Enhancement of phenotyping for fetal investigation using next‐generation sequencing

Mone, Fionnuala; Homfray, Tessa; Kagan, Karl Oliver; Kilby, Mark D.

doi:10.1002/uog.26301

Cited by 2 publications

(1 citation statement)

References 44 publications

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“…Within the limitations of reporting, advanced neurosonography was not specifically reported and fetal MRI was documented only as having been performed in under a third of cases, which is likely a significant under-representation. 52 , 53 Interestingly, Type 1 cortical anomalies demonstrated the greatest yield, highlighting the importance of investigating a primary or secondary microcephaly (defined prenatally as a head circumference (HC) more than 3 standard deviations (SDs) below the mean for gestational age) which may only manifest in the third trimester and the challenges regarding megalencephaly (HC more than 2SDs above the mean for gestational age) which rarely present prenatally but have a strong association with genes within the P13L-AKT-mTOR pathway and often lead to developmental delay, intellectual disability and early onset seizures. 54 It is important to consider that the cause may also be benign/familial in nature hence it is always useful to measure the parental occipital frontal circumference.…”

Section: Discussionmentioning

confidence: 99%

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

Blayney,

Laffan,

Jacob

et al. 2023

Prenatal Diagnosis

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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.

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Section: Discussionmentioning

confidence: 99%

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

Blayney,

Laffan,

Jacob

et al. 2023

Prenatal Diagnosis

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The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta‐analysis

Reilly,

Sonner,

McCay

et al. 2024

Prenatal Diagnosis

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ObjectivesTo determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra‐cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification.MethodsA systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010‐February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF‐PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747.ResultsOverall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%–21.6%), 9.3% (95% CI, 6.6%–12.3%) and 35.9% (95% CI, 21.0%–52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%–65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%).ConclusionThe likelihood of a monogenic aetiology in fetuses with multi‐system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

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Enhancement of phenotyping for fetal investigation using next‐generation sequencing

Cited by 2 publications

References 44 publications

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

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

The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta‐analysis

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