Targeted Whole-Exome Sequencing for Carrier Screening of Couples Having Previously Affected Pregnancies with Suspected Autosomal Recessive Diseases

Abstract There are many severe or life threatening autosomal recessive conditions leading to death in the prenatal, early postnatal, or early childhood period without a precise diagnosis being made. Often, genetic counselling and postmortem analysis are not available, and phenotypic descriptions are insufficient. Targeted whole exome sequencing of the couple is the best test when the proband is not available for sampling. It is estimated that couples with previous babies being affected by a particular phenotype are more likely to harbour a heterozygous variant for the given phenotype. Here, we report our experiences with targeted whole exome sequencing for the carrier screening of autosomal recessive lethal disorders in couples with one or more affected foetuses or children. We selected 11 consanguineous and four nonconsanguineous consecutive couples at risk for severe autosomal recessive disorders seen at the genetic clinic of the Mahatma Gandhi Mission Medical College and Umang Maternity and IVF Centre. The couples were counseled for carrier screening with targeted next generation sequencing. The inclusion criteria included the loss of at least one child before the age of 2 years due to a severe/lethal condition and/or one or more miscarriages with pathological findings in the fetus. The couple's genetic testing results were reviewed to assess their risk of passing on inherited conditions to their children. A total of 15 couples were identified with a bad obstetric history in the last 2 years, from June 2022 to May 2024. Out of the 15 couples, 11 had a consanguineous union. Exome was negative in one couple, and only one parent harboured a pathogenic variant in another couple. Of the 15 couples investigated, 4 couples (cases 3, 11, 13, and 15) had lost one child. The remaining 11 couples had lost more than one pregnancy. A likely causative variant for the symptoms of the deceased children was identified in 5 out of the 15 couples investigated (33.33%). Out of the 12 couples, 5 couples were carriers of likely pathogenic variants, and the remaining 7 couples were carriers of variants of uncertain significance. Our data showed that whole exome sequencing in couples based on phenotype in previous pregnancies or children was a high yield strategy for identifying lethal autosomal recessive disorders.