PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing

• Published in: Prenatal diagnosis 2023-11, Vol.43 (12), p.1556-1566
• Main Authors: Brewer, Casey J, Makhamreh, Mona M, Shivashankar, Kavya, McLaren, Rodney, Toro, Mariella, Berger, Seth I, Al-Kouatly, Huda B
• Format: Article
• Language: English
• Subjects: Diagnostic systems; Erythrocytes; Exome Sequencing; Female; Genetics; Genomics; Humans; Hydrops fetalis; Hydrops Fetalis - diagnosis; Ion Channels - genetics; Phenotypes; Pregnancy
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.6451

To clarify the relevance of PIEZO1 variants detected by prenatal exome in the context of non-immune hydrops fetalis (NIHF). A systematic review of prenatal exome studies from 1/1/2000-8/1/2022 was performed. Thirty-six studies met the inclusion criteria. PIEZO1 variants were categorized by disease mode (dominant (AD) versus recessive (AR)) and classified by the American College of Medical Genetics and Genomics (ACMG) guidelines. Twenty-two pregnancies with 35 distinct PIEZO1 variants were included. We deemed PIEZO1 variants to be "likely diagnostic" in 12/22 pregnancies, "possibly diagnostic" in 7/22, and "unlikely diagnostic" in 3/22. In total, 19 of 191 NIHF cases diagnosed by prenatal exome were attributed to PIEZO1. Among likely diagnosed cases, the disease mode was AR in eight and AD in four. PIEZO1 variants causing AR NIHF were characterized by loss of function and isolated NIHF phenotype. PIEZO1 variants causing AD NIHF were characterized by gain of function in red blood cells, scarcity in databases, and sporadic inheritance. Missense variants associated with NIHF were clustered in three domains: transmembrane helical unit 4 (THU4), THU5, and the Cap. PIEZO1 variants were reported in 10% of NIHF cases diagnosed by prenatal exome, making PIEZO1 the most common single gene reported in NIHF.