Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay

Abstract

Duane retraction syndrome (DRS) is a rare congenital strabismus condition with genetic heterogeneity. DRS associated with intellectual disability or developmental delay is observed in several genetic diseases: syndromes such as Goldenhar or Wildervanck syndrome and chromosomal anomalies such as 12q12 deletion. We report on the case of a patient with DRS, developmental delay and particular facial features (horizontal and flared eyebrows, long and smooth philtrum, thin upper lip, full lower lip and full cheeks). We identified a duplication of the long arm of chromosome 8 (8q12) with SNP-array. This is the third case of a patient with common clinical features and 8q12 duplication described in the literature. The minimal critical region is 1.2 Mb and encompasses four genes: CA8, RAB2, RLBP1L1 and CHD7. To our knowledge, no information is available in the literature regarding pathological effects caused by to overexpression of these genes. However, loss of function of the CHD7 gene leads to CHARGE syndrome, suggesting a possible role of the overexpression of this gene in the phenotype observed in 8q12 duplication patients. We have observed that patients with 8q12 duplication share a common recognizable phenotype characterized by DRS, developmental delay and facial features. Such data combined to the literature strongly suggest that this entity may define a novel syndrome. We hypothesize that CHD7 duplication is responsible for a part of the features observed in 8q12.2 duplication.

Figure 1

(a) Front and lateral view of the patient at the age of 4 and a half years. Note esotropia of the left eye, flaring of the proximal part of the eyebrows, bulbous tip of the nose with large nostrils, wide mouth with long philtrum, eversion of the lower lip and full cheeks, (b) FISH results from the patient, revealing 2 green spots (indicated by doted and vertical arrows) corresponding to the centromeric control probe (pZ8.4) and 3 red spots (indicated by full and horizontal arrows) corresponding to 8q12.2 region (probe RP11-33I11 encompassing the CHD7 gene), and (c) schematic representation of the three 8q12 duplications reported in the literature. Note that the minimal critical region (delineated by the black vertical bars) contains only 4 genes namely CA8, RAB2, RLBP1L1 and CHD7. Note also the distance between the minimal critical region and the CPA6 gene corresponding to the DRS locus located at 8q13.2. The color reproduction of this figure is available at the European Journal of Human Genetics online.