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Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-07-24 , DOI: 10.1111/cge.14037
Parneet Kaur 1 , Michelle C do Rosario 1 , Malavika Hebbar 1 , Suvasini Sharma 2 , Neethukrishna Kausthubham 1 , Karthik Nair 1 , Shrikiran A 3 , Ramesh Bhat Y 3 , Leslie Edward S Lewis 3 , Sheela Nampoothiri 4 , Siddaramappa J Patil 5 , Narayanaswami Suresh 2 , Sunita Bijarnia Mahay 6 , Ratna Dua Puri 6 , Shivanand Pai 7 , Anupriya Kaur 8 , Rakshith Kc 7 , Nutan Kamath 9 , Shruti Bajaj 10 , Ali Kumble 11 , Rajesh Shetty 12 , Rathika Shenoy 13 , Mahesh Kamate 14 , Hitesh Shah 15 , Mamta N Muranjan 16 , Yatheesha Bl 17 , K Shreedhara Avabratha 18 , Girish Subramaniam 19 , Rajagopal Kadavigere 20 , Stephanie Bielas 21 , Katta Mohan Girisha 1 , Anju Shukla 1
Affiliation  

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

中文翻译:

104个印度中枢神经系统白质异常家庭的临床和遗传谱

以中枢神经系统白质异常 (CNS WMA) 为主的遗传性疾病,也称为脑白质营养不良,是异质性实体。我们确定了来自 104 个无关家庭的 117 名 CNS WMA 患者。对16个家庭进行了靶向基因检测,其中13个家庭确诊。对三个家庭进行了染色体微阵列 (CMA),其中一个得到了诊断。Mendeliome 测序用于检测 11 个家庭,所有家庭都得到了诊断。在 80 个家庭中进行了全外显子组测序 (WES),并在 52 个家庭 (65%) 中进行了诊断。单例 WES 对 50/75 (66.67%) 个家庭具有诊断意义。总体而言,在 77 个家庭 (74.03%) 中获得了基因诊断。在该队列中观察到的 47 种不同疾病中,有 22 种以前未在印度个体中报告过。尤其,核线粒体病理学疾病最为常见(20 个家族中有 9 种疾病)。75 种致病变异中有 37 种 (49.33%) 是新的。总而言之,本队列描述了我们人群中 CNS WMA 遗传病的表型和基因型谱。它证明了 WES,尤其是单例 WES,是诊断这些异质实体的有效工具。它还强调了我们人群中可能的创始人事件和反复发作的致病变异及其对测试策略的影响。特别是单例 WES,作为诊断这些异构实体的有效工具。它还强调了我们人群中可能的创始人事件和反复发作的致病变异及其对测试策略的影响。特别是单例 WES,作为诊断这些异构实体的有效工具。它还强调了我们人群中可能的创始人事件和反复发作的致病变异及其对测试策略的影响。
更新日期:2021-07-24
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