Edition of 17 July 2026

A new study published in Brain presented homozygous missense variants in the EIPR1 gene, which encodes a protein implicated in the process of delivering endosome-derived transmembrane cargos to the plasma membrane and the trans-Golgi network. The variants were found among 8 individuals from 6 unrelated consanguineous families, with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies and neutropenia. Various analyses highlighted the role of EIPR1 in endosomal recycling and dense core vesicle biogenesis, processes essential for the development and function of the nervous system, and established EIPR1 as a novel locus associated with neurodevelopmental disorders.

A new study published in Nature Genetics presented recessive homozygous and compound heterozygous variants in the RNU4-2 gene, which is transcribed into the U4 small nuclear RNA component of the major spliceosome. The variants were found among a cohort of 38 individuals, with a clinical phenotype described in a subset of 31 individuals. The core feature had phenotypic similarities with the dominant ReNU syndrome, including global developmental delay, marked speech and language delay, and seizures. Individuals also suffered from distinctive traits such as dysmorphic facial features and specific white matter changes (mainly dilation of perivascular spaces in the periventricular white matter and white matter volume loss). Various analyses suggest a loss-of-function disease mechanism that is distinct from the mechanism underlying the dominant ReNU syndrome, and expand the phenotypic and genotypic spectrum of neurodevelopmental disorders associated with RNU4-2.

A new study published in American Journal of Medical Genetics Part A characterized a homozygous nonsense variant in TGFBR3, which encodes a receptor of the TGF-β signalling pathway playing a pivotal role in bone formation and cranial suture biology. The variants were found among 2 male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low-set ears, undescended testes, and developmental hip dysplasia. Various analyses confirmed the role of TGFBR3 in human cranial suture biology and variants in this gene as a genetic cause of syndromic craniosynostosis based on a novel pathogenic mechanism of TGF-β signalling via a truncated protein lacking its intracellular C-terminus, perhaps disrupting critical regulatory or interaction domains.