A number sign (#) is used with this entry because of evidence that familial horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development (HGPPS2) is caused by homozygous mutation in the DCC gene (120470) on chromosome 18q21.

Heterozygous mutation in the DCC gene can cause mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600).

For a discussion of genetic heterogeneity of HGPPS, see HGPPS1 (607313).

Jamuar et al. (2017) reported 2 brothers, born of consanguineous Mexican parents, and an unrelated girl, born of consanguineous Saudi Arabian parents, with a similar disorder characterized by global developmental delay, delayed walking, impaired intellectual development, horizontal gaze palsy, and childhood-onset progressive scoliosis. Brain imaging showed agenesis of the corpus callosum (ACC), absence of the anterior and hippocampal commissures, hypoplasia of the pons and midbrain, and midline cleft throughout the brainstem, contributing to a butterfly-shaped medulla. In addition, the boys showed hypotonia and mirror movements, although the girl did not. One of the boys had hyperreflexia and ankle clonus. The boys could walk independently and speak in full sentences, whereas the girl had an unsteady gait and used only single words. Diffusion MRI from the Saudi Arabian girl showed striking abnormalities, including no commissural tracts, misguided Probst bundles along the lateral ventricles, disorganized white matter tracts, and decreased axonal integrity and myelination compared to controls. Associational and subcortical fiber tracts were also abnormal, and fibers were arranged in a radial fashion. There was also failure of the superior cerebellar peduncles to decussate and absence of transverse pontine fibers. Associational and subcortical fiber tracts were also abnormal. The parents who were assessed did not show mirror movements, suggesting variability or incomplete penetrance.

The transmission pattern of HGPPS2 in the family reported by Jamuar et al. (2017) was consistent with autosomal recessive inheritance.

In 3 patients from 2 unrelated families with HGPPS2, Jamuar et al. (2017) identified homozygous intragenic deletions in the DCC gene (120470.0010-120470.0011), both resulting in premature termination and functional null alleles. The deletion in the first family was found by a combination of homozygosity mapping and CNV analysis; the deletion in the second family was found by targeted sequencing of the DCC gene. The findings confirmed that DCC is essential for both forebrain and brainstem midline crossing in the human CNS. An unrelated patient with ACC and mildly impaired intellectual development was found to have a homozygous missense variant in the DCC gene (Q691K) at a conserved residue in the third fibronectin repeat, but no clinical information was available and functional studies of the variant were not performed.