PRENATAL WHOLE EXOME SEQUENCING OF FETAL SONOGRAPHIC ABNORMALITIES IN QATAR: DIAGNOSTIC YIELD AND GENETIC FINDINGS

Abstract

Background: Fetal sonographic abnormalities at birth is estimated to be 2-3% of the global prevalence and are responsible for approximately 17%-42% of all perinatal deaths. Prenatal karyotype (KT) and chromosomal microarray (CMA) are typically diagnostic in ~9% and ~6% of cases, respectively. This leaves approximately 85% of the cases genetically undiagnosed. Previous studies illustrated that an additional 20% to 80% of cases could be diagnosed using prenatal whole exome sequencing (WES), a powerful tool for sequencing the protein-coding part of the genome. Aim: We aim to investigate the utility and diagnostic yield of prenatal WES since its implementation in Qatar in 2014 and to characterize the genetic findings and conditions identified by prenatal WES. Methodology: A retrospective chart review was conducted for 143 eligible cases of fetal sonographic abnormalities that were presented to the prenatal genetics clinic in Qatar from Oct 2014 to Dec 2023 and who underwent WES after nondiagnostic KT and/or CMA. Results: Our study revealed an overall prenatal WES diagnostic yield of 45.45% (65 solved cases out of the 143 cases), with statistical significance between the solved to the unsolved cases (p= <0.001). A total of 68 different pathogenic or likely pathogenic variants in 49 different genes were identified. Of these, 73.8% were autosomal recessive, 24.6% were autosomal dominant, and 1.6% were X-linked. The most common condition was Nemaline Myopathy type 2, seen in 21.5% (n=14) of solved cases. Ten of which belonged to consanguineous Qatari families from the same tribe and were caused by the same homozygous c.11806-1G>A pathogenic variant in the NEB gene, supporting a potential founder effect. A total of 56 cases were classified as uncertain as they either had nondiagnostic results (n=8) or had variants of uncertain significance (VUSs) (n=48). The reassessment of these VUSs resulted in the consideration of three variants (CLEC16A: c.1555_1558del, VTA1: c.52C>T, and ATP1A2: c.2260 T>C) as being likely contributing to the observed fetal sonographic abnormalities, suggesting pathogenicity in the three concerned cases in our cohort. Conclusion: This is the first retrospective analysis of its kind conducted in Qatar. It highlights the significant potential of WES as a diagnostic tool in the prenatal setting, emphasizing the need to study the utility of WES being offered as first-tier testing. Our study sheds light on a number of variants, including a potential founder variant (c.11806-1G>A) causing lethal Nemaline Myopathy 2, which could be used for premarital screening. Our study recommends facilitating segregation analysis, especially in uncertain cases, and stresses the need to consider population-specific genetic backgrounds in prenatal diagnostics and counseling.