Genes and phenotypes in vascular malformations

Abstract

Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of autosomal dominant germline mutations. Genotype-phenotype correlation is influenced by many factors. Individual genes can induce different phenotypes (pleiotropy), and similar phenotypes can be due to different genes/mutations (redundancy). The phenotypic spectrum of somatic mutations is wide, and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. The phenotype of germline mutations is determined by penetrance and expressivity, and is influenced by epigenetic factors (DNA methylation, histone modification) or 'second-hit' somatic mutations. Except for disorders with pathognomonic phenotypes such as Proteus syndrome or a characteristic constellation of symptoms such as CLOVES [congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal naevi and scoliosis/ skeletal/spinal anomalies] or PIK3CA-related overgrowth spectrum syndrome, differential diagnosis of VM is therefore difficult. It will be greatly facilitated with increasing analytic sensitivity of sequencing techniques such as next-generation sequencing. High-sensitivity molecular techniques are a prerequisite for targeted pharmacotherapy, i.e. selective therapeutic inhibition of activating mutations underlying VM, which has shown promising results in preliminary studies.

A Rare Case of an Asymmetric Overgrowth Syndrome in a Kenyan African Child: A Case Report and Review of Literature

“…Additionally, he had lymphangiomas, cystic lesions, lipomas, dolichocephaly, down-slanting palpebral fissures with ptosis, and a flattened nasal bridge. The patient's clinical presentation fits the clinical criteria for diagnosis of PS, as an asymmetric overgrowth syndrome that is progressive and typically noted in childhood, as presented in Figure 7 [4, 10,12,14,15]. Phenotypic presentations are induced by individual genes or different genes can produce one phenotype [16].…”

RSDB: A rare skin disease database to link drugs with potential drug targets for rare skin diseases

“…Rare diseases affect fewer than 1 in 200,000 people in the U.S. or 1 in 2,000 people in Europe 1 , 2 . Although most rare diseases are complex, disabling, and life-threatening 3 , they lack related studies and approved treatments 4 due to the limited prevalence and market 5 . Skin diseases cause significant nonfatal disability worldwide 6 , especially in resource-poor regions 7 .…”

Association Between the miR-100 rs1834306 A>G Polymorphism and Susceptibility to Venous Malformation

“…Methylation of specific genes is significantly correlated with the occurrence of VMs. 10 , 12 The phenotypic spectrum of somatic mutations is wide and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. It has been shown that in vascular endothelial cells, methyl-binding proteins bind to methylated promoters of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 (VEGFR2).…”