Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population.

IF 1.7 4区生物学 Q3 GENETICS & HEREDITY

American Journal of Medical Genetics Part A Pub Date : 2024-10-29 DOI:10.1002/ajmg.a.63914

Namanpreet Kaur, Michelle C do Rosario, Purvi Majethia, Selinda Mascarenhas, Lakshmi Priya Rao, Karthik Vijay Nair, Bhagesh Hunakunti, Adarsh Pooradan Prasannakumar, Rohit Naik, Dhanya Lakshmi Narayanan, Shalini S Nayak, Vivekananda Bhat, Suvasini Sharma, Y Ramesh Bhat, B L Yatheesha, Rajesh Kulkarni, Siddaramappa J Patil, Sheela Nampoothiri, Shahyan Siddiqui, Katta Mohan Girisha, Stephanie Bielas, Anju Shukla

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Abstract

Several genetic disorders are associated with either a permanent deficit or a delay in central nervous system myelination. We investigated 24 unrelated families (25 individuals) with deficient myelination after clinical and radiological evaluation. A combinatorial approach of targeting and/or genomic testing was employed. Molecular diagnosis was achieved in 22 out of 24 families (92%). Four families (4/9, 44%) were diagnosed with targeted testing and 18 families (18/23, 78%) were diagnosed using broad genomic testing. Overall, 14 monogenic disorders were identified. Twenty disease-causing variants were identified in 14 genes including PLP1, GJC2, POLR1C, TUBB4A, UFM1, NKX6-2, DEGS1, RNASEH2C, HEXA, ATP7A, SETBP1, GRIN2B, OCLN, and ZBTB18. Among these, nine (45%) variants are novel. Fourteen families (82%, 14/17) were diagnosed using proband-only exome sequencing (ES) complemented with deep phenotyping, thus highlighting the utility of singleton ES as a valuable diagnostic tool for identifying these disorders in resource-limited settings.

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从神经成像到基因型：划定印度人群髓鞘缺失症的范围

有几种遗传疾病与中枢神经系统髓鞘化永久性缺失或延迟有关。经过临床和放射学评估，我们对 24 个髓鞘缺失的非亲缘家庭（25 人）进行了调查。我们采用了靶向和/或基因组检测的组合方法。24 个家族中有 22 个（92%）获得了分子诊断。4个家庭（4/9，44%）通过靶向检测确诊，18个家庭（18/23，78%）通过广泛的基因组检测确诊。总体而言，共发现了 14 种单基因疾病。在 14 个基因中发现了 20 个致病变体，包括 PLP1、GJC2、POLR1C、TUBB4A、UFM1、NKX6-2、DEGS1、RNASEH2C、HEXA、ATP7A、SETBP1、GRIN2B、OCLN 和 ZBTB18。在这些变异中，有 9 个（45%）是新变异。有14个家庭（82%，14/17）是通过仅进行探针外显子组测序（ES）并辅以深度表型分析而确诊的，从而凸显了单基因外显子组测序作为一种有价值的诊断工具在资源有限的环境中鉴别这些疾病的实用性。

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来源期刊

American Journal of Medical Genetics Part A 生物-遗传学

CiteScore

3.50

自引率

5.00%

发文量

432

审稿时长

2-4 weeks

期刊介绍： The American Journal of Medical Genetics - Part A (AJMG) gives you continuous coverage of all biological and medical aspects of genetic disorders and birth defects, as well as in-depth documentation of phenotype analysis within the current context of genotype/phenotype correlations. In addition to Part A , AJMG also publishes two other parts: Part B: Neuropsychiatric Genetics , covering experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. Part C: Seminars in Medical Genetics , guest-edited collections of thematic reviews of topical interest to the readership of AJMG .