Elevated Leukodystrophy Incidence Predicted From Genomics Databases.

Background: Leukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants.

Methods: From 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database.

De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer.

Synaptic neurotransmission protein UNC-13 affects RNA interference in neurons.

Caenorhabditis elegans UNC-13 is an integral component of the synaptic vesicle cycle, functioning in the priming step. A recent yeast two-hybrid screen against UNC-13 identified three interacting proteins that are thought to function in pathways other than neurotransmitter release. One such protein, ERI-1, negatively regulates exogenous RNA interference in the nervous system and other tissues.