Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations

Abstract Horizontal gaze palsy and progressive scoliosis (HGPPS) is an autosomal recessive neurologic disorder caused by homozygous or compound heterozygous mutations in the ROBO3 gene on chromosome 11. We clinically evaluated seven individuals with HGPPS from five previously unreported consanguineous families. We sequenced ROBO3 in all affected individuals, additional unaffected members of each family, and ethnic controls. All affected individuals had severe horizontal gaze restriction, progressive scoliosis, and lower brainstem hypoplasia on neuroimaging, the hallmarks of this syndrome. One individual experienced head trauma with a right subdural hematoma associated with a right hemiparesis, observations that confirm clinically for the first time that corticospinal tracts in HGPPS are uncrossed. We found five novel homozygous ROBO3 mutations (four missense mutations and one base deletion) distributed throughout the extracellular domain of the gene. The ROBO3 gene does not appear to have an obvious hot spot area for mutations; therefore, we recommend sequencing all exons and exon–intron boundaries in patients with clinical and/or radiologic features of HGPPS.