Diagnosis of inborn errors of metabolism through prenatal exome sequencing with targeted analysis for fetal structural anomalies

Abstract

AbstractObjectivesThe value of prenatal exome sequencing (pES) for fetuses with structural anomalies is widely reported. In England, testing is conducted through trio exome sequencing and analysis of a gene panel. Over a 30‐month period testing of 921 pregnancies resulted in a genetic diagnosis in 32.8% of cases (302/921). Here we review cases diagnosed with an inborn error of metabolism.MethodsDiagnoses of inborn errors of metabolism (IEM) were classified according to the ICIMD classification system. Genetic diagnoses were assessed against Human Phenotype Ontology terms, gestation of scan findings and literature evidence.Results35/302 diagnoses (11.6%) represented IEM. Almost half affected metabolism of complex macromolecules and organelles (n = 16), including congenital disorders of glycosylation (n = 8), peroxisome biogenesis disorders (n = 4), and lysosomal storage disorders (n = 4). There were eight disorders of lipid metabolism and transport, the majority being genes in the cholesterol biosynthesis pathway, eight disorders of intermediary metabolism, of which seven were defects in “energy” processes, and two diagnoses of alkaline phosphatase deficiency.ConclusionsReview of pES diagnoses and ultrasound scan findings is key to understanding genotype‐phenotype correlations. IEM are genetically heterogeneous and may present with variable scan findings, which makes an individual diagnosis difficult to suspect. Diagnosis during pregnancy is particularly important for many IEM with respect to prognosis and early neonatal management.