Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder.

Rare heterozygous variants in exons 33-34 of the SRCAP gene are associated with Floating-Harbor syndrome and have a dominant-negative mechanism of action. At variance, heterozygous null alleles falling in other parts of the same gene cause developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) syndrome. We report an 18-year-old man with DEHMBA syndrome and obstructive sleep apnea, who underwent exome sequencing (ES) and whole transcriptome sequencing (WTS) on peripheral blood. Trio analysis prioritized the de novo heterozygous c.5658+5 G > A variant. WTS promptly demostrated four different abnormal transcripts affecting >40% of the reads, three of which leading to a frameshift. This study demonstrated the efficacy of a combined ES-WTS approach in solving undiagnosed cases. We also speculated that sleep respiratory disorder may be an underdiagnosed complication of DEHMBA syndrome.

Compound Heterozygosity for OTOA Truncating Variant and Genomic Rearrangement Cause Autosomal Recessive Sensorineural Hearing Loss in an Italian Family.

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.

Non-Syndromic Autosomal Dominant Hearing Loss: The First Italian Family Carrying a Mutation in the NCOA3 Gene.

Hearing loss (HL) is the most frequent sensory disorder, affecting about 1-3 per 1000 live births, with more than half of the cases attributable to genetic causes. Despite the fact that many HL causative genes have already been identified, current genetic tests fail to provide a diagnosis for about 40% of the patients, suggesting that other causes still need to be discovered. Here, we describe a four-generation Italian family affected by autosomal dominant non-syndromic hearing loss (ADNSHL), in which exome sequencing revealed a likely pathogenic variant in NCOA3 (NM_181659.3, c.2909G>C, p.(Gly970Ala)), a gene recently described as a novel candidate for ADNSHL in a Brazilian family. A comparison between the two families highlighted a series of similarities: both the identified variants are missense, localized in exon 15 of the NCOA3 gene and lead to a similar clinical phenotype, with non-syndromic, sensorineural, bilateral, moderate to profound hearing loss, with a variable age of onset. Our findings (i.e., the identification of the second family reported globally with HL caused by a variant in NCOA3) further support the involvement of NCOA3 in the etiopathogenesis of ADNSHL, which should, thus, be considered as a new gene for autosomal dominant non-syndromic hearing loss.

Putative TMPRSS3/GJB2 digenic inheritance of hearing loss detected by targeted resequencing.

The paper describes a putative digenic form of deafness in two siblings affected by non-syndromic hereditary hearing loss, detected by a Targeted resequencing approach. Given that a previous paper suggested TMPRSS3 and GJB2 genes as responsible for a digenic form of hearing loss, our data support and reinforce this hypothesis.

Speech recognition with BAHA simulator in subjects with acquired unilateral sensorineural hearing loss.

CONCLUSION: We question the justification for the cost of a surgically implanted device for the restoration of limited circumstances of audible communication, although we understand that the decision is taken depending on the social relevance of communication or personal criteria. OBJECTIVES: The purpose of this study was to evaluate the effect of the BAHA simulator (BAHAS) system in subjects with acquired unilateral sensorineural hearing loss. In particular we tested the changes of speech reception threshold (SRT) in relation to different speech source positions, with a background of diffuse noise. METHODS: The primary message consisting of lists of Italian sentences was delivered from a loudspeaker placed at horizontal azimuths of 0°, 90°, 180° and 270°; the interference consisted of uncorrelated speech-shaped noise simultaneously delivered by four loudspeakers at a fixed intensity. The speech recognition tests were administered to 11 patients with BAHAS either on or off; hence each patient underwent 8 acoustic conditions (4 primary message directions × 2 BAHAS conditions). The SRT (50% correct responses) was measured by a simple 2 dB step adaptive procedure. Ten normal-hearing subjects served as the control group. RESULTS: Our data demonstrated that even for the acoustic condition where BAHAS should be more useful (i.e. lateral speech toward the impaired side), it was definitely ineffective in the study conditions.

Bilateral sudden profound hearing loss and vertigo as a unique manifestation of bilateral symmetric inferior pontine infarctions.

OBJECTIVES: We present a case of sudden bilateral profound deafness and vertigo, without any accompanying neurologic signs, secondary to bilateral infarctions of the cochlear and vestibular nuclei. METHODS: Vertigo, vomiting, tinnitus, and bilateral profound deafness suddenly developed in a 65-year-old woman without any accompanying neurologic signs. In particular, she did not present dysarthria, numbness, cranial nerve palsies, or visual or cerebellar signs. RESULTS: Magnetic resonance imaging of the brain revealed 2 fresh infarctions of 8 to 10 mm symmetrically localized in the posterolateral bulbopontine junction. Angiography revealed a complete occlusion of the basilar artery, with a well-represented backward flow of its distal portion from the carotid artery via posterior communicating arteries. Excluding a transient ischemic attack that occurred 16 days after the acute episode, the patient had had no other neurologic events at 8 months of follow-up. CONCLUSIONS: Acute vertigo and sudden deafness in a patient with known cerebrovascular occlusive disease may represent the warning signs of an impending brain stem or cerebellar infarction, even when other neurologic signs are absent. These events are fortunately very rare, but should be considered by clinicians who see patients with vertigo.