Donald School Journal of Ultrasound in Obstetrics and Gynecology

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VOLUME 14 , ISSUE 2 ( April-June, 2020 ) > List of Articles

Original Article

Early Sonographic Findings for Suspecting de novo Single-gene Mutation

Takako Nakamura, Hideaki Chiyo

Keywords : Exome sequencing, Fetus, First-trimester, Single gene mutation, Ultrasound

Citation Information : Nakamura T, Chiyo H. Early Sonographic Findings for Suspecting de novo Single-gene Mutation. Donald School J Ultrasound Obstet Gynecol 2020; 14 (2):125-130.

DOI: 10.5005/jp-journals-10009-1643

License: CC BY-NC 4.0

Published Online: 30-07-2020

Copyright Statement:  Copyright © 2020; The Author(s).


Introduction: Currently, many obstetrics departments widely use prenatal genetic screening tests in the first trimester, including noninvasive prenatal genetic tests (NIPT), sonographic examination, and combined tests. However, many cases with de novo single-gene mutations are detected after birth. The introduction of next-generation sequencing (NGS) needs careful pretest and posttest counseling, informed consent, and trio-based sequencing of the fetus and parents. Next-generation sequencing turnaround time has been reduced, but it takes a long period from an ultrasound anomaly scan at 18–20 weeks to post-NGS counseling. Ideally, the starting point of the anomaly scan should be early. Still, it has not yet been concluded whether there are clear criteria for the fetal indication to NGS in the first trimester of pregnancy. Aim: To investigate first-trimester sonographic findings in cases with nonfamilial de novo single-gene mutation and to discuss early fetal findings as criteria for prenatal NGS test. Materials and methods: For five months between August and December in 2019, after sonographic examinations between 11 and 13 gestational weeks for all fetuses, chorionic villous sampling (CVS) was done for suspected cases. DNA was extracted immediately after CVS for a rapid test of quantitative fluorescence-polymerase chain reaction (QF-PCR) and further examinations, such as, microarrays and exome sequencing. Confirming normal G-banding results, followed by further examinations of exome sequencing. Results: Seven cases with de novo single-gene mutations were detected by target exome sequencing; one case of Costello syndrome, one of Campomelic dysplasia, one of Cornelia de Lange syndrome, and four of Noonan syndrome. All of those gene mutations were confirmed by following Sanger sequencing. All seven cases had common sonographic findings, increased NT ≥5 mm, low-set ears, and micrognathia. Three Noonan syndrome cases with PTPN11 mutation had tachycardia, but Noonan with RAF1 mutation had normal heart rate. Limb abnormality or contracture was detected in one case of Noonan syndrome, Campomelic dysplasia, and Cornelia de Lange syndrome. Conclusion: Nonfamilial de novo single-gene disorders can be suspected in the first trimester by ultrasound findings of NT ≥5 mm, low-set ears, and micrognathia from our case series. Further case studies will be required.

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