Genotypes and phenotypes of 162 families with a glomulin mutation

Abstract

A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

Keywords: Anomaly; Gene; Glomulin; Glomuvenous malformation; Vascular.

Fig. 1

A Representative GVM family with mutation in glomulin (c.107dup), illustrating autosomal dominant inheritance with reduced penetrance (individuals 4, 51 and 52, unaffected carriers) and phenotypic variability. Most lesions are small and nodular (Blo-3, lower eyelid; Blo-5, left thigh; Blo-8, left arm; Blo-31, right elbow; and Blo-80, back). Blo-810 with large plaque-like lesion on back. Tested individuals numbered. Small horizontal bar = Clinically examined; black symbol = affected individual; dotted symbol = carrier. Adapted from Brouillard et al. [2008], with permission of Oxford University Press, USA. B-E Typical histology of GVM. B Hematoxylin-eosin-stained section at 40× magnification: dilated venous channels and normal overlying skin. C, D 100× and 200× magnifications demonstrate rounded glomus cells (arrows). E CD31 staining at 200×; normal endothelial cell layer (arrowheads). F-H Patients with GLMN mutation initially diagnosed as VM or VMCM.

Fig. 2

GLMN mutations. A Gene with shared mutations (top) and private ones (below). Red = Direct stop codon; black = frameshift leading to premature truncation; green = splice-site alteration; purple = deletion of asparagine 393. B Frequency of mutations in 162 families. Private mutations only identified in one index case or family. C Proportion of the different mutations.