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

ObjectivesThe 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. What's already known about this topic?Prenatal exome sequencing (pES) for monogenic disorders in fetuses with structural anomalies is known to increase diagnostic yieldEligibility for pES is predominantly determined by detailed ultrasound evaluation and accurately defining the fetal phenotypeThe majority of metabolic conditions present postnatally, with some presenting prenatally where the defect interferes with fetal developmentWhat does this study add?This study illustrates the contribution of pES in identifying metabolic diagnoses in pregnancies investigated by the National Health Service prenatal diagnostic ES service.Metabolic diagnoses are reviewed according to classification, ultrasound scan findings, and in context of the literatureWhere inborn errors of metabolism present prenatally, in some cases there may be non-specific and variable scan findings, and reports of prenatal ascertainment per gene may be rare or non-existent.