Four common glomulin mutations cause two thirds of glomuvenous malformations (“familial glomangiomas”): evidence for a founder effect

<jats:p> <jats:bold>Background:</jats:bold> Glomuvenous malformation (GVM) (“familial glomangioma”) is a localised cutaneous vascular lesion histologically characterised by abnormal smooth muscle-like “glomus cells” in the walls of distended endothelium lined channels. Inheritable GVM has been linked to chromosome <jats:italic>1p21-22</jats:italic> and is caused by truncating mutations in <jats:italic>glomulin</jats:italic>. A double hit mutation was identified in one lesion. This finding suggests that GVM results from complete localised loss of function and explains the paradominant mode of inheritance.</jats:p> <jats:p> <jats:bold>Objective:</jats:bold> To report on the identification of a mutation in <jats:italic>glomulin</jats:italic> in 23 additional families with GVM.</jats:p> <jats:p> <jats:bold>Results:</jats:bold> Three mutations are new; the others have been described previously. Among the 17 different inherited mutations in <jats:italic>glomulin</jats:italic> known up to now in 43 families, the <jats:italic>157delAAGAA</jats:italic> mutation is the most common and was present in 21 families (48.8%). Mutation <jats:italic>108C</jats:italic>→<jats:italic>A</jats:italic> was found in five families (11.8%), and the mutations <jats:italic>554delA+556delCCT</jats:italic> and <jats:italic>1179delCAA</jats:italic> were present together in two families (4.7% each). Polymorphic markers suggested a founder effect for all four mutations.</jats:p> <jats:p> <jats:bold>Conclusions:</jats:bold> Screening for these mutations should lead to a genetic diagnosis in about 70% of patients with inherited GVM. So far, a mutation in <jats:italic>glomulin</jats:italic> has been found in all GVM families tested, thus demonstrating locus homogeneity.</jats:p>