Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly

Liu, Mandi; Smith, Christopher L.; Biko, David M.; Li, Dong; Pinto, Erin; O’Connor, Nora; Skraban, Cara; Zackai, Elaine H.; Hákonarson, Hákon; Dori, Yoav; Sheppard, Sarah E.

doi:10.1038/s41431-022-01123-9

Cited by 16 publications

(24 citation statements)

References 19 publications

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“…Analysis of CSFEs identified both likely pathogenic and VOUS variants in PIEZO1 . Common features among this group included nuchal edema and pleural effusions that were similar to phenotypes observed in recently described PIEZO1 cases 39 . Homozygous or compound heterozygous variants in PIEZO1 are associated with GLAs and marked fetal hydrops, while heterozygous variants are associated with DHS with or without perinatal edema 19,30,45–49 .…”

Section: Discussionsupporting

confidence: 75%

Investigation into the genetics of fetal congenital lymphatic anomalies

et al. 2023

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Objective: Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing.Methods: Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup.Results: CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1.Conclusions: WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections. Key pointsWhat's known on this topic? � Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development.� Variants in several genes are known to cause LAs though many of variants remain unknown.� The full contribution of LA genes to fetal hydrops and nuchal edema remains unknown.

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Section: Discussionsupporting

confidence: 75%

Investigation into the genetics of fetal congenital lymphatic anomalies

et al. 2023

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“…In addition to PIEZO1 , FLT4 (Schneider et al, 2022) and EPHB4 (Martin‐Almedina et al, 2016) have been associated with chylothorax. The association of PIEZO1 with chylothorax is likely related to the importance of these gene in lymphatic valve formation (Nonomura et al, 2018) and the development of normal lymphatic anatomy and drainage patterns (Liu et al, 2022). In contrast, FLT4 is required for lymphangiogenesis, encoding the vascular endothelial growth factor receptor 3, which is tyrosine protein kinase that acts as a cell surface receptor for Vascular endothelial growth factor C (Schneider et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1

Kovesi

Rojas

Boycott

2023

American J of Med Genetics Pt A

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PIEZO1 is required for lymphatic valve formation, and several lymphatic abnormalities have been reported to be associated with autosomal recessive PIEZO1 pathogenic variants including neonatal hydrops, lymphedema involving various body regions, and chylothorax. Persistent or recurrent chylothorax has been infrequently described in association with pathogenic variants in the PIEZO1 gene. We present a 4-year-old female with bilateral pleural effusions detected prenatally, who was diagnosed with bilateral chylothoraces post-partum. She subsequently had recurrent pleural effusions involving both pleural cavities, which tended to improve with restriction of her fat intake, and, one occasion, subcutaneous octreotide. She also had bilateral calf, and intermittent cheek swelling. Genetic testing revealed two deleterious variants in PIEZO1: c.2330-2_2330-1del and c.3860G > A (p.Trp1287*), both of which were classified as likely pathogenic. This supported a diagnosis of Lymphatic Malformation Type 6 (OMIM 616843), also known as Hereditary Lymphedema Type III.Hereditary Lymphedema type III can be associated with persistent chylothorax that can vary in size over time.

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“…Isolated mosaic RASopathies involving the vascular system include low‐flow and arteriovenous vascular malformations with pathogenic variants in the KRAS , NRAS , BRAF , MAP2K1 , and RASA1 genes (Al‐Olabi et al, 2018; Diociaiuti et al, 2022) and lymphatic anomalies with pathogenic variants in SOS1 , KRAS , ARAF , BRAF , NRAS , and CBL (Foster et al, 2020; Li et al, 2019; Liu et al, 2022; Mäkinen et al, 2021; Manevitz‐Mendelson et al, 2018; Zenner et al, 2022).…”

Section: Isolated Mosaic Rasopathiesmentioning

confidence: 99%

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

Carli¹,

Resta

Ferrero

et al. 2022

American J of Med Genetics Pt C

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Mosaic RASopathies are a heterogeneous group of diseases characterized by the presence at birth or early onset of congenital anomalies, cutaneous and vascular anomalies, segmental overgrowth, and increased cancer risk. They are caused by somatic pathogenic variants of the genes belonging the RAt Sarcoma Mitogenactivated protein kinase (RAS/MAPK) pathway causing its hyperactivation. Here, we review the clinical and molecular characteristics of this heterogeneous group of diseases, including the possibilities of molecular diagnosis and new therapeutic perspectives.

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Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly

Cited by 16 publications

References 19 publications

Investigation into the genetics of fetal congenital lymphatic anomalies

Investigation into the genetics of fetal congenital lymphatic anomalies

Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

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