Andres Erin M, Neely Heather L, Hafeez Huma, Yasmin Tahira, Kausar Farzana, Basra M Asim Raza, Raza Muhammad Hashim
University of Kansas, Child Language Doctoral Program.
School of Chemistry, University of the Punjab.
Meta Gene. 2021 Dec;30. doi: 10.1016/j.mgene.2021.100966. Epub 2021 Aug 27.
Language impairment (LI) is highly heritable and aggregates in families. Genetic investigation of LI has revealed many chromosomal regions and genes of interest, though very few studies have focused on rare variant analysis in non-English speaking or non-European samples. We selected four candidate genes ( and ) strongly suggested for specific language impairment (SLI), a subtype of LI, and investigated rare protein coding variants through Sanger sequencing of probands with LI ascertained from Pakistan. The probands and their family members completed a speech and language family history questionnaire and a vocabulary measure, the Peabody Picture Vocabulary Test-fourth edition (PPVT-4), translated to Urdu, the national language of Pakistan. Our study aimed to determine the significance of rare variants in these SLI candidate genes through segregation analysis in a novel population with a high rate of consanguinity. In total, we identified 16 rare variants (according to the rare MAF in the global population in gnomAD v2.1.1 database exomes), including eight variants with a MAF <0.5 % in the South Asian population. Most of the identified rare variants aggregated in proband's families, one rare variant (c.*9T>C in ) co-segregated in a small family (PKSLI-64) and another (c.2465C>T in ) co-segregated in the proband branch (PKSLI-27). The lack of complete co-segregation of most of the identified rare variants indicates that while these genes could be involved in overall risk for LI, other genes are likely involved in LI in this population. Future investigation of these consanguineous families has the potential to expand our understanding of gene function related to language acquisition and impairment.
语言障碍（LI）具有高度遗传性且在家族中聚集。对LI的基因研究已经揭示了许多感兴趣的染色体区域和基因，不过很少有研究聚焦于非英语或非欧洲样本中的罕见变异分析。我们选择了四个强烈提示与特定语言障碍（SLI，LI的一种亚型）相关的候选基因，并通过对从巴基斯坦确诊的LI先证者进行桑格测序来研究罕见的蛋白质编码变异。先证者及其家庭成员完成了一份言语和语言家族史问卷以及一项词汇测试，即翻译成巴基斯坦国语乌尔都语的皮博迪图片词汇测试第四版（PPVT - 4）。我们的研究旨在通过在一个近亲结婚率高的新人群中进行分离分析，来确定这些SLI候选基因中罕见变异的意义。我们总共鉴定出16个罕见变异（根据gnomAD v2.1.1数据库外显子中全球人群的罕见最小等位基因频率），其中包括8个在南亚人群中最小等位基因频率<0.5%的变异。大多数鉴定出的罕见变异聚集在先证者家族中，一个罕见变异（c.*9T>C在[基因名称未给出]中）在一个小家族（PKSLI - 64）中共同分离，另一个（c.2465C>T在[基因名称未给出]中）在先证者分支（PKSLI - 27）中共同分离。大多数鉴定出的罕见变异缺乏完全的共同分离，这表明虽然这些基因可能与LI的总体风险有关，但其他基因可能也参与了该人群的LI。对这些近亲家族的进一步研究有可能扩展我们对与语言习得和障碍相关的基因功能的理解。
