December 2, 2022

Application of Prenatal Whole Exome Sequencing for Structural Congenital Anomalies—Experience from a Local Prenatal Diagnostic Laboratory

Theodora Hei Tung Lai 1, Leung Kuen Sandy Au 1 2, Yuen Ting Eunice Lau 1 2, Hei Man Lo 1 2, Kelvin Yuen Kwong Chan 1 2, Ka Wang Cheung 1, Teresa Wei Ling Ma 3, Wing Cheong Leung 4, Choi Wah Kong 5, Wendy Shu 6, Po Lam So 7, Anna Ka Yee Kwong 8, Christopher Chun Yu Mak 8, Mianne Lee 8, Martin Man Chun Chui 8, Brian Hon Yin Chung 8, Anita Sik Yau Kan 1

Two to three percent of all pregnancies are complicated by fetal structural congenital abnormalities (SCAs). SCAs can be categorized into predefined subcategories, including central nervous system (CNS)-related, cardiac, musculoskeletal, increased nuchal translucency (defined as >3.5 mm), or cystic hygroma, gastrointestinal, urogenital abnormalities, craniofacial dysmorphism, and intrauterine growth restriction. In this publication,  Fu, et al. (2022, PMID: 36307859) conducted a study to examine the application of exome sequencing (ES) in fetuses with SCAs identified on prenatal ultrasound. 

Geneyx Analysis enabled biomedical professionals to leverage comprehensive biomedical knowledgebases to identify 18 pathogenic variants and 10 likely pathogenic variants across 20 different genes. Nineteen fetuses were found to have disorders inherited in an autosomal dominant manner and the most common phenotypic features in fetuses with pathogenic variants were musculoskeletal and cardiac conditions. 

According to the researchers, their study was the largest cohort of prenatal ES published in Hong Kong to date. In the researched cohort, diagnostic genetic variants assumed to be causally related to SCAs were identified in 29.2% (19/65) of those with more than one SCA and 15.4% (6/39) of those with only one SCA. The authors noted that ES is a feasible and encouraging prenatal diagnosis method for fetuses with SCAs and inconclusive chromosome microarray analysis (CMA) results. The integration of karyotyping, CMA, and ES will improve molecular diagnostic performance in the prenatal setting. Prenatal ES, according to the authors, should be considered especially for fetuses with musculoskeletal and complex cardiac SCAs if their initial genetic testing was negative. 

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