Molecular characterization of FAM222B as a novel disease gene for dominant cardiovascular laterality defects.

Missense variants in FAM222B, a substrate of the kinase NLK involved in left-right axis determination, with Arg300 modelled as the NLK recognition site and loss of function disrupting cardiac looping in zebrafish.

The authors searched for cardiovascular laterality genes beyond primary ciliary dyskinesia-related causes, using exome sequencing in 16 case-parent trios followed by an exome survey of 2,109 individuals with situs inversus totalis, heterotaxy or isolated congenital heart disease. Six different FAM222B variants were found in a gene previously discussed only as a candidate for cerebral cavernous malformations, and c.899G>A (p.300Arg>His) arose de novo in two unrelated families. FAM222B is a described substrate of the kinase NLK, which is associated with left-right axis determination, and structural modelling suggests a role for Arg300 in NLK recognition. In zebrafish, double knockout of the fam222ba/bb homologues produced aberrant cardiac looping in larvae and an enlarged atrium and ventricle in adults. Injection of human mRNA carrying c.899G>A into wildtype Tg(kdrl:EGFP) reporter fish also perturbed cardiogenesis, leading the authors to propose FAM222B as a novel candidate gene.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The evidence hangs together — the same missense recurring de novo in two unrelated families, a knockout animal model, an effect of the mutant mRNA — but it rests on a single replicated variant and on a zebrafish looping phenotype that is not very specific. The authors themselves say candidate gene: faced with fetal heterotaxy, a FAM222B variant is still of uncertain significance today, and what will change first is how this gene is annotated in exomes that have already been sequenced. Further unrelated families with documented segregation in affected relatives would be needed before calling this an established disease gene.

Analysis by Dr Thibaut Benquey