Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (1): 27-33.doi: 10.6040/j.issn.1671-7554.0.2021.0363

Previous Articles     Next Articles

Novel pathogenic gene variants in a pedigree with nonsyndromic hearing loss

LI Xingxing1, ZHOU Yongan2, LI Zhe1, BAI Yuan1   

  1. 1. Graduate School, Shanxi Medical University, Taiyuan 030001, Shanxi, China;
    2. Department of Blood Transfusion, Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China
  • Published:2022-01-08

PDF (PC)

232

Abstract: Objective To explore the genetic basis of a pedigree with nonsyndromic hearing loss(NSHL). Methods Peripheral blood samples of all family members were collected and whole-exome sequencing(WES)technique was performed in four members. Then Sanger sequencing was performed in all members to identify the genetic cause of the disease and pathogenicity was detected with cytology. Results All patients in this pedigree carried PCDH15c.4765delC(p.Leu1589Serfs*13)and CDH23c.9617G>A(p.Arg3206His)heterozygous variants, while other members carried PCDH15c.4765delC(p.Leu1589Serfs*13)or CDH23c.9617G>A(p.Arg3206His)single heterozygous variant, of which PCDH15c.4765delC was an unreported new variant. The frame shift mutation of PCDH15 gene caused a truncated protein and its expression decreased significantly. Immunofluorescence showed that mutant proteins accumulated in cytoplasm, which might be caused by the gene variant. Conclusion The PCDH15c.4765delC(p.Leu1589Serfs*13)and CDH23c.9617G>A(p.Arg3206His)digenic variants may cause the NSHL in the pedigree. The detection of new variant enriches the variants spectrum of deafness-causing genes and enables genetic counseling and prenatal diagnosis of the family.

Key words: Nonsyndromic hearing loss, Digenic heterozygous variants, PCDH15 gene, CDH23 gene

CLC Number: 

