Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss
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Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss Hye Ri Park1 · Sumaira Kanwal2 · Si On Lim1 · Da Eun Nam1 · Yu Jin Choi1 · Ki Wha Chung1 Received: 7 September 2020 / Accepted: 25 November 2020 / Published online: 2 December 2020 © Springer Nature B.V. 2020
Abstract Autosomal recessive nonsyndromic hearing loss (DFNB) is relatively frequent in Pakistan, which is thought to be mainly due to relatively frequent consanguinity. DFNB genes vary widely in their kinds and functions making molecular diagnosis difficult. This study determined the genetic causes in five Pakistani DFNB families with prelingual onset. The familial genetic analysis identified four pathogenic or likely pathogenic homozygous mutations by whole exome sequencing: two splicing donor site mutations of c.787+1G>A in ESRRB (DFNB35) and c.637+1G>T in CABP2 (DFNB93) and two missense mutations of c.7814A>G (p.Asn2605Ser) in CDH23 (DFNB12) and c.242G>A (p.Arg81His) in TMIE (DFNB6). The ESRRB and TMIE mutations were novel, and the TMIE mutation was observed in two families. The two missense mutations were located at well conserved sites and in silico analysis predicted their pathogenicity. This study identified four homozygous mutations as the underlying cause of DFNB including two novel mutations. This study will be helpful for the exact molecular diagnosis and treatment of deafness patients. Keywords Autosomal recessive hearing loss (DFNB) · ESRRB · CDH23 · CABP2 · TMIE · Pakistan
Introduction Hye Ri Park and Sumaira Kanwal have contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-06037-7) contains supplementary material, which is available to authorized users. * Ki Wha Chung [email protected] Hye Ri Park [email protected] Sumaira Kanwal [email protected] Si On Lim [email protected] Da Eun Nam [email protected] Yu Jin Choi [email protected] 1
Department of Biological Sciences, Kongju National University, 56 Gongjudaehak‑ro, Gongju 32588, Korea
Department of Biosciences, COMSATS University Islamabad, Sahiwal, Pakistan
2
Hereditary hearing loss is a group of genetically and clinically heterogeneous disorders. As the most common sensorineural disorder, its prevalence is approximately estimated to 1–3 in 1000 newborns [1]. Clinical severity is categorized from mild to profound hearing loss based on an audiometry test, and the ages of onset are very wide ranging from congenital to adult. All the hereditary patterns are involved in hearing loss: autosomal dominant and recessive inheritance and X-linked dominant and recessive inheritance. In addition, mitochondrial or nonmonogenic defects have been also occasionally observed in some cases. Recent genome-wide association studies suggested that many genetic factors may have secondary causes or may be genetic modifiers [2, 3]. Several human diseases, such as Usher syndrome, Alpo
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