Edition of 11 February 2025

A new study published in Brain characterized biallelic variants in EPB41L3, which encodes a membrane-cytoskeleton adaptor with key roles to support oligodendrocyte axon adhesions essential for proper myelination. The variants were found among 6 individuals from 5 unrelated families with a neurodevelopmental disorder characterized by early-onset seizures, global developmental delay, hypotonia, neuroregression and myelination delayed. Various analyses confirmed the role of EPB41L3 in oligodendrocyte differenciation and myelination, explaining the de­layed myelination pathology of EPB41L3 dysfunction.

A new study published in Human molecular genetics described a heterozygous variant in GFAP, which encodes an intermediate filament protein expressed in astrocytes of the adult CNS and retina of mammals. The variants were found among multiple individuals in a six-generation family, presenting with gliosis of the optic nerve head and visual impairment. Various analysis supported the importance of GFAP in retinal development and highlighted a rare form of autosomal dominant optico-retinal disorder caused by mutations in GFAP.

A new study published in Journal of Medical Genetics presented homozygous loss-of-function variants in JPH1, which belong to the family of junctophilins, key proteins implicated in the formation of triad junctions essential for excitation-­contraction coupling and Ca2+ homeostasis in striated muscle. The variants were shown within 4 unrelated inidividuals sharing similar clinical presentations: a congenital myopathy with prominent facial, ocular and bulbar features characterised by myopathic facies, bilateral ptosis, opthalmoplegia and fatigabilty. Various analyses emphasized the role of JPH1 in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype.

A new study published in Annals of Neurology described biallelic variants in SRPK3, which encodes a protein responsible for the specific phosphorylation of serine-arginine proteins which act as splicing factors. The variants were found among 9 individuals from 5 unrelated families, presenting with intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia as common clinical features. Various analyses emphasized the role of SRPK3 in brain, cognitive and ocular development and established the relevance of its mutations in the pathogenesis of X-linked intellectual disability.