Prenatal diagnosis using next-generation sequencing in genetic counseling: Novel mutations in three large Iranian families: A case series.

Background: All considerable families are seeking genetic counseling aiming to manage the next pregnancy according to the positive family history of heterogenetic disorders. Prenatal diagnosis utilizing next-generation sequencing provides a significant means to identify the causes of genetic abnormalities, allowing for timely interventions that support informed family planning. This study explores the power of whole-exome sequencing (WES) in uncovering genetic variants in couples who are seeking genetic counseling for their next pregnancy.

Case presentations: In this study, WES was used to identify genetic variations associated with disability in families seeking genetic counseling. 3 families who had at least 1 child with developmental delay (DD) and/or intellectual disability (ID) participated in a genetic counselling clinic, Yazd Reproductive Science Institute, Yazd, Iran to have successful outcomes for the next pregnancy. 3 distinct mutation sites from 3 families were diagnosed, following the WES for affected children with intellectual disabilities. Results showed a homozygous de novo stop-gain mutation in malate dehydrogenase 1gene (NM_005917.4:c.4C $>$ T; p.Arg2Ter), a splice acceptor mutation in the post-glycosylphosphatidylinositol attachment to proteins inositol deacylase 1 gene (NM_024989.4:c.1221-1G $>$ T), and a missense mutation in the lysosomal trafficking regulatorgene (NM_000081.4:c.949G $>$ A; p.Glu317Lys) in each family, respectively.

Conclusion: For cases with DD and unexplained ID, WES is a very successful diagnostic approach. Unfortunately, large Iranian families exhibit significant genetic heterogeneity, highlighting the critical role of de novo variants in diagnosis. The results of this study confirm that proteins inositol deacylase 1, malate dehydrogenase 1, and lysosomal trafficking regulatorare involved in the pathophysiology of ID/DD and the transformative potential of prenatal genetic screening.