Resequencing of <scp>VEGFR3</scp> pathway genes implicate <scp><i>GJC2</i></scp> and <scp><i>FLT4</i></scp> in the formation of primary congenital chylothorax

Schneider, Sophia; Köllges, Ricarda; Stegmann, Jil D.; Thieme, Frederic; Hilger, Alina C.; Waffenschmidt, Lea; Fazaal, Julia; Kalanithy, Jeshurun C; Geipel, A.; Strizek, Brigitte; Ludwig, Kerstin U.; Reutter, Heiko; Müller, Andreas

doi:10.1002/ajmg.a.62643

Cited by 3 publications

(9 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Serine phosphorylation was also detected although the exact phosphorylated residues were not defined (Dixelius et al, 2003). Interestingly, three variants in the carboyterminal tail are reported in hereditary lymphedema (Melikhan‐Revzin et al, 2015; Schneider et al, 2022; Vora et al, 2020), two of which affect Serine residues (Melikhan‐Revzin et al, 2015; Vora et al, 2020) in addition to the cases we report here. The histopathology analysis showed that our two fetuses have numerous hypoplastic lymphatic capillaries compared with age‐matched controls which exhibited normally sized few lymphatics vessels.…”

Section: Discussionsupporting

confidence: 62%

“…Genetic molecular testing found in both cases a variation affecting the 1275 codon that resides within the cytoplasmic domain of the VEGFR3 receptor in the carboxyterminal tail above the tyrosine kinase catalytic domain. Most of the variants reported to cause hereditary lymphedema are missense and in frame insertions or deletions located within the tyrosine kinase catalytic domain (from codon 845 to codon 1173) (Connell et al, 2009; Gordon et al, 2013; Melikhan‐Revzin, Kurolap, Dagan, Mory, & Gershoni‐Baruch, 2015; Schneider et al, 2022). However, variations in the carboxyterminal tail have also been reported (Melikhan‐Revzin et al, 2015; Schneider et al, 2022; Vora et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Most of the variants reported to cause hereditary lymphedema are missense and in frame insertions or deletions located within the tyrosine kinase catalytic domain (from codon 845 to codon 1173) (Connell et al, 2009; Gordon et al, 2013; Melikhan‐Revzin, Kurolap, Dagan, Mory, & Gershoni‐Baruch, 2015; Schneider et al, 2022). However, variations in the carboxyterminal tail have also been reported (Melikhan‐Revzin et al, 2015; Schneider et al, 2022; Vora et al, 2020). The carboxyterminal tail is known to harbor six tyrosine residues located beyond the tyrosine kinase domain which serve as phosphorylation sites (Dixelius et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

Lajmi

Lœuillet²,

Petrilli³

et al. 2022

Birth Defects Research

View full text Add to dashboard Cite

Background Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. Cases In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. Conclusion Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

Lajmi

Lœuillet²,

Petrilli³

et al. 2022

Birth Defects Research

View full text Add to dashboard Cite

show abstract

“…Among 137 children with primary lymphedema, 4 (2.9%) had neonatal pleural effusion. 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).…”

Section: Discussionmentioning

confidence: 99%

“…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). EPHB4 binds to Ephrin B2, activating signaling cascades that are required for lymphatic vessel remodeling and valve formation during fetal development (Korhonen et al, 2022; Martin‐Almedina et al, 2016).…”

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

View full text Add to dashboard Cite

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.

show abstract

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease

Kuonqui,

Campbell,

Sarker

et al. 2023

Cells

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.

show abstract

Resequencing of VEGFR3 pathway genes implicate GJC2 and FLT4 in the formation of primary congenital chylothorax

Cited by 3 publications

References 15 publications

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

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

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease

Contact Info

Product

Resources

About