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

Abstract

Objectives: Determine 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.

Methods: Data 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.

Results: Thirty 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.

Conclusions: Prenatal 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.

FIGURE 1

PRISMA flow diagram (*Authors contacted for further information **Includes unpublished audit of NHS England cases).

FIGURE 2

Quality assessment of 29 studies included in systematic review, using modified Standards for Reporting of Diagnostic Accuracy criteria (ACMG, American College of Medical Genetics and Genomics; ES, exome sequencing).