Splice‐site mutations in <i>VEGFC</i> cause loss of function and Nonne‐Milroy‐like primary lymphedema

Fastré, Elodie; Lanteigne, Lydia-Elizabeth; Helaers, Raphaël; Giacalone, Guido; Revençu, Nicole; Dionyssiou, Dimitrios; Demiri, Efterpi; Brouillard, Pascal; Vikkula, Miikka

doi:10.1111/cge.13204

Cited by 19 publications

(26 citation statements)

References 7 publications

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“…This is evidenced clinically with slightly less severe lower limb lymphedema and by the lymphoscintigraphies demonstrating significantly more uptake of tracers within lymphatic vessels compared to those in Milroy disease. With this report, it has also been shown that splice-site variants in VEGFC should be considered as a causative agent of disease, which corroborates the findings of Fastre et al [8]. While only three previous studies have been published, it is clear that there is intra-familial variation in the age of onset and severity of lymphedema.…”

Section: Discussionsupporting

confidence: 90%

“…Congenital primary lymphedema associated with VEGFC is a rare primary lymphedema with only three, previously reported studies [6,7,8]. In this study, we provide independent evidence that VEGFC mutations are causative of primary lymphedema of the type originally described by Gordon et al [6].…”

Section: Discussionsupporting

confidence: 74%

“…Recently, a study identified a VEGFC mutation in seven individuals from a three-generation family presenting with congenital lower limb lymphedema consistent with autosomal dominant inheritance [6]. This finding has been followed by two further reports of 13 individuals from three families with a similar phenotype [7,8]. These are the only reports of patients with mutations in VEGFC (Lymphedema, hereditary, ID, [MIM 615907] or congenital primary lymphedema of Gordon).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon

Nadarajah

Schulte

McConnell

et al. 2018

IJMS

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Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon

Nadarajah

Schulte

McConnell

et al. 2018

IJMS

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“…Vascular endothelial growth factor (VEGF)‐C, a VEGFR3 ligand, is required for the sprouting of the first lymphatic vessels from embryonic veins. VEGF‐C mutations were reported in an autosomal dominant congenital primary lymphoedema resembling MD . Here we report a novel VEGFR3 / FLT4 mutation associated with a novel VEGF‐C mutation in familial MD.…”

mentioning

confidence: 73%

“…In our cases, the mutated residue L73P was located within the N‐terminal propeptide, which is removed to produce the mature forms of VEGF‐C, conferring increased VEGFR3 affinity and activation. Three VEGF‐C mutations causing Milroy‐like lymphoedema have been reported to date, all of which are truncating mutations . However, the VEGF‐C mutation reported here is a missense mutation within the N‐terminal propeptide.…”

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confidence: 75%

A Milroy case with FLT 4 / VEGFR 3 mutation and an unusual skin biopsy

Liu

Lou

et al. 2018

Br J Dermatol

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Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy‐like lymphedema: First prenatal case report

Huynh

Degré

Bréon

et al. 2022

American J of Med Genetics Pt A

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Deleterious variants in the vascular endothelial growth factor C (VEGFC) gene have been recently associated with Milroy-like primary lymphedema, an autosomal dominant disorder, characterized mainly by swelling of the lower limbs due to functional impairment of the lymphatic vessels. To date, only 26 patients with congenital lymphedema harboring VEGFC pathogenic variants were documented. Here, we describe the first prenatal case of a fetus with Milroy-like disease. Fetal ultrasound showed bilateral foot swelling. Chromosomal microarray analysis revealed a 137-kb copy number loss in 4q34.3 including only VEGFC gene in the propositus fetus. Segregation analysis showed that the deletion was inherited from the affected mother and grandmother. Taken together, our study highlights the important role of microarray analysis to detect subtle chromosomal imbalances in the prenatal setting and contributes to delineate the fetal phenotype of VEGFC-related primary congenital lymphedema.

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Splice‐site mutations in VEGFC cause loss of function and Nonne‐Milroy‐like primary lymphedema

Cited by 19 publications

References 7 publications

A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon

A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon

A Milroy case with FLT 4 / VEGFR 3 mutation and an unusual skin biopsy

Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy‐like lymphedema: First prenatal case report

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