Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3

Boston Children's Hospital, Boston, Massachusetts, United States
Journal of Medical Genetics (Impact Factor: 6.34). 04/2006; 43(3):e11. DOI: 10.1136/jmg.2005.035436
Source: PubMed


Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder characterised by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to decussate in the medulla. We previously reported that HGPPS patients from consanguineous pedigrees harbour homozygous mutations in the axon guidance molecule ROBO3.
We now report two sporadic HGPPS children of non-consanguineous parents who harbour compound heterozygous mutations in ROBO3. The mother of one of the children also had scoliosis DNA was extracted from a blood sample from each participant using a standard protocol, and the coding exons of ROBO3 were amplified and sequenced as previously described.
Each patient harboured two unique heterozygous mutations in ROBO3, having inherited one mutation from each parent.
HGPPS can result from compound heterozygous mutations. More comprehensive examinations of parents and siblings of HGPPS patients are required to determine if the incidence of scoliosis in individuals harbouring heterozygous ROBO3 mutations is greater than in the general population.

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Available from: Elias Traboulsi, Feb 09, 2014
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    • "Horizontal gaze palsy with progressive scoliosis (HGPPS) is characterized by defective eye movement and abnormal curvature of the spine. To date, mutations in the Robo3 gene are the only identified genetic cause for this rare disorder (Chan et al., 2006). Of note is the recurrent R704P missense mutation , which is located on the extracellular part of Robo3 and is found in HGPPS patients from different pedigrees and ethnicities (Kurian et al., 2013). "
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    • "Phenotypic variability appears to be quite common in genomic syndromes, and a variety of hypotheses, ranging from a two hit model [9], to occult compound heterozygous mutations within deleted regions [10] "
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    • "One patient displayed bilateral synergistic convergence without pupil constriction upon attempting to gaze horizontally to one side or the other [5]. Vertical eye movements are mainly unaffected [2,7]. Nystagmus presents in many patients and is mostly horizontal and pendular, with low amplitude [2,3,8]. "
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    ABSTRACT: Clinical and molecular characterization of patients with horizontal gaze palsy with progressive scoliosis (HGPPS) to extend existing knowledge of the phenotype caused by mutations in the Roundabout homolog of Drosophila 3 (ROBO3) gene. Four patients (aged 6 months to 13 years), two of them siblings, with features of horizontal gaze palsy and their parents were examined clinically and by molecular testing of the ROBO3 gene. The three families were unrelated, but parents in each family were consanguineous. We identified three novel homozygous ROBO3 mutations in four patients with typical ophthalmologic signs of HGPPS. We found an exonic insertion/deletion mutation (c.913delAinsTGC; p.Ile305CysfsX13), a 31 bp deletion including the donor splice site of exon 17 and adjacent exonic and intronic sequences (c.2769_2779del11, 2779+1_+20del20), and a missense mutation located next to a splice donor site (c.3319A>C) resulting in skipping of exon 22, as shown by cDNA analysis. We describe three novel mutations in the ROBO3 gene and the detailed clinical phenotype of HGPPS. One patient displayed marked convergence upon attempting smooth pursuits to both sides. In one patient, the typical ophthalmologic phenotype, the neuroradiologic findings, and molecular testing led to the diagnosis even before scoliosis developed. In addition to the typical magnetic resonance imaging brain signs of HGPPS, this patient had marked hypoplasia of the frontal lobes and corpus callosum. In summary, diagnosis of HGPPS may be established by ophthalmologic and molecular investigation early in life, allowing ongoing orthopedic surveillance from an early stage.
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