Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

Abstract

Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.

The Enigmatic Genetic Landscape of Hereditary Hearing Loss: A Multistep Diagnostic Strategy in the Italian Population

“…Concerning SHL subjects, WES analysis was fundamental to highlight the molecular cause in 55% of patients. These results are in line with previous studies, from both Italian cohorts and international ones, that verified how the overall diagnostic yield in HHL patients is around 50% [ 32 , 33 , 34 , 35 ].…”

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

“…Among the repeated variants, there were five that had been previously described (c.2171_2174del, g.(_43890333)_(43940887_? )del in the STRC gene [ 23 , 24 ], c.11864G>A and c.12234_12235del in the USH2A gene [ 25 , 26 ], c.1001G>T in the SLC26A4 gene [ 27 , 28 ] and three that had not been previously described (c.107A>C in the SLC26A4 gene, c.2656del and c.4903A>T in the OTOF gene). Families carrying these variants were from different regions of the Russian Federation.…”

Advanced Omics Techniques for Understanding Cochlear Genome, Epigenome and Transcriptome in Health and Disease

“…Their significant improvement has been possible due to advanced omics, and Table 2 summarizes the advanced genomics, transcriptomics and epigenomics techniques that have been applied in cochlear research, alongside the improvement that they have provided in the field. For instance, genome sequencing has allowed to identify new variants in genetic hearing loss and represents a great improvement in the diagnosis of genetic deafness in newborns [72][73][74]. Nonetheless, studies on the cochlea are particularly challenging compared to other sensory organs, because of several practical limitations.…”

“…The discovery of novel variants represents a fundamental step forward in the understanding of the molecular basis of cochlear diseases, and indeed it has improved the diagnosis of genetic hearing loss, as well as the prediction of its severity and prognosis. So far, a number of studies have benefitted from genome sequencing (via either WES or WGS) for early detection of hearing loss [72][73][74]. For instance, a recent study has shown that the combination of conventional hearing screening and extended genetic sequencing improves the early diagnosis of inherited hearing loss in newborns, with important implications for their clinical management [75].…”