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Abstract
Hearing loss (HL) affects 1–3 newborns per 1000 and, in industrialized countries, recognizes a genetic etiology in more than 80% of the congenital cases. Excluding GJB2 and GJB6, OTOA is one of the leading genes associated with autosomal recessive non-syndromic HL. Allelic heterogeneity linked to OTOA also includes genomic rearrangements facilitated by non-allelic homologous recombination with the neighboring OTOAP1 pseudogene. We present a couple of Italian siblings affected by moderate to severe sensorineural hearing loss (SNHL) due to compound heterozygosity at the OTOA locus. Multigene panel next-generation sequencing identified the c.2223G>A, p.(Trp741*) variant transmitted from the unaffected mother. Assuming the existence of a second paternal deleterious variant which evaded detection at sequencing, genomic array analysis found a ~150 Kb microdeletion of paternal origin and spanning part of OTOA. Both deleterious alleles were identified for the first time. This study demonstrates the utility of an integrated approach to solve complex cases and allow appropriate management to affected individuals and at-risk relatives.
Highlights
Hearing loss (HL) is a global health issue involving 1 to 3 newborns per 1000 worldwide [1]
We report a pedigree with two affected siblings with autosomal recessive nonsyndromic HL due to compound heterozygosity in OTOA
The proband was a 2-year-old girl referred to our tertiary care Audiology Outpatient Clinic because of failed newborn hearing screening with both transient otoacoustic emissions (TOAEs) and automated auditory brainstem response (A-ABR), and increased threshold at auditory brainstem response (ABR)
Summary
Hearing loss (HL) is a global health issue involving 1 to 3 newborns per 1000 worldwide [1]. The impact of HL on the quality of life of affected individuals is variable and mostly influenced by age at onset and severity. Pre-lingual HL may significantly impact the neurodevelopmental trajectory of the affected individual by impairing cognitive functions and social competences. HL is a treatable condition by a variety of interventions, including surgical procedures, hearing aids and cochlear implants, which are guided by the underlying pathogenesis and patient’s characteristics. For these reasons, early diagnosis and etiological classification of HL are both crucial for optimal treatment of the index cases as well as relatives at risk
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