Genetic Diagnosis of Neurodevelopmental Disorders in India

摘要 遗传性神经发育障碍(NDDS)儿童在LMICs中的发病率很高，而且 对医疗资源造成巨大负担。虽然个别遗传的NDD很少见，但总的来说，它们会影响 数以百万计的人。确定NDDS的遗传病因对家庭、社区和科学都是有益的。 基因诊断使家庭能够认识到复发的风险，并根据预期的预后采取行动。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。这些基因 原因NDDS提供了对正常大脑发育和疾病发病机制的分子洞察力。整体 外显子组测序(WES)已经上升到HMIC基因测试的前沿，因为它具有发现 遗传性NDD的遗传基础，但在LMIC中很少使用。博士之间正在进行的合作。 印度马尼帕尔大学卡斯图尔巴医学院的Shukla博士和人文系的Bielas博士 美国密歇根大学的遗传学已经制定了一项可持续的战略，将基于WES的测试用于 印度NDDS的基因诊断。随着诊断产量与HMIC持平，基于WES的基因测试将是 这是解决印度遗传性新城疫负担加重的重要工具。我们提议用实验来描绘 东南亚血统的遗传多样性。对于我们确定的两个新的NDDS基因病因， 在无关的受影响印度家庭中也发现了相同的致病变异，表明存在创始人效应 在印度人口中有较高的载频。这一发现突显了不同的 基因组研究中的种群。序列表示和功能研究中缺乏奇偶性 来自印度的是一项科学和健康挑战，对基因变异的解释产生了负面影响。我们 基因组测序研究中不同群体代表性差异影响的假设 在印度，有害等位基因的解释和NDDS的基因诊断是导致性别不平等的原因 全球基因组医学。我们将通过在更大的人群中定义遗传多样性来应对这一挑战 东南亚血统(Aim1)，从功能上表征变体以支持其分类为 致病(目标2)和减少不同群体在基因组医学中的不平衡表现 一个可搜索的基于网络的平台，用于公开识别印度血统中未识别的基因多样性 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， 促进可持续战略，以解决这些重要问题。

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.