Challenges in genetic diagnosis of hearing loss patients by Whole Exome Sequencing: to be or not to be syndromic

BUONFIGLIO, PAULA I.; PACE MARIELA; LOTERSZTEIN VANESA; BIBIANA PAOLI; MENAZZI, SEBASTIÁN; ANA BELEN ELGOYHEN; DALAMÓN VIVIANA KARINA

Rio de Janeiro

Congreso; The 26th Human Genome Meeting; 2023

HUGO-HGM

Hearing loss (HL) is the most common disorder affecting 1:500 newborn children. Identification of the causative variants is demanding due to the large number (more than 100) genes involved. Whole-exome sequencing (WES) has become a cost-effective alternative approach for molecular diagnosis of HL. However, new challenges arise from the genotype/phenotype correlation in particular when molecular genetic results reveal a syndrome condition whereby extracochlear symptoms have not been developed yet. In this study, we investigated the genetic causes of 50 patients with sensorineural HL from Argentina (40 non-syndromic HL and 10 syndromic cases). WES was performed after the exclusion of frequent GJB2-GJB6 mutations by Sanger Sequencing. Candidate variants were interpreted following the latest guidelines of the HL Variant Curation Expert Panel.Disease-causing variants were detected in 18 known deafness genes in 21/50 patients (44%): ACTG1, ADGRV1 (GPR98), CDH23, CHD7, COL4A3, COL4A5, EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, PEX6, P2RX2, TECTA, TMPRSS3, USH2A and WSF1. Of the 27 causative variants detected, 13 were novel. Remarkably, four cases presenting nonsyndromic HL at consultation resulted in pathogenic variants in genes associated both with syndromic and non-syndromic forms: 2 Usher, 1 Perrault and 1 Waardenburg syndromes. For instance, pathogenic variants in MYO7, a gene related both with Usher syndrome and non-syndromic forms drift in clinical follow-up looking for any sign of visual defects. A similar scenario happened with a pathogenic variant in the MITF gene. On the other hand, reported pathogenic variants in USH2A were detected in a patient only presenting HL allowing clinical redefinition and resulted in a therapeutic action (immediate cochlear implant and visual takecare). Finally, two cochlear implanted brothers resulted in LARS2 pathogenic variants. Since extracochlear sign is premature ovarian failure affecting only females, the syndromic form was overlooked. The corresponding genetic counseling was adjusted in all cases. Another case to consider consisted of a patient with incipient retinitis and negative molecular results for Usher two years ago. However, the clinical detection of abnormalities in secondary dentition and dental enamel of her sister´s led us to suspect of imperfect amelogenesis and made possible to extend the analysis through other genes reaching to detect two reported variants in the PEX6 gene, related to Heimler syndrome.These molecular genetic results illustrate how thin is the line that separates syndromic from non-syndromic HL and shows the advantages of patients´ clinical follow-up as well as carrying out a complete study of all genes. This ensures proper medical counseling, earlier and better therapeutic measurements which benefit the evolution of the pathology, improving the quality of life of the patient.