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

Gillian Blayney, Eoghan Laffan, Preethi Jacob, Caitlin Baptiste, Heinz Gabriel, Teresa Sparks, Yuval Yaron, Mary Norton, Karin Diderich, Yiming Wang, Karen Chong, David Chitayat, Neelam Saini, Shagun Aggarwal, Montse Pauta, Antoni Borrell, Kelly Gilmore, Natalie Chandler, Stephanie Allen, Neeta VoraAbdul Noor, Caitriona Monaghan, Mark Kilby, Ronald Wapner, Lyn Chitty, Fionnuala Mone

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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.

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.

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.

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.

Original languageEnglish
Number of pages10
JournalPrenatal Diagnosis
Early online date06 Dec 2023
Publication statusEarly online date - 06 Dec 2023


  • central nervous system
  • incremental yield
  • fetal brain
  • next generation sequencing
  • exome sequencing
  • fetus


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