Genetic Diagnosis of Neurodevelopmental Disorders in India

摘要 在中低收入国家，遗传性神经发育障碍（NDD）儿童的发病率很高， 医疗资源的巨大负担。虽然个别遗传性NDD很少见，但总体而言， 数百万人确定NDD的遗传病因对家庭、社区和科学都是有益的。 基因诊断使家庭认识到复发的风险，并采取行动的预期疾病。遗传 这些发现推动了旨在通过社区遗传学减少疾病负担的公共卫生政策。的基因 NDD提供了对正常大脑发育和疾病发病机制的分子见解。整个 外显子组测序（WES）已经上升到HMIC基因检测的最前沿，基于其发现 遗传性NDD的遗传基础，但很少用于LMIC。正在进行的合作博士。 Shukla博士在印度Manipal大学Kasturba医学院，Bielas博士在人类学系， 美国密歇根大学的遗传学研究人员开发了一种可持续的策略，使用基于WES的测试， 印度的NDD基因诊断。由于诊断率与HMIC相当，基于WES的基因检测将成为 这是解决印度遗传性NDD负担增加的重要工具。我们提出实验来描绘 东南亚血统的遗传多样性。对于我们鉴定为NDD的新遗传病因的两个基因， 在不相关的受影响的印度家庭中检测到相同的致病性变体，表明了奠基者效应 在印度人群中携带频率更高。这一发现突出了不同群体的代表性不均衡。 基因组研究中的种群。序列表示和功能研究中缺乏奇偶性， 这是一个科学和健康挑战，对遗传变异的解释产生了负面影响。我们 假设基因组测序研究中不同人群代表性的差异影响 有害等位基因的解释和印度NDD的遗传诊断，这导致了 全球基因组医学我们将通过在一个更大的群体中定义遗传多样性来应对这一挑战。 东南亚血统（Aim1），功能上表征变异，以支持其分类为 致病性（目标2），并通过开发基因组药物减少不同人群的不均衡代表性 一个可搜索的基于网络的平台，使去识别的遗传多样性在印度血统鉴定 可用（目标3）。我们的实验战略优先考虑教育交流和研究基础设施， 制定可持续的战略来解决这些重要问题。

ABSTRACT The incidence of children with inherited neurodevelopmental disorders (NDDs) is high in LMICs, and an enormous burden on heathcare resources. While individual inherited NDDs are rare, in aggregate they affect millions of people. Identifying the genetic etiology of NDDs is beneficial to families, communities and science. Genetic diagnosis allows families to recognize risk of recurrence, and act on anticipatory prognoses. Genetic discoveries drive public health policy aimed at reducing disease burden through community genetics. Genes that cause NDDs provide molecular insights into normal brain development and pathogenesis of disorders. Whole exome sequencing (WES) has risen to the forefront of genetic testing in HMIC, based on its potential to uncover the genetic basis of inherited NDDs, but is infrequently used in LMICs. An ongoing collaboration between Dr. Shukla at Kasturba Medical College at Manipal University, India and Dr. Bielas in the Department of Human Genetics at University of Michigan, US, has developed a sustainable strategy to use WES-based testing for genetic diagnosis of NDDs in India. With a diagnostic yield on par with HMIC, WES-based genetic testing will be an important tool in address the elevated burden of inherited NDD in India. We propose experiments to delineate genetic diversity of South-East Asian ancestry. For two genes we identified as novel genetic etiologies of NDDs, the same pathogenic variant was detected in unrelated affected Indian families, indicative of a founder effect with higher carrier frequency in the Indian population. This finding highlights the uneven representation of diverse populations in genomic studies. The lack of parity in sequence representation and functional studies originating from India, is a scientific and health challenge that negatively impact interpretation of genetic variants. We hypothesize that disparities in representation of diverse populations in genomic sequencing studies impact interpretation of deleterious alleles and genetic diagnosis of NDDs in India, which contribute to inequity in genomic medicine globally. We will address this challenge by defining genetic diversity in a larger cohort of South-East Asian ancestry (Aim1), functionally characterizing variants to support their classification as pathogenic (Aim 2) and reduce uneven representation of diverse populations in genomic medicine by developing a searchable web-based platform to make de-identified genetic diversity identified in Indian ancestry publically available (Aim 3). Our experimental strategy prioritizes educational exchange and research infrastructure, that fosters sustainable strategies to tackle these important problems.