Investigation into the genetics of fetal congenital lymphatic anomalies |
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Authors: | Daniella Rogerson Anna Alkelai Jessica Giordano Madhulatha Pantrangi Meng-Chang Hsiao Chia-Ling Nhan-Chang Joshua E Motelow Vimla Aggarwal David Goldstein Ron Wapner Carrie J Shawber |
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Institution: | 1. Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
Department of Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA;2. Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, USA;3. Department of Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA;4. Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA;5. Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA |
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Abstract: | Objective Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing. Methods Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup. Results CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1. Conclusions WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections. |
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