The ROBO3 gene is one of the roundabout genes controlling axon guidance during development and promotes midline crossing of axons (PMID: 15105459, 26586761). Homozygous pathogenic variants in the ROBO3 gene were first reported in multiple consanguineous families in 2004 in relation to autosomal recessive Horizontal Gaze Palsy with Progressive Scoliosis (PMID: 15105459). Neuroimaging and electrophysiology findings included “butterfly” medulla with midline cleft, decreased size of basis pontis, and absence of decussating somatosensory fibers (PMID: 15105459) Since then, numerous (at least 2 distinct variants including 2 recurrent variants) null and missense variants in homozygous and compound heterozygous patterns have been reported, with latest report from 2020, reaching the maximum genetic evidence score of 12 (PMID: 15105459, 16525029, 19633821, 18829051, 21592015, 27749773, 29215389, 30985235, 32705527). The gene-disease relationship is further supported by experimental data with evidence of expression of ROBO3 in the basis pontis of fetal human brain (PMID: 15105459). Additional mouse models have shown association of ROBO3 to proper midline crossing of axons and neurons that underlies pathophysiology of Horizontal Gaze Palsy with Progressive Scoliosis (PMID: 15084255, 15233918).
In summary, the ROBO3 gene has a definitive relationship with autosomal recessive Horizontal Gaze Palsy with Progressive Scoliosis, supported by clinical and experimental evidence demonstrated over time. This classification was approved by the Brain Malformations GCEP on July 12, 2022.
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