A sibling pair with cardiofaciocutaneous syndrome (CFC) secondary to BRAF mutation with unaffected parents—the first cases of gonadal mosaicism in CFC?

Abstract

Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro-intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein-kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations. Two brothers with clinical features of CFC and mutations in BRAF (c.770A > G, p.Gln257Arg) are described. Neither parent (both phenotypically normal) had the BRAF mutation in their leukocyte DNA. Although this mutation is one of the most common mutations in CFC, to our knowledge, this is the first molecularly confirmed BRAF mutation causing CFC in siblings. This observation also likely represents the first description of germ cell mosaicism in CFC and so it is important to provide optimal genetic counselling to families regarding the risk of reoccurrence.

Familial cardio‐facio‐cutaneous syndrome: Vertical transmission of the BRAF p.G464R pathogenic variant and review of the literature

“…A limitation of some case reports in the literature is that mosaicism in the affected parent was not ruled out through additional cascade family member testing or analysis of a second tissue type. There has been one case of probable germline mosaicism reported in CFC whereby phenotypically normal parents had two affected siblings with CFC that harbored the common BRAF p.Q257R variant (Geoghegan et al, 2018). Interestingly, recent studies have identified that spontaneous male germline mutations in RASopathy genes PTPN11 , HRAS , KRAS , BRAF , CBL , MEK1 , MEK2 , CRAF , and SOS1 are common in spermatogonia stem cells and this leads to clonal expansion which results in elevated mutation levels in sperm over time (Goriely et al, 2009; Maher et al, 2018).…”