Sloan-Heggen Christina M, Babanejad Mojgan, Beheshtian Maryam, Simpson Allen C, Booth Kevin T, Ardalani Fariba, Frees Kathy L, Mohseni Marzieh, Mozafari Reza, Mehrjoo Zohreh, Jamali Leila, Vaziri Saeideh, Akhtarkhavari Tara, Bazazzadegan Niloofar, Nikzat Nooshin, Arzhangi Sanaz, Sabbagh Farahnaz, Otukesh Hasan, Seifati Seyed Morteza, Khodaei Hossein, Taghdiri Maryam, Meyer Nicole C, Daneshi Ahmad, Farhadi Mohammad, Kahrizi Kimia, Smith Richard J H, Azaiez Hela, Najmabadi Hossein
Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
J Med Genet. 2015 Dec;52(12):823-9. doi: 10.1136/jmedgenet-2015-103389. Epub 2015 Oct 7.
Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes.
Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families.
We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations.
This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.
在文化上接受近亲结婚的国家为研究罕见隐性遗传疾病提供了独特资源。虽然遗传性听力损失（HHL）并不罕见，但它具有遗传异质性，超过85个基因与非综合征性听力损失（NSHL）存在因果关系。这种异质性使得许多基因特异性类型的NSHL极其罕见。我们试图通过调查常见和罕见的致聋基因来确定伊朗常染色体隐性HHL的谱系。
我们使用定制的靶向基因组富集（TGE）面板，同时对302个GJB2基因阴性的伊朗家庭队列中的所有已知NSHL遗传病因进行检测。
我们为67%的先证者及其家庭建立了基因诊断，所有诊断中超过一半归因于五个基因的变异：SLC26A4、MYO15A、MYO7A、CDH23和PCDH15。作为近亲图谱绘制能力的体现，26个基因首次被确定为伊朗人群中NSHL的致病基因。总共在201名先证者的40个基因中鉴定出179个致聋变异，包括110个新的单核苷酸或小插入缺失变异和三个新的拷贝数变异（CNV）。有几个变异代表奠基者突变。
本研究证明了TGE和大规模平行测序作为评估伊朗听力损失诊断工具的能力，并扩展了我们对该国HHL遗传学的理解。该面板上所代表基因变异阴性的家庭是新基因发现的优秀队列。
