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.
Our collaborative group of scientists and clinicians in India and the United States strive to address global health equity by establishing genomic tools and research in India to diagnosis and treat neurodevelopmental disorders that are lethal or cause lifelong impairments. These resources will be available to patients across the socioeconomic spectrum. Identifying genetic contributions to disease risk in diverse populations will promote reliable genetic diagnosis important for effective treatment.