Inherited vascular malformations are commonly autosomal dominantly inherited with high, but incomplete, penetrance; they often present as multiple lesions. We hypothesized that Knudson's two-hit model could explain this multifocality and partial penetrance. We performed a systematic analysis of inherited glomuvenous malformations (GVMs) by using multiple approaches, including a sensitive allele-specific pairwise SNP-chip method. Overall, we identified 16 somatic mutations, most of which were not intragenic but were cases of acquired uniparental isodisomy (aUPID) involving chromosome 1p. The breakpoint of each aUPID is located in an A- and T-rich, high-DNA-flexibility region (1p13.1-1p12). This region corresponds to a possible new fragile site. Occurrences of these mutations render the inherited glomulin variant in 1p22.1 homozygous in the affected tissues without loss of genetic material. This finding demonstrates that a double hit is needed to trigger formation of a GVM. It also suggests that somatic UPID, only detectable by sensitive pairwise analysis in heterogeneous tissues, might be a common phenomenon in human cells. Thus, aUPID might play a role in the pathogenesis of various nonmalignant disorders and might explain local impaired function and/or clinical variability. Furthermore, these data suggest that pairwise analysis of blood and tissue, even on heterogeneous tissue, can be used for localizing double-hit mutations in disease-causing genes.

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This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.

Vascular anomalies are divided into vascular tumours (mainly infantile haemangiomas) and vascular malformations. Vascular malformations are subdivided following the type of vessel affected: venous, capillary, arteriovenous and lymphatic. In addition to the pure forms, combined lesions are frequently encountered. Most of these malformations are sporadic, i.e. there is no family history, but familial cases, transmitted as an autosomal dominant or recessive trait, exist. During the last 10 years, the identification of disease‐causing genes implicated in the familial forms have resulted in a better classification of vascular anomalies, which has helped in assessment of treatment efficacy. These data have also unravelled the physiological role of the identified proteins during human vascular development. Key concepts Classification of vascular tumours and vascular malformations. Vascular malformations are developmental anomalies. Vascular malformations are classified depending on the affected vessels to capillary, venous, arterial, lymphatic or combined. Sporadic and familial forms exist. Familial cases are often transmitted as an autosomal dominant disorder. Several causative genes have been identified.