Constitutional mosaicism in <i>RASA1</i>‐related capillary malformation‐arteriovenous malformation

Gordo, Gema; Rodríguez‐Laguna, Lara; Agra, Noelia; Mendez, Pilar; Feito, Marta; Lapunzina, Pablo; López-Gutiérrez, Juan Carlos; Martinez-Glez, Víctor

doi:10.1111/cge.13499

Cited by 11 publications

(7 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As de novo mutation rate is estimated to be as high as 25%,3 4 it was logical to also identify mosaic mutations, like in other autosomal dominant disorders with high de novo mutation rate, such as in tuberous sclerosis 8. While our manuscript was under review, another group published RASA1 mosaic mutations in two patients with CM-AVM 9. Our study reinforces these results.…”

Section: Discussionsupporting

confidence: 82%

RASA1mosaic mutations in patients with capillary malformation-arteriovenous malformation

et al. 2019

View full text Add to dashboard Cite

BackgroundCapillary malformation-arteriovenous malformation is an autosomal dominant disorder, characterised by capillary malformations and increased risk of fast-flow vascular malformations, caused by loss-of-function mutations in the RASA1 or EPHB4 genes. Around 25% of the patients do not seem to carry a germline mutation in either one of these two genes. Even if other genes could be involved, some individuals may have mutations in the known genes that escaped detection by less sensitive techniques. We tested the hypothesis that mosaic mutations could explain some of previously negative cases.MethodsDNA was extracted from peripheral blood lymphocytes, saliva or vascular malformation tissues from four patients. RASA1 and EPHB4 coding regions and exon/intron boundaries were analysed by targeted custom gene panel sequencing. A second panel and/or Sanger sequencing were used to confirm the identified mutations.ResultsFour distinct mosaic RASA1 mutations, with an allele frequency ranging from 3% to 25%, were identified in four index patients with classical capillary malformation-arteriovenous malformation phenotype. Three mutations were known, one was novel. In one patient, a somatic second hit was also identified. One index case had three affected children, illustrating that the mosaicism was also present in the germline.ConclusionThis study shows that RASA1 mosaic mutations can cause capillary malformation-arteriovenous malformation. Thus, highly sensitive sequencing techniques should be considered as diagnostic tools, especially for patients with no family history. Even low-level mosaicism can cause the classical phenotype and increased risk for offspring. In addition, our study further supports the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in this disorder.

show abstract

Section: Discussionsupporting

confidence: 82%

RASA1mosaic mutations in patients with capillary malformation-arteriovenous malformation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Also, three patients with GNAQ: p.Arg183Gln variants presented with KTS/DCMO. Furthermore, protein truncating variants in RASA1 , reported in Parkes Weber syndrome,46 50–53 were found in three patients (germline or somatic) with a phenotype partially overlapping KTS/DCMO, two of which without typical arteriovenous malformations. In this respect, it seems relevant to point out that the cases we studied have been accumulated over 10 years, a time period in which some clinical definitions have changed, such as that between KTS and DCMO, and this might have impacted on our clinical classification 40…”

Section: Discussionmentioning

confidence: 98%

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

et al. 2022

View full text Add to dashboard Cite

BackgroundPostzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.MethodsWe performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed.Results93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK.ConclusionWe confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

show abstract

“…The intrafamilial variability and the multifocal lesions in PKWS involving segmental overgrowth of soft tissue, endothelium, and bone are strongly suggestive of a somatic second-hit model (Lapinski et al 2018). To date, there are at least two case reports of confirmed second somatic hits in RASA1 (one germline and one somatic) (Revencu et al 2013;Macmurdo et al 2016;Gordo et al 2019)-only one of them with proven somatic second hit in trans of the germline pathogenic change (Lapinski et al 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Given recent reports in the literature and collective clinical experience, there is increasing evidence to support that a substantial number of patients with segmental overgrowth syndromes (with or without vascular dysplasias) are caused by somatic pathogenic variants without necessarily having germline involvement (Gordo et al 2018(Gordo et al , 2019. A recent publication by Gordo et al (2019) reported two unrelated occurrences of CM-AVM caused by constitutional RASA1 pathogenic mosaic variants detected in a blood sample and the affected tissue in one of the affected individuals. There was no evidence of a second hit identified in the affected tissue.…”

Section: Discussionmentioning

confidence: 99%

Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1

Daboub

Grimmer

Frigerio

et al. 2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline RASA1 testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in RASA1 consistent with the c.934_938del, p.(Glu312Argfs * 14) and the c.2925del, p.(Asn976Metfs * 20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in RASA1. To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the RASA1 gene in DNA from a vascular lesion.

show abstract

Constitutional mosaicism in RASA1‐related capillary malformation‐arteriovenous malformation

Cited by 11 publications

References 21 publications

RASA1mosaic mutations in patients with capillary malformation-arteriovenous malformation

RASA1mosaic mutations in patients with capillary malformation-arteriovenous malformation

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1

Contact Info

Product

Resources

About