Acrocallosal syndrome: Identification of a novel KIF7 mutation and evidence for oligogenic inheritance

ObjectiveAcrocallosal syndrome (ACLS) is a rare genetically heterogeneous disorder characterised by a variety of developmental anomalies including agenesis or hypoplasia of the corpus callosum. ACLS and the related disorder, hydrolethalus syndrome, have recently been reported to be caused by mutations in the KIF7 gene. In the present study we report a 15 year follow up of a consanguineous family with ACLS and the results of exome sequencing.ResultsA novel in-frame deletion KIF7 mutation (p.218-221del) was detected. This is the first deletion mutation in KIF7 described in ACLS and is predicted to disrupt the KIF7 protein within the kinesin motor domain. Also present, in addition to the homozygous KIF7 mutation, were loss of function variants in known ciliopathy genes; AHI1 (p.R830W), BBS2 (p.N70S) and BBS4 (p.M472V).ConclusionKIF7 has previously been demonstrated to regulate function of primary cilia and ACLS is now categorised as a ciliopathy – a group of disorders in which oligogenic disease is frequent. The finding of known loss of function variants in ciliopathy associated genes, AHI1, BBS2 and BBS4 in addition to KIF7 mutations provides evidence for oligogenic inheritance in ACLS and suggests that this might contribute to the phenotypic variability of KIF7-related disorders.

► Exome sequencing was performed in a consanguineous family with acrocallosal syndrome.
► A novel KIF7 mutation is described in a family with acrocallosal syndrome.
► An affected individual also had evidence of variants in other ciliopathy genes suggesting oligogenic inheritance.