Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent

J Mol Diagn. 2024 Jun;26(6):510-519. doi: 10.1016/j.jmoldx.2024.03.005. Epub 2024 Apr 4.

Abstract

The genetically isolated yet heterogeneous and highly consanguineous Indian population has shown a higher prevalence of rare genetic disorders. However, there is a significant socioeconomic burden for genetic testing to be accessible to the general population. In the current study, we analyzed next-generation sequencing data generated through focused exome sequencing from individuals with different phenotypic manifestations referred for genetic testing to achieve a molecular diagnosis. Pathogenic or likely pathogenic variants are reported in 280 of 833 cases with a diagnostic yield of 33.6%. Homozygous sequence and copy number variants were found as positive diagnostic findings in 131 cases (15.7%) because of the high consanguinity in the Indian population. No relevant findings related to reported phenotype were identified in 6.2% of the cases. Patients referred for testing due to metabolic disorder and neuromuscular disorder had higher diagnostic yields. Carrier testing of asymptomatic individuals with a family history of the disease, through focused exome sequencing, achieved positive diagnosis in 54 of 118 cases tested. Copy number variants were also found in trans with single-nucleotide variants and mitochondrial variants in a few of the cases. The diagnostic yield and the findings from this study signify that a focused exome test is a good lower-cost alternative for whole-exome and whole-genome sequencing and as a first-tier approach to genetic testing.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Consanguinity
  • DNA Copy Number Variations*
  • Exome / genetics
  • Exome Sequencing* / methods
  • Female
  • Genetic Diseases, Inborn / diagnosis
  • Genetic Diseases, Inborn / epidemiology
  • Genetic Diseases, Inborn / genetics
  • Genetic Testing* / economics
  • Genetic Testing* / methods
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • India / epidemiology
  • Infant
  • Male
  • Phenotype
  • Young Adult