A Novel Homozygous Missense Mutation of PIEZO1 Leading to Lymphatic Malformation-6 Identified in a Family With Three Adverse Pregnancy Outcomes due to Nonimmune Fetal Hydrops

Abstract

Lymphatic malformation-6 (LMPHM6) is a rarer form of nonimmune hydrops that often manifests as widespread lymphedema involving all segments of the body, namely, subcutaneous edema, intestinal/pulmonary lymphangiectasia, chylothoraces, and pleural/pericardial effusions. Here, we detected one rare and previously unobserved homozygous missense variant in PIEZO1 (c.5162C>G, p.Ser1721Trp) as a novel genetic cause of autosomal recessive LMPHM6, in a family with three adverse pregnancy outcomes due to nonimmune fetal hydrops. Although, the loss-of-function mutations such as those usually including nonsense, frameshift, splice site, and also fewer missense variants in PIEZO1 have been proved to lead to LMPHM6, among these, the biallelic homozygous mutations resulting in the loss of function of PIEZO1 have not been reported before. Here, we first strongly implicated impaired PIEZO1 function-associated LMPHM6 with a homozygous missense mutation in PIEZO1.

Keywords: PIEZO1; a novel mutation; lymphatic malformation-6; nonimmune fetal hydrops; whole exome sequencing.

FIGURE 1

Prenatal ultrasound. (A) Thalamus transverse section: subcutaneous edema: 3 mm; (B) thorax transverse section: bilateral hydrothorax: 4 mm; (C) abdominal transverse section: no subcutaneous edema; (D) sagittal section of the thigh: no subcutaneous edema; (E) no placental thickening; (F) cerebellum transverse section: subcutaneous edema: 14 mm; (G) thorax transverse section: subcutaneous edema: 10 mm, bilateral hydrothorax: 10 mm, and lung collapse, heart pressed; (H) abdominal transverse section: subcutaneous edema: 10 mm; (I) sagittal section of the thigh: subcutaneous thickening: 9 mm; and (J) placental thickening: 53 mm.

FIGURE 2

Copy number analyses via CMA. Weighted log2 ratio: values of tested SNP log signal intensity compared to the reference sample SNP intensity are processed through a Bayes wavelet shrinkage estimator, and then these processed values are input to the CNState algorithm HMM; intensity ratio of 0 = 2 copies; intensity ratio of −1 = 1 copies; values of chromosomes X and Y are centered below 0 and −1, respectively, indicating sex chromosome mosaicism. Allele difference is computed based on differencing A signal and B signal; genotype “AA”: (0.5 + 0.5)–(0) = 1; genotype “AB”: (0.5)–(0.5) = 0; genotype “BB”: (0)–(0.5 + 0.5) = −1; values of chromosome X indicates maternal uniparental disomy of chromosome X.

FIGURE 3

Pedigrees and DNA sequences. The arrow in III shows the proband. The red arrows indicate the mutations.

FIGURE 4

3D modeling of PIEZO1 p.Ser1721Trp. (A) Ribbon modeling of PIEZO1 (1–2,521). (B) Close-up of PIEZO1 p.Ser1721Trp is depicted in magenta.

FIGURE 5

Blood smear microscopy, PIEZO1 protein expression and the aborted fetus. (A) Blood smear microscopy showing occasional stomatocytes and spherocytes (red arrows) in III 4. (B) PIEZO1 mRNA expression is defective in III 4. (C) PIEZO1 protein expression is defective in III 4. (D) The appearance of the aborted fetus was male and manifested generalized subcutaneous edema, especially face and neck swelling.