Hamıde Betul GERİK CELEBİ, Murat AKBAS, Tuncay YÜCE, Serdar CEYLANER, Sırrı ÇAM

A very rare disease of lymphatic malformation 6: two novel PIEZO1 variants and review of the literature

Objective: Lymphatic Malformation 6 (MIM no:616843) is characterized by generalized edema, bilateral pleural effusion, ascites and non-immune hydrops fetalis. PIEZO1 gene has been associated with the this disorder. Here, we aimed to evaluate cases with various clinical presentations of generalized lymphatic dysplasia. Materials and Methods: Between January 2015 and January 2021, 5 cases with were evaluated with a pre-diagnosis of generalized lymphatic dysplasia. Whole exome sequencing was performed on the probands, and family segregation analysis was performed by Sanger sequencing. Results: We identified a novel compound heterozygous PIEZO1 gene: NM_001142864.4: c.4030_4032delGAG (E1344del)/ c.5455_5456delAA (K1819Efs*46) variants in the first family and a novel homozygous PIEZO1 gene: c.5876A>G (D1959G) variant in the second family. Conclusion: This study, which presents the clinical features and variations of five cases with long-term follow-up, contributed to the phenotypic and mutation spectrum a very rare disease of Lymphatic Malformation 6. The novel compound heterozygous E1344del/K1819Efs*46 variation leads to a premature stop codon that caused a shorter PIEZO1 protein product. It was thought that two compound nonsense variations might be associated with the poor prognosis of family 1. Also, the second novel c.5876A>G (D1959G) homozygous mutation was thought to be associated with impaired PIEZO1 by causing loss of function. Also, this study was the first LMPHM6 report from the Turkish population.

Anahtar Kelimeler:

Lymphatic malformation 6, PIEZO1 gene, novel variants

A very rare disease of lymphatic malformation 6: five new patients and review of the literatur

Objective: Lymphatic Malformation 6 (MIM no:616843) is characterized by generalized edema, bilateral pleural effusions, ascites and non-immune hydrops fetalis. PIEZO1 gene has been associated with the LMPHM6 disorder. Here, we aimed to evaluate five patients from two different families, with various clinical presentations of generalized lymphatic dysplasia. Materials and Methods: Between January 2015 and January 2021, 5 cases with were evaluated with a pre-diagnosis of congenital lymphatic malformation. Whole exome sequencing was performed on the probands, and family segregation analysis was performed by Sanger sequencing. Results: We identified a novel compound heterozygous PIEZO1 gene: NM_001142864.4: c.4030_4032delGAG (E1344del)/ c.5455_5456delAA (K1819Efs*46) variants in the first family and a novel homozygous PIEZO1 gene: c.5876A>G (D1959G) variant in the second family. Conclusion: This study, which presents the clinical features and variations of five patients with long-term follow-up, contributed to the phenotypic and mutation spectrum of Lymphatic Malformation 6. The novel compound heterozygous E1344del/K1819Efs*46 variation leads to a premature stop codon that caused a shorter protein product. It was thought that two compound nonsense variations might be associated with the poor prognosis of family 1. Also, the second novel c.5876A>G (D1959G) biallelic homozygous mutation was thought to be associated with impaired PIEZO1 by causing loss of function. This study was the first LMPHM6 report from the Turkish population. Keywords: Neurofibromatosis type 1, Next generation DNA sequencing, NF1 gene, novel variants

Keywords:

Lymphatic malformation 6, PIEZO1 gene, novel variants,

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Andolfo, I, De Rosa, G, et al. PIEZO1 hypomorphic variants in congenital lymphatic dysplasia cause shape and hydration alterations of red blood cells, Frontiers in physiology, 2019, 10, 258.
Fotiou, E, Martin-Almedina, S, et al. Author Correction: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis, Nature communications, 2019, 10, 1951.
Andolfo, I, Alper S.L, et al., Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1, Blood, 2013, 121, 3925-3935.
Richards, S, Aziz, N, et al., ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genetics in Medicine, 2015, 17, 405-24.
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Andolfo, I, Alper, S.L, et al., Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1, Blood, 2013, 121, 3925-3935.
Richards, S, Aziz, N, et al., ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genetics in Medicine, 2015, 17, 405-24.
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Yates, C.L, Monaghan, K.G, et al., Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development, Genetics in Medicine, 2017, 19, 1171-1178.
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Guo, W, Lai, Y, et al., Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations, Human mutation, 2020, 41, 432-448.
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