Genetics of hearing loss in the Arab population of Northern Israel.
Genetics of hearing loss in the Arab population of Northern Israel.
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DOI：
10.1038/s41431-018-0218-z
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Shalev SA
中科院分区：
文献类型：
--
作者：
Danial-Farran N;Brownstein Z;Gulsuner S;Tammer L;Khayat M;Aleme O;Chervinsky E;Zoubi OA;Walsh T;Ast G;King MC;Avraham KB;Shalev SA
几代人以来，以色列北方的大部分阿拉伯人口一直生活在近亲婚姻和大家庭的社区中。这些群体在理解隐性性状的遗传学方面特别合作和提供信息。我们研究了这一人群中听力损失的遗传学，评估了来自46个不同村庄的168个家庭。通过桑格测序筛选所有家族的创始人变体，并通过使用我们的靶向基因面板HEar-Seq测序所有已知的听力损失基因来进一步评估13个家族。168个家族中有34个（20%）的耳聋由GJB 2、SLC 26 A4或OTOF的创始者变异解释。在使用HEar-Seq评估的13个家族中的6个（46%）中，耳聋由SLC 26 A4、MYO 15 A、OTOG、LOXHD 1和TBC 1D 24的破坏性等位基因解释。在一些对听力至关重要的基因中，解释可能影响剪接的变异特别困难，因为这些基因不在可接近的组织中表达。为了解决MYO 15 A可能的剪接改变变体的这个问题，我们评估了转染到HEK 293细胞中的小基因。结果显示MYO 15 A c.9083+ 6 T>A的信息中的外显子跳跃，以及MYO 15 A c.8340G>A的信息中的内含子保留，在每种情况下导致过早停止，并且与每种听力损失变体的纯合性共分离一致。该人群中听力损失的遗传学特征反映了听力损失的遗传异质性，以及合成技术在评估未在可及组织中表达的基因中的潜在因果变异方面的有用性。
For multiple generations, much of the Arab population of Northern Israel has lived in communities with consanguineous marriages and large families. These communities have been particularly cooperative and informative for understanding the genetics of recessive traits. We studied the genetics of hearing loss in this population, evaluating 168 families from 46 different villages. All families were screened for founder variants by Sanger sequencing and 13 families were further evaluated by sequencing all known genes for hearing loss using our targeted gene panel HEar-Seq. Deafness in 34 of 168 families (20%) was explained by founder variants in GJB2, SLC26A4, or OTOF. In 6 of 13 families (46%) evaluated using HEar-Seq, deafness was explained by damaging alleles of SLC26A4, MYO15A, OTOG, LOXHD1, and TBC1D24. In some genes critical to hearing, it is particularly difficult to interpret variants that might affect splicing, because the genes are not expressed in accessible tissue. To address this problem for possible splice-altering variants of MYO15A, we evaluated minigenes transfected into HEK293 cells. Results revealed exon skipping in the message of MYO15A c.9083+6T>A, and intron retention in the message of MYO15A c.8340G>A, in each case leading to a premature stop and consistent with co-segregation of homozygosity for each variant with hearing loss. The profile of genetics of hearing loss in this population reflects the genetic heterogeneity of hearing loss and the usefulness of synthetic technologies to evaluate potentially causal variants in genes not expressed in accessible tissues.
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影响因子：
2
作者：
Zlotogora, Joel;Barges, Saleh;Shalev, Stavit A.
通讯作者：
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影响因子：
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3.9
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通讯作者：
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14.9
作者：
The UniProt Consortium
通讯作者：
The UniProt Consortium