Prenatal Exome Sequencing Identifies Two PIEZO1 Variants In Recurrent Nonimmune Hydrops Fetalis: A Case Report

Tedy Teguh Satriadi; Dheafitri Riezka Fahmi; Ketut Rama Wijaya; Rachmad Nugroho; Rudianto  Halim Putera

doi:10.55227/ijhet.v5i4.1288

Authors

Tedy Teguh Satriadi Department of Obstetrics and Gynecology, RSUD Kanujoso Djatiwibowo, Indonesia
Dheafitri Riezka Fahmi Department of Obstetrics and Gynecology, Universitas Indonesia, Indonesia
Ketut Rama Wijaya Department of Obstetrics and Gynecology, Universitas Gadjah Mada, Indonesia
Rachmad Nugroho Department of Obstetrics and Gynecology, Universitas Gadjah Mada, Indonesia
Rudianto Halim Putera Department of Obstetrics and Gynecology, Universitas Gadjah Mada, Indonesia

DOI:

https://doi.org/10.55227/ijhet.v5i4.1288

Keywords:

PIEZO1; nonimmune hydrops fetalis; recurrent fetal hydrops; generalized lymphatic dysplasia; prenatal exome sequencing; intrauterine transfusion; EPHB4.

Abstract

Nonimmune hydrops fetalis (NIHF) is a heterogeneous fetal condition characterized by abnormal fluid accumulation in two or more fetal compartments. Prenatal exome sequencing has increasingly identified monogenic causes of otherwise unexplained NIHF, with PIEZO1 among the most frequently implicated genes. Biallelic loss-of-function PIEZO1 variants are associated with autosomal recessive generalized lymphatic dysplasia with NIHF. A 26-year-old woman, gravida 3 para 1 abortus 1, had one prior pregnancy complicated by hydrops fetalis that ended in pregnancy loss. In the current pregnancy, cell-free DNA screening at 16 weeks 4 days showed low risk for common aneuploidies and selected microdeletion syndromes, with a female fetus and fetal fraction of 9.1%. Maternal serology for cytomegalovirus, toxoplasmosis, syphilis, and parvovirus B19 was non-reactive or negative. Ultrasound demonstrated ascites, bilateral pleural effusions, generalized edema, increased nuchal translucency, tricuspid regurgitation, a cavum velum interpositum cyst, and increased abdominal circumference, fulfilling criteria for NIHF. Prenatal chromosomal microarray showed no phenotype-related copy-number variant and a normal chromosomal constitution. Prenatal exome sequencing of amniotic fluid identified a heterozygous likely pathogenic PIEZO1 nonsense variant, NM_001142864.2:c.1857C>A p.(Tyr619*), and a second heterozygous PIEZO1 missense variant of uncertain significance, NM_001142864.2:c.6338C>T p.(Pro2113Leu). A heterozygous EPHB4 variant of uncertain significance was also reported as potentially relevant. Parental segregation was recommended to determine whether the two PIEZO1 variants were in trans. At 20 weeks' gestation, cordocentesis and intraperitoneal intrauterine transfusion were performed for suspected fetal anemia/hemolytic hydrops. Maternal irregular red-cell antibody screening and direct antiglobulin testing were negative, supporting a nonimmune mechanism. This case highlights recurrent NIHF in a family in whom prenatal exome sequencing identified two PIEZO1 variants after chromosomal, infectious, and alloimmune evaluations were unrevealing. The PIEZO1 findings represent the leading molecular explanation, but a definitive autosomal recessive diagnosis requires parental segregation and further evidence regarding the VUS. Early genomic testing can refine etiologic assessment, recurrence counseling, and reproductive planning in unexplained or recurrent NIHF.

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