Abstract
Background: Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. HGPPS is associated with mutations of the ROBO3 gene. In this study, the objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations.Methods: Thirteen Tunisian patients from six unrelated consanguineous families all manifesting HGPPS were genetically investigated. We searched for the causative variants for HGPPS using classical Sanger and whole exome sequencing.Results: Four distinct homozygous mutations were identified in ROBO3 gene. Two of these were newly identified homozygous and non-synonymous mutations, causing effectively damage to the protein by in silico analysis. The other two mutations were previously reported in Tunisian patients with HGPPS. Mutations were validated by Sanger sequencing in parents and affected individuals.Conclusion: To the best of our knowledge, this is the largest ever reported cohort on families with HGPPS in whom ROBO3 mutations were identified. These molecular findings have expanded our knowledge of the ROBO3 mutational spectrum. The relevance of our current study is two-fold; first to assist proper management of the scoliosis and second to protect families at risk.
Highlights
Aberrant axon connectivity in human results in many rare genetic disorders including corpus callosum agenesis, L1 syndrome, Joubert syndrome, Kallmann syndrome, Duane retraction syndrome, and Horizontal Gaze Palsy with Progressive Scoliosis.Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS; MIM 607313), first described in 1970 [1], is a rare autosomal recessive disorder belonging to a group of disorders known as congenital cranial dysinnervation disorders (CCDDs)
The first description of HGPPS in a family with scoliosis associated with progressive external ophthalmoplegia was reported by Dretakis [14]
Dretakis and Kondoyannis later described 5 other cases of early onset scoliosis associated with horizontal gaze palsy in 2 consanguineous Greek families [1]
Summary
Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS; MIM 607313), first described in 1970 [1], is a rare autosomal recessive disorder belonging to a group of disorders known as congenital cranial dysinnervation disorders (CCDDs). It results from errors in cranial nuclear development and dysinnervation of the ocular and facial muscles [2,3,4]. Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. The objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations
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