Implication of chromosomal microarray analysis prior to in‐utero repair of fetal open neural tube defect

Abstract

Objective In‐utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in‐utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in‐utero ONTD repair. Methods This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy‐assisted fetoscopic repair or open‐hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy‐number variants (CNV) were detected (reportable‐CNV group) or not (normal‐CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non‐parametric statistical tests were employed as appropriate. Results During the study period, 146 fetuses with ONTD were eligible for and underwent in‐utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749‐kb central 22q11.21 deletion spanning low‐copy‐repeat regions B–D of chromosome 22; the second case was diagnosed with a 1.3‐Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. Conclusions Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in‐utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case‐by‐case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single‐center series, a larger, multicenter long‐term study should be conside...

Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN

“…90,91 Two recent retrospective studies report a rate of pathogenic copy number variants of 3.5% and 2.6% in cohorts of 62 and 77 cases of fetal open dysraphisms. 91,92 The role of exome and whole genome sequencing is currently in the field of clinical research. ultrasound between open dysraphism and limited dorsal myeloschisis (LDM).…”

“…96,97 The prognosis is much better than that of the open dysraphism. 92,93 Many forms are asymptomatic and if symptoms are present, they are usually moderate.…”