Recessive pathogenic variants that lead to a loss-of-function in ELMO2 have been determined as the genetic cause of VMOS. All pathogenic variants described until today are in consanguineous families and thus are homozygous. However, compound heterozygous variants also can be associated with VMOS. The heterozygous carriers of the pathogenic variants appear completely normal.
ELMO2 is a 22-exon gene located on chromosome 20q13.12, with 20 protein-coding exons. Four pathogenic variants in five families have been linked to VMOS until now. Two of these are splice site mutations (c.1065+1G>A, c.1802-1G>C), one is 1-bp deletion in the last exon causing a frameshift (c.2080delC), and one is a complex rearrangement deleting the first exon and promoter region of ELMO2. A focus on c.1065+1G>A variant shows that this variant impedes RAC1 signalling and leads to diminished cell migration in primary fibroblasts from an affected individual.
Recently, it was reported that a homozygous missense mutation (p.Ile160Ser) in ELMO2 may cause Ramon syndrome (OMIM #266270), which is characterized by multiple craniofacial fibrous dysplasias (Mehawej et al., 2018). However, several clinical similarities between VMOS and Ramon Syndrome and a lack of angiographic or pathological studies in the individuals with this missense mutation obscure the diagnosis. Thus, VMOS must be kept in mind for differential diagnosis in Ramon syndrome-like cases and ELMO2 gene should be screened for mutations. Similarly, malformations previously diagnosed as intraosseous cavernous hemangioma, extraspinal osseous hemangioma, central hemangioma, cavernous angiomata of skull, and cystic angiomatosis should also be tested for ELMO2 mutations.
Sequencing of all exons, including the non-protein-coding exons of ELMO2 will help ascertain the diagnosis of VMOS in suspected individuals. As a homozygous Copy Number Variation (CNV) in at least one family has been identified, absence of PCR amplification would suggest a homozygous deletion. These cases must be handled carefully and suspected CNVs should be confirmed by other methods such as quantitative or breakpoint-specific PCR methods. In individuals for whom pathogenic ELMO2 variants cannot be determined, homozygosity mapping (in cases of parental consanguinity), linkage analysis, massively parallel sequencing methods may be useful in indirect genetic diagnosis, determination of non-coding pathogenic variants, determination of CNVs and discovery of other disease-related genes.