Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.

For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families. All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition. The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation, and homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model. Recently, a homozygous truncating variant in CPLX1 was suggested to be causative for migrating epilepsy and structural brain abnormalities. ID was not reported although it cannot be completely ruled out. However, the currently limited knowledge on CPLX1 suggests that loss of complexin 1 function may lead to a complex but variable clinical phenotype, and our findings encourage further investigations of CPLX1 in patients with ID, developmental delay and myoclonic epilepsy to unravel the phenotypic spectrum of carriers of CPLX1 variants.

Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature.

Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.