AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance

Abstract

Background: Auditory synaptopathy/neuropathy (AS/AN) is a heterogeneous disorder, which may be caused by environmental factors like postnatal hyperbilirubinemia or by genetic factors. The genetic forms are subdivided into syndromic and non-syndromic types, and show different inheritance patterns with a strong preponderance of autosomal-recessive forms. To date, only a single locus for non-syndromic autosomal-dominant AS/AN (AUNA1) has been reported in a single family, in which a non-coding DIAPH3 mutation was subsequently described as causative. Materials and Methods: Here, we report detailed clinical data on a large German AS/AN family with slowly progressive postlingual hearing loss. Affected family members developed their first symptoms in their second decade. Moderate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members. Comprehensive audiological and neurological tests were performed in the affected family members. Genetic testing comprised linkage analyses with polymorphic markers and a genome-wide linkage analysis using the Affymetrix GeneChip® Human Mapping 250K. Results and Conclusion: We identified a large family with autosomal-dominant AS/AN. By means of linkage analyses, the AUNA1 locus was excluded, and putatively linked regions on chromosomal bands 12q24 and 13q34 were identified as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2). AUNA2 is associated with a slowly progressive postlingual hearing loss without any evidence for additional symptoms in other organ systems.

TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad

“…Our sequence analysis of individuals S60 and S61 did not uncover any nonsynonymous variants in genes already known to be associated with ANSD such as autosomal recessive OTOF (Yasunaga et al., ) and PJVK (Delmaghani et al., ), and autosomal dominant AUNA1 (Kim et al., ), leaving rs35725509 in the TMTC2 gene as the likely causal mutation. Even the recently proposed AUNA2 (Lang‐Roth et al., ), encompassing 1.7 and 3 Mb on regions 12q24 and 13q34, respectively, did not add any likely candidates. However, our sequencing efforts did uncover five additional nonsynonymous variants in other genes previously reported to contain mutations associated with hearing impairments (Table ).…”

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

“…Although several genes are involved in AN, only mutations of the OTOF gene are responsible for TSAN (Del Castillo and Del Castillo, 2012). To date, five loci (including four identified genes) and six genes are known to be associated with NSAN: DFNB9 (OTOF gene), DFNB59 (PJVK gene), and GJB2 for autosomal recessive AN; AUNA1 (DIAPH3 gene), AUNA2 (undefined gene), SLC17A8, PCDH9, DIAPH1, and TMEM43 for autosomal dominant AN; DFNX5 (AIFM1 gene) for X-linked recessive AN; and mitochondrial 12S rRNA (T1095C) (Varga et al, 2003;Cheng et al, 2005;Wang et al, 2005;Delmaghani et al, 2006;Ruel et al, 2008;Santarelli et al, 2008;Grati et al, 2009;Schoen et al, 2010;Zong et al, 2015;Lang-Roth et al, 2017;Wu et al, 2020;Jang et al, 2021). However, variants of the OTOF gene have been shown to be major contributors to NSAN (Varga et al, 2006;Rodríguez-Ballesteros et al, 2008;Romanos et al, 2009;Chiu et al, 2010;Wang et al, 2010).…”

Early diagnosis of Auditory Neuropathy in children: a systematic review

“…Sugerem ainda a utilização do tom de sonda de 1KHz, ou a realização com dois tons de sonda diferentes, 1KHz e 226 Hz (Boudewyns et al, 2016;Fang et al, 2020). Os reflexos estapédicos estão ausentes ou presentes, porém com má morfologia a níveis muito elevados de intensidade, sugerindo uma disfunção a nível neuronal (Rance & Starr, 2015;Lang-Roth et al, 2017;Emami & Abdoli, 2019;Brough, 2020). Alguns autores especificam que devem ser as de 500Hz, 1KHz, 2KHz e 4KHz (Tobia et al, 2019;Fang et al, 2020).…”

“…Stapedial reflexes are either absent or present with poor morphology at very high intensity levels, suggesting neural dysfunction (Rance & Starr, 2015;Lang-Roth et al, 2017;Emami & Abdoli, 2019;Brough, 2020). Some authors specify that frequencies of 500 Hz, 1 kHz, 2 kHz, and 4 kHz should be tested (Tobia et al, 2019;Fang et al, 2020).…”

“…Indivíduos com hipoacusia ligeira ou moderada apresentam os resultados dos PEAC dentro da normalidade, enquanto os indivíduos com um grau de hipoacusia superior apresentam respostas atrasadas e diminuídas. Estes achados corroboram o respetivo grau de desenvolvimento da linguagem e a compreensão da fala, no sentido em que os indivíduos que demonstraram uma maturação normal do córtex conseguem desenvolver as capacidades referidas acima dentro dos padrões de normalidade (Lang-Roth et al, 2017). Este exame é um indicador do prognóstico após a reabilitação auditiva, sendo de suma importância a sua realização, uma vez que apenas cerca de 1/3 das crianças com PENA demonstram resultados normais nos PEAC, mesmo com a utilização das próteses auditivas, o que demonstra que 2/3 destas crianças não foram estimuladas o suficiente para o normal desenvolvimento da fala e compreensão linguística (Lang-Roth et al, 2017;Emami & Abdoli, 2019).…”