Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis

ObjectivesDetermine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities.MethodsData were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model.ResultsThirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus.ConclusionsPrenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex. What is already known about this topic?Prenatal next-generation sequencing increases the incremental diagnostic yield in fetuses with sonographic structural abnormalities and a normal G-banding karyotype and/or chromosome microarray.Published diagnostic yields specific to central nervous system abnormalities are variable, highlighting the need for a systematic review.What does this study add?This is the first systematic review and meta-analysis of the literature available to date in this area with sub-classification by a pediatric neuroradiologistA subgroup analysis provides the incremental diagnostic yield for specific anatomical CNS anomalies