, three (USH2A, ADGRV1 (GPR98) and WHRN) in Usher type 2, the most frequent form, and one, CLRN1, in Usher type 3. For many years, molecular diagnosis of Usher syndrome was laborious as many of these genes consist of numerous exons (e.g. 49 for MYO7A and 72 for USH2A, the most frequently involved genes). In the last years, implementation of MPS (Massively parallel sequencing) in diagnosis laboratories permits simultaneous sequencing of all the USH genes, thus making molecular studies of Usher patients much easier and faster. Yet, additional tools to search for hidden mutations or to classify the numerous variants of unknown clinical significance are needed in order to offer a proper comprehensive diagnosis. When gene panels include additional genes mimicking USH syndrome, it becomes possible to address subtle differential diagnoses. However, since several USH genes are involved in non‐syndromic HL as well, they can now be screened in patients presenting with apparent non‐syndromic form. Then, the challenge is to provide the most accurate genetic counselling as whether a child carrying two USH1 pathogenic variants will develop Usher syndrome or not. Finally, elucidating the molecular causes of Usher syndrome remains the essential step to build patient cohorts and to develop therapeutic approaches.