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Background: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent-offspring trios and proband only analysis., Methods: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation., Results: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications., Conclusion: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities., (© 2024. The Author(s).)

Key content: In the presence of a fetal structural anomaly, fetal DNA can be obtained through invasive testing (e.g. amniocentesis and chorionic villus sampling) in order to undertake genomic testing to attempt to uncover a unifying genetic diagnosis.There are number of traditional and more novel genomic tests available, which can identify aneuploidy, chromosomal structural variation and/or sequence variants within genes.The cumulative diagnostic yield of such technologies is approximately 25%, 6% and up to 80% in some cohorts for QF‐PCR/G‐banding karyotype, chromosome microarray and exome sequencing, respectively. Learning objectives: To understand the technical basis and clinical indications for QF‐PCR, G‐banding karyotype, chromosome microarray and exome sequencing.To appreciate the potential benefits and challenges associated with exome sequencing.To gain awareness of modern technologies that may be utilised to address recurrence risk, e.g. preimplantation genetic diagnosis and non‐invasive prenatal diagnosis. Ethical issues: Not all technologies are currently available across all four nations of the UK, hence challenges are raised regarding healthcare equity.There can be uncertainty around the interpretation of prenatal genomic test results, which can have implications in counselling, particularly regarding termination of pregnancy.Incidental findings may be revealed, which can have implications for counselling and the future health of the fetus and the parents. [ABSTRACT FROM AUTHOR]

The role of genetics in epilepsy has been recognized for a long time. Over the past decade, genome-wide technologies have identified numerous genes and variants associated with epilepsy. In the clinical setting, a myriad of genetic testing options are available, and a subset of specific genetic diagnoses have management implications. Furthermore, genetic testing can be a dynamic process. As a result, fundamental knowledge about genetics and genomics has become essential for all specialists. Here, we review current knowledge of the genetic contribution to various types of epilepsy, provide an overview of types of genetic variants, and discuss genetic testing options and their diagnostic yield. We also consider advantages and limitations of testing approaches. [ABSTRACT FROM AUTHOR]

Introduction: The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). Methods: This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in n = 147 cases of prenatally diagnosed CHD was assessed. Results: In 34.7% (n = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (n = 23/147), 13.7% (n = 17/124), and 10.2% (n = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (n = 11/35), p = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (n = 10/44), p = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (n = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1–5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (n = 5/107) with ES, with none in the CMA group. Conclusion: In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD. [ABSTRACT FROM AUTHOR]