2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Deciphering the Clinical Relevance of PIEZO1 Variants Detected by Prenatal Exome Sequencing in Nonimmune Hydrops Fetalis

Deciphering the Clinical Relevance of PIEZO1 Variants Detected by Prenatal Exome Sequencing in Nonimmune Hydrops Fetalis
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Pdf Summary
This study aimed to investigate the clinical relevance of PIEZO1 gene variants detected in cases of nonimmune hydrops fetalis (NIHF) using prenatal exome sequencing. PIEZO1 encodes a mechanosensitive ion channel that converts mechanical stimulation into cation influx. Variants in PIEZO1 have been associated with both autosomal dominant (AD) and autosomal recessive (AR) disease forms. The study analyzed 22 pregnancies with NIHF and a reported PIEZO1 variant(s) and identified 35 different PIEZO1 variants. These variants were reclassified using the ACMG/AMP guidelines. The interpretation of variant pathogenicity was concordant with reported results in 14 out of 22 cases. Among the discordant cases, six variants were downgraded to variants of uncertain significance (VUS) or likely benign, while two VUS were upgraded to pathogenic or likely pathogenic. The study classified the reported PIEZO1 variants as likely diagnostic in 12 pregnancies, possibly diagnostic in seven pregnancies, and unlikely diagnostic in three pregnancies. The study found that PIEZO1 variants causing AD NIHF were characterized by gain of function in red blood cells and were rare in population databases. PIEZO1 variants causing AR NIHF were characterized by loss of function and an isolated NIHF phenotype. The study also found that PIEZO1 variants were the most common single gene reported in NIHF, accounting for 10% of cases diagnosed by exome sequencing. It was observed that some variants with unknown mechanisms were reported in the same NIHF pregnancy along with other PIEZO1 variants, suggesting that co-inheritance of multiple variants may contribute to the NIHF phenotype. In conclusion, this study provides insights into the clinical relevance of PIEZO1 variants in NIHF. It highlights the different disease mechanisms associated with PIEZO1 variants and emphasizes the importance of accurate variant classification for proper diagnosis and genetic counseling of affected families. Further research is needed to understand the range of variants causing AD NIHF and the potential contribution of additional PIEZO1 variants to the phenotype.

Asset Subtitle

Presenting Author - Casey J. Brewer, PhD; Co-Author - Mona M. Makhamreh, MD; Co-Author - Kavya Shivashankar, MD; Co-Author - Mariella Toro, BA; Co-Author - Hiba Mustafa, MD; Co-Author - Seth I. Berger, MD, PhD; Co-Author - Huda B. Al-Kouatly, MD, FACOG, FACMG;

Meta Tag

Exome sequencing

Fetal Pathology

Genetic Testing

Genotype-Phenotype Correlations

Identification of Disease Genes

Inheritance Patterns

NextGen Sequencing

Phenotype

Prenatal Diagnosis

Sequencing

Ultrasound

Variant Detection

Co-Author Mona M. Makhamreh, MD

Co-Author Kavya Shivashankar, MD

Co-Author Mariella Toro, BA

Co-Author Hiba Mustafa, MD

Co-Author Seth I. Berger, MD, PhD

Co-Author Huda B. Al-Kouatly, MD, FACOG, FACMG

Presenting Author Casey J. Brewer, PhD

Keywords

PIEZO1 gene variants

nonimmune hydrops fetalis

prenatal exome sequencing

mechanosensitive ion channel

autosomal dominant disease

autosomal recessive disease

variant pathogenicity

variants of uncertain significance

diagnostic PIEZO1 variants

genetic counseling