LAUSR

Several intracellular proteins are involved in mediating vesicular transport of protein and lipid cargo from the endoplasmic reticulum (ER) to the Golgi apparatus (GA) in eukaryotic cells. Errors in membrane trafficking between ER and GA have been implicated in brain disorders [1, 7], showing that these processes are critical for neuronal biogenesis. An important protein in these processes is YIF1B, an intracellular 314-residue transmembrane protein. Hippocampal neurons from Yif1B knockout (KO) mice showed that Yif1B is implicated in anterograde trafficking and Golgi architecture [1], where depletion of Yif1b caused disorganization, fragmentation, and volume reduction of the GA in pyramidal neurons. Here we describe six patients from five unrelated families presenting with profound developmental and motor delay with dystonia, dysphagia, hypotonia, epilepsy and microcephaly, and homozygous truncating variants in YIF1B encountered by whole exome sequencing (WES), identifying YIF1B as a novel disease gene in humans (Fig. 1, Supplementary Fig. 1, Supplementary Table 1, online resource for detailed clinical information). Clinical examinations revealed that all patients had an unremarkable pregnancy and birth, and no major dysmorphic features. Hypotonia and global developmental delay were noticed in infancy with smiling and partial babbling as their best achieved social and language skills. Motor development remained profoundly affected without head control, rolling or sitting. By age 2–3 years distal, limb choreiform movements started in four individuals which evolved into axial and limb dystonia with dyskinesia by the age of 4–8 years. Dystonia was unresponsive to levodopa or carbidopa but partially improved Mohammed AlMuhaizea, and Rawan AlMass have equal contribution.