A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis‐2 with impaired intellectual development

Abstract

Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence. We report three new patients with HGPPS2 in a consanguineous Pakistani family, presenting varying degrees of progressive scoliosis, developmental delays, horizontal gaze palsy, agenesis of corpus callosum, and absence of cerebral commissures. Analysis of genotyping data identified shared loss of heterozygosity (LOH) region on chromosomes 5p15.33-15.31, 6q11.2-12, and 18q21.1-21.3. A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11). Interestingly, DCC gene is present in the LOH region on chromosome 18. Variant (c.2399dupA) in the DCC gene is considered as the most probable candidate variant for HGPPS2 based on the presence of DCC in the LOH region, previously reported role of DCC in HGPPS2, perfect segregation of candidate variant with the disease, prediction of variant pathogenicity, and absence of variant in variation databases. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. DCC encodes a netrin-1 receptor protein; its role in the development of the CNS has recently been established. Biallelic DCC mutations have previously been shown to cause HGPPS2. A novel homozygous variant in patients of the reported family extend the genotypic and phenotypic spectrum of HGPPS2.

Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis

“…2 HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures. 3,4 Here, we report new phenotypes of abnormal horizontal tongue movements and brachycephaly and reveal deviation from normal developmental trajectories in gross motor rather than fine motor development by the developmental assessment scale in our HGPPS patient. To the best of our knowledge, it is the first report of developmental assessment in HGPPS patients.…”

Report of a Novel Homozygous Intragenic <i>DCC</i> Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome

“…To date, including the case presented in this study, altogether five different pathogenic variants causing HGPPS2 have been described in the medical literature [1,7]. One patient with a homozygous DCC c.2071C>A p.(Gln691Lys) did not have intellectual disability suggesting that pathogenic missense variants may result in a milder phenotype.…”

“…The horizontal gaze palsy may be caused by midline axon guidance defects in tracts in the hindbrain that control conjugated horizontal eye movements [18,19]. The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance [3,7].…”

“…Original report described altogether 4 patients with biallelic DCC variants including an intragenic deletion and a missense variant in DCC, as well as a large genomic deletion including DCC [1]. Later, Zaka et al [7] reported 3 patients with a homozygous single nucleotide duplication in DCC leading to a frameshift.…”

“…To date, only four different homozygous pathogenic variants in the DCC gene have been identified in 8 patients with HGPPS2 phenotype [1,7]. HGPPS2 phenotype caused by biallelic DCC variants appears to be fully penetrant and shows a similar clinical presentation including developmental delay, intellectual disability, neuromuscular scoliosis, horizontal gaze palsy, agenesis of corpus callosum, and the absence of cerebral commissures.…”