Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families
Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families
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DOI：
10.1038/ejhg.2009.190
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发表时间：
2010-04-01
影响因子：
5.2
通讯作者：
Kanaan, Moien
中科院分区：
文献类型：
--
作者：
Shahin, Hashem;Walsh, Tom;Kanaan, Moien
在近亲比例高，隐性表型流行率高的社区，SNP阵列的纯合性定位是一种有效的基因发现方法。在20名巴勒斯坦语前非综合征性听力损失患者中，我们生成了反映与表型连锁的纯合性图谱。家庭规模从两个受影响的孩子，一个未受影响的兄弟姐妹和父母的小核心家庭到12个受影响的亲属的多代亲属。通过包括未受影响的父母和兄弟姐妹和筛选250 K SNP阵列，即使是小的核心家庭也产生了信息丰富的概况。在14个家庭中，我们通过筛选最长纯合区域中的单个候选基因来确定负责听力损失的等位基因。新的等位基因包括CDH 23、MYO 7A、MYO 15 A、OTOF、PJVK、Pendrin/SLC 26 A4、TECTA、TMHS和TMPRSS 3的错义、无义和剪接位点突变，以及耳安可蛋白（OTOA）的大基因组缺失。所有的点突变在巴勒斯坦人群中都是罕见的（288个无关对照组中为零携带者）; OTOA基因组缺失的携带者频率为1%。在6个家族中，我们确定了5个基因组区域可能在染色体1p13.3（DFNB 82），9 p23-p21.2/p13.3-q21.13（DFNB 83），12q14.3-q21.2（DFNB 84; 2个家族），14q23.1-q31.1和17 p12-q11.2（DFNB 85）上携带人类听力损失的新基因。European Journal of Human Genetics（2010）18，407-413; doi：10.1038/ejhg.2009.190; 2009年11月4日在线发表
In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85). European Journal of Human Genetics (2010) 18, 407-413; doi:10.1038/ejhg.2009.190; published online 4 November 2009