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A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound
Author(s) -
CorstenJanssen Nicole,
Bouman Katelijne,
Diphoorn Janouk C. D.,
Scheper Arjen J.,
Kinds Rianne,
Mecky Julia,
Breet Hanna,
Verheij Joke B. G. M.,
Suijkerbuijk Ron,
Duin Leonie K.,
Manten Gwendolyn T. R.,
Langen Irene M.,
Sijmons Rolf H.,
SikkemaRaddatz Birgit,
Westers Helga,
Diemen Cleo C.
Publication year - 2020
Publication title -
prenatal diagnosis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.956
H-Index - 97
eISSN - 1097-0223
pISSN - 0197-3851
DOI - 10.1002/pd.5781
Subject(s) - prenatal diagnosis , medicine , exome sequencing , fetus , genetic testing , genetic counseling , omim : online mendelian inheritance in man , obstetrics , pathology , genetics , pregnancy , biology , gene , mutation , phenotype
Objective Conventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide polymorphism‐array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first‐degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. Results We established a genetic rES‐based diagnosis in 8 out of 23 fetuses (35%) without QF‐PCR or array abnormalities. Diagnoses included MIRAGE ( SAMD9 ), Zellweger ( PEX1 ), Walker‐Warburg ( POMGNT1 ), Noonan ( PTNP11 ), Kabuki (KMT2D ), and CHARGE ( CHD7 ) syndrome and two cases of Osteogenesis Imperfecta type 2 ( COL1A1 ). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8‐20) days. Conclusion Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.