Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss
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Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss Jing Yu1†, Wei Jiang2,3†, Li Cao1, Xiaoxue Na2,3 and Jiyun Yang2,3*
Abstract Mutations in HARS2 are one of the genetic causes of Perrault syndrome, characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction. Here, we identified two novel putative pathogenic variants of HARS2 in a Chinese family with sensorineural hearing loss including two affected male siblings, c.349G > A (p.Asp117Asn) and c.908 T > C (p.Leu303Pro), through targeted next-generation sequencing methods. The two affected siblings (13 and 11 years old) presented with early-onset, rapidly progressive SNHL. The affected siblings did not have any inner ear malformations or delays in gross motor development. Combined with preexisting clinical reports, Perrault syndrome may be latent in some families with non-syndromic deafness associated with HARS2 mutations. The definitive diagnosis of Perrault syndrome based on clinical features alone is a challenge in sporadic males, and preadolescent females with no signs of POI. Our findings further expanded the existing spectrum of HARS2 variants and Perrault syndrome phenotypes, which will assist in molecular diagnosis and genetic counselling of patients with HARS2 mutations. Keywords: HARS2, Perrault syndrome, Next-generation sequencing
Introduction The HARS2 gene is mapped to chromosome 5q31.3, contains 13 exons and spans approximately 7.9 kb. The HARS2 gene encodes the highly conserved mitochondrial histidyl tRNA synthetase, which is involved in mitochondrial protein translation [1, 2]. In 2011, Mutations in HARS2 were first identified as a cause of Perrault syndrome by genome-wide linkage analysis and candidate gene sequencing [1]. Perrault syndrome is an autosomal recessive disorder with main clinical features * Correspondence: [email protected] † Jing Yu and Wei Jiang contributed equally to this work. 2 The Key Laboratory for Human Disease Gene Study of Sichuan Province , Prenatal Diagnosis Center, Sichuan Provincial People’s Hospital, the University of Electronic Science and Technology of China, The First Ring Road West Section 2 #32, Chengdu, Sichuan 610071, PR China 3 School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610071, PR China Full list of author information is available at the end of the article
of bilateral SNHL, a mild to profound degree of hearing loss, and ovarian dysgenesis in females. When the onset of moderate SNHL is in early childhood, it may present as progressive hearing loss. Ovarian dysfunction ranges from primary amenorrhea to primary ovarian insufficiency (POI), which can lead to infertility. Affected males, on the other hand, show normal pubertal development and are typically fertile [3]. Diagnosis of Perrault syndrome is often based on common clinical manifestations of SNHL in females and males as well as ovarian dysfunction in females with normal karyotypes [1, 4]. Further, this dia
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