Research Projects

Rationale: Fetal structural anomalies detected in 2%–5% of pregnancies are a common cause of mortality and morbidity accounting for 20% of perinatal mortality.1 An underlying genetic abnormality is an important cause of malformations and can range from aneuploidy to single gene disorders. Commonly used investigations such as G-banded Karyotyping, Chromosomal microarray, QFPCR and Fluorescent in-situ hybridization targeted at detecting aneuploidies are limited by low resolution. A combination of these tests can identify a genetic etiology in up to 40% of dysmorphic fetuses thus leaving majority undiagnosed. While sequencing studies such as Whole Genome and Whole Exome Sequencing have the potential to provide answers in these undiagnosed cases, Targeted gene sequencing and gene panels have limited application in prenatal diagnosis due to the incomplete or evolving phenotype unlike in postnatal period. WES yields 25%-30% results in postnatal testing of unsolved cases on basic investigations. With the advent of Next generation sequencing techniques, the lower cost, lower amount of fetal DNA required, rapid turnaround time and greater sequencing depth with WES makes it a practical prenatal testing option. Most of the studies testing the yield of various genetic tests including application of WES have been done in regions with low degree of consanguinity. South India being a region with high degree of consanguinity, the yield of WES in euploid fetuses with anomalies is likely to be much higher and there is a need to develop a strategy to efficiently evaluate such cases as applicable to local population. Objectives: Primary objective is to, 1. Estimate the diagnostic yield of WES in euploid fetuses with structural malformation among consanguineous couples 2. Diagnostic yield of WES according to Fetal phenotype and organ system involved Secondary: 1. Distribution of actionable variants around regions of loss of heterozygosity (LOH) on CMA 2. Size of loss of heterozygosity on CMA 3. Proportion of cases showing VOUS with completely or partially matching phenotype requiring parental WES 4. Description of phenotype on prenatal ultrasound, postmortem examination and neonatal evaluation at 28 days Experiments to be carried out: Consenting pregnant women with fetal anomalies will undergo a detailed ultrasound for confirmation of diagnosis. Prenatal testing for cytogenetic abnormalities will be done on Amniotic fluid/CVS/FBS samples as First step. Those cases which are reported to be normal on Microarray and give H/L Consanguinity will be tested with WES for single gene disorders. Significance of the Result: Can give us information on the rate of autosomal disorders in the presence of fetal anomalies in euploid fetuses and history of consanguinity. Such strategy that takes into consideration the local social structure and needs can guide us to the best approach to investigate fetal malformations.