Edition of 04 December 2018

A study published in The American Journal of Human Genetics identified six individuals from three unrelated families with mutations in PIGS, encoding a GPI transamidase, found via whole-exome sequencing or whole-genome sequencing. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. In terms of biochemistry and phenotype, loss of function of PIGS shared features with PIGT deficiency and other inherited GPI deficiencies.

Using next-generation sequencing, authors of an article published in The American Journal of Human Genetics identified CACNA1E variants in 30 individuals with developmental and epileptic encephalopathies, characterised by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. This gene encodes part of a voltage-gated channel which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. The pathogenic variants could cause developmental and epileptic encephalopathies and authors postulate facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Researchers identified two siblings from a consanguineous family with recurrent bleeding and normal platelet counts. Whole exome sequencing identified a variant of EPHB2, encoding an ephrin transmembrane receptor family of tyrosine kinases involved in platelet function. The variant was associated with platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow. The results of the study were published in Blood.