  • R764.43
[1] Morgan A, Koboldt DC, Barrie ES, et al. Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss [J]. Hum Mutat, 2019, 40(12): 2286-2295.
[2] Zhai R, Feng H, Li Q, et al. Auditory neuropathy spectrum disorder(ANSD)-clinical characteristics and pathogenic variant analysis of three nonsyndromic deafness families [J]. Biomed Res Int, 2020, 2020: 8843539. doi: 10.1155/2020/8843539.
[3] 袁慧军, 戴朴, 刘玉和, 等. 遗传性非综合征型耳聋的临床实践指南[J]. 中华医学遗传学杂志, 2020, 37(3): 269-276. YUAN Huijun, DAI Pu, LIU Yuhe, et al. Clinical practice guidelines for hereditary non-syndromic deafness [J]. Chinese Journal of Medical Genetics, 2020, 37(3): 269-276.
[4] Morgan A, Koboldt DC, Barrie ES, et al. Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss [J]. Hum Mutat, 2019, 40(12): 2286-2295.
[5] Schäffer AA. Digenic inheritance in medical genetics [J]. J Med Genet, 2013, 50(10): 641-652.
[6] Schrauwen I, Chakchouk I, Acharya A, et al. Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment [J]. BMC Med Genet, 2018, 19(1): 122.
[7] Deltas C. Digenic inheritance and genetic modifiers [J]. Clin Genet, 2018, 93(3): 429-438.
[8] 解洪强, 王丽娟, 黄色新, 等. Ⅱ型粘多糖贮积症致病基因内含子中一个新的RNA剪切变异[J]. 中华医学遗传学杂志, 2020, 37(7): 713-716. XIE Hongqiang, WANG Lijuan, HUANG Sexin, et al. Identification of a novel splicing variant of IDS gene in a pedigree affected with typeⅡglycosaminoglycan product storage disease [J]. Chinese Journal of Medical Genetics, 2020, 37(7): 713-716.
[9] 王洁琼, 夏艳洁, 王亚男, 等. 一个先天性挛缩蜘蛛指畸形综合征家系的FBN2基因变异分析及产前诊断[J]. 中华医学遗传学杂志, 2020, 37(5): 497-500. WANG Jieqiong, XIA Yanjie, WANG Yanan, et al. Pathological variant of FBN2 gene identified in a pedigree affected with congenital contracture arachnodactyly [J]. Chinese Journal of Medical Genetics, 2020, 37(5): 497-500.
[10] 刘晓伟, 高明, 邹洋, 等. COL4A5基因新变异导致遗传性血尿肾病耳聋综合征一家系[J]. 中华医学遗传学杂志, 2020, 37(8): 807-810. LIU Xiaowei, GAO Ming, ZOU Yang, et al. Identification of a novel variant of COL4A5 gene in a pedigree affected with alport syndrome [J]. Chinese Journal of Medical Genetics, 2020, 37(8): 807-810.
[11] 阳彦, 刘艳秋, 陈佳, 等. 应用全外显子测序技术对一个丙酸血症家系进行基因分析及产前诊断[J]. 中华医学遗传学杂志, 2020, 37(7): 751-754. YANG Yan, LIU Yanqiu, CHEN Jia, et al. Analysis of a pedigree affected with propionic acidemia by trio whole exome sequencing [J]. Chinese Journal of Medical Genetics, 2020, 37(7): 751-754.
[12] Newsted D, Rosen E, Cooke B, et al. Approach to hearing loss [J]. Can Fam Physician Med De Fam Can, 2020, 66(11): 803-809.
[13] Huang Z, Zhou Y, Fu X, et al. A novel INDEL mutation in the PTCH1 gene in a Chinese family with Gorlin syndrome [J]. Int J Clin Exp Pathol, 2018, 11(12): 6042-6046.
[14] 冯永, 马璐. 遗传性耳聋致病基因的研究现状[J]. 医学临床研究, 2020, 37(4): 481-485. FENG Yong, MA Lu. Current status of research on the pathogenic genes of hereditary deafness [J]. Journal of Clinical Research, 2020, 37(4): 481-485.
[15] Ahmed ZM, Riazuddin S, Aye S, et al. Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome [J]. Hum Genet, 2008, 124(3): 215-223.
[16] Jaiganesh A, Narui Y, Araya-Secchi R, et al. Beyond Cell-Cell adhesion: sensational cadherins for hearing and balance [J]. Cold Spring Harb Perspect Biol, 2018, 10(9): a029280.
[17] Oroz J, Galera-Prat A, Hervás R, et al. Nanomechanics of tip-link cadherins [J]. Sci Rep, 2019, 9(1): 13306.
[18] Zheng QY, Yan D, Ouyang XM, et al. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans [J]. Hum Mol Genet, 2005, 14(1): 103-111.
[19] Gazzo AM, Daneels D, Cilia E, et al. DIDA: a curated and annotated digenic diseases database [J]. Nucleic Acids Res, 2016, 44(d1): 900-907.
[20] Kazmierczak P, Sakaguchi H, Tokita J, et al. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells [J]. Nature, 2007, 449(7158): 87-91.
[21] Grillet N, Xiong W, Reynolds A, et al. Harmonin mutations cause mechanotransduction defects in cochlear hair cells [J]. Neuron, 2009, 62(3): 375-387.
[22] Sakaguchi H, Tokita J, Müller U, et al. Tip links in hair cells: molecular composition and role in hearing loss [J]. Curr Opin Otolaryngol Head Neck Surg, 2009, 17(5): 388-393.
[23] 聂红云. PCDH15跨膜运输机制的初步探讨[D]. 济南: 山东大学, 2017.
[24] Narui Y, Sotomayor M. Tuning inner-ear tip-link affinity through alternatively spliced variants of protocadherin-15 [J]. Biochemistry, 2018, 57(11): 1702-1710.
[25] Wu L, Pan L, Zhang C, et al. Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia [J]. J Biol Chem, 2012, 287(40): 33460-33471.
[26] Michel V, Pepermans E, Boutet de Monvel J, et al. Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells [J]. Sci Rep, 2020,10(1): 16430.
[27] Dionne G, Qiu X, Rapp M, et al. Mechanotransduction by PCDH15 relies on a novel Cis-Dimeric architecture [J]. Neuron, 2018, 99(3): 480-492.
[1] ZHU Famei, ZHENG Jiafa, XIE Dinghua, HU Peng. Analysis of SLC26A4 gene mutations in 5 families associated with enlarge vestibular aqueduct syndrome [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(10): 90-95.
[2] BIAN Zhi-qiang,LIU Ya-qun,LI Du-min,CUI Feng-yu. Multi-slice computed tomography imaging for congenital sensorineural hearing loss in infants [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2007, 45(12): 1257-1260.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] LYU Longfei, LI Lin, LI Shuhai, QI Lei, LU Ming, CHENG Chuanle, TIAN Hui. Application of laparoscopic fine needle catheter jejunostomy in minimally invasive McKeown resection of esophageal cancer[J]. Journal of Shandong University (Health Sciences), 2020, 1(7): 77 -81 .
[2] SHAO Haigang, WANG Xuan, WANG Qing. Anatomy of the root canal system of mandibular first premolar in population of Shandong Province[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(9): 85 -89 .
[3] HUANG Fei,WANG Huaijing,XING Yi,GAO Wei,LI Yonggang,XING Ziying,LI Zhenzhong. Protective effects of NGF and GM1 on primary sensory neurons in SD rat with sciatic nerve injury[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2006, 44(4): 332 -335 .
[4] JIANG Bao-dong,MA Xiang-xing,WANG Qing,WANG Qian,FENG Xiao-yuan,LI Ke,YU Fu-hua. Imaging parameters of multislice spiral CT venography in cerebral veins[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2008, 46(11): 1084 -1086 .
[5] LI Yu-liang,WANG Yong-zheng,WANG Xiao-hua,ZHANG Fu-jun,ZHU Li-dong,ZHANG Wang-ming,LI Zheng,LI Zhen-jia,ZHANG Kai-xian. I implantation combined with Gemcitabine in the treatment of advanced pancreatic cancer[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2007, 45(4): 393 -396 .
[6] TANG Fang1,2, ZHANG Yingqian3, WANG Zhiqiang4, KANG Dianmin4,
WANG Jiezhen1, XUE Fuzhong1. A 2D minimal spanning tree model of the spatial structures of natural focal disease[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2009, 47(01): 106 -110 .
[7] WANG Xiaoju1，　WANG Mingming2，　XU Wansu2,　ZHAO Shengmei3，CUI Sunan2，　LI Xiaoying2，　LIU Chunhua1
. Expression of peripheral blood lymphocyte ubiquitin mRNA in chronic HBV infection with active inflammation and its clinical significance[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2009, 47(02): 58 -61 .
[8] MA Li-Xin, LI Gang, SU Yu-Hang, ZHANG Cai, ZHANG Jian. Expression of NKG2D on NK cells in intracranial tumors[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2009, 47(5): 88 -91 .
[9] ZHU Xiaoli1, GUO Shuling1, SU Lei1, FENG Yuxin2, YUAN Fangshu1. Extraction of total proteins from demodex and qualification of their molecular weights[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(5): 58 -62 .
[10] HAN Xue, WANG Qing, CUI Fengyu. Application of multislice CT angiography  in living renal donors before nephrectomy[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2010, 48(4): 102 -105 .
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd