Investigation into the genetics of fetal congenital lymphatic anomalies.

TitleInvestigation into the genetics of fetal congenital lymphatic anomalies.
Publication TypeJournal Article
Year of Publication2023
AuthorsRogerson D, Alkelai A, Giordano J, Pantrangi M, Hsiao M-C, Nhan-Chang C-L, Motelow JE, Aggarwal V, Goldstein D, Wapner R, Shawber CJ
JournalPrenat Diagn
Date Published2023 Jun
KeywordsFemale, Fetus, Humans, Hydrops Fetalis, Infant, Newborn, Ion Channels, Lymphatic Abnormalities, p120 GTPase Activating Protein, Pregnancy

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.

Alternate JournalPrenat Diagn
PubMed ID36959127
PubMed Central IDPMC10330091
Grant ListR03 HD092662 / HD / NICHD NIH HHS / United States
T35 DK093430 / DK / NIDDK NIH HHS / United States
Related Faculty: 
Madhulatha Pantrangi, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700