Clinical Utility and Yield of Carrier Exome Sequencing in High-Risk Indian Couples.

Objective: To evaluate the diagnostic yield and spectrum of monogenic disorders identified through exome sequencing (ES) based couple carrier screening in high-risk couples.

Methods: We retrospectively reviewed the results of carrier screening by ES conducted between 2016 and 2023 at a tertiary care center in India for couples at increased risk of inherited genetic disease in their children. After pre-test genetic counseling, all couples underwent carrier screening through ES. We defined high-risk couples as those at an increased risk of inherited genetic disease in their children, and classified them as Category I (couples with a significant obstetric history, such as a previous fetus or child with a suspected genetic disorder), Category II (couples with a family history of a suspected genetic disorder in a parent or close relative) and Category III (couples opting for expanded carrier screening without any significant contributory history). Category I was further subcategorized based on the phenotype of the affected fetus, neonate, or child into: Ia - multiple malformations including non-immune hydrops and skeletal dysplasia; Ib - features suggestive of other system involvement; Ic - neurological phenotype with or without intellectual disability; and Id - unexplained intrauterine/neonatal death or stillbirth.

Results: Of the 137 couples evaluated, 130 (95%) belonged to category I, of which 48/130 (37%) were subcategorised as Ia, 61/130 (47%) as Ib, 8/130 (6%) as Ic and 24/130 (18.5%) as Id. Nine couples had more than one subcategory indication for ES. Four couples (3%) belonged to category II, and three (2%) belonged to category III. Consanguinity was noted in 23.4% (32/137). The overall diagnostic yield in the cohort was 38.7% (53/137), mainly contributed by category I (52/130, 40%), with the highest yield in subcategory Ib (39/61, 64%).

Conclusion: Carrier screening by ES is useful for identifying couples at high risk of having an offspring with genetic disorders. The yield is higher in couples with an affected previous pregnancy. ES allows comprehensive carrier screening in genetically diverse populations.