Deletion at 14q22‐23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies

Abstract

Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high-resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22-23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22-23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22-23 deletion patients.

Chromosomal Rearrangements and Novel Genes in Disorders of Eye Development, Cataract and Glaucoma

“…Analysis of the severe phenotype in 14q22-23 deletion patients and the t(3;14)(q28;q23.2) patient also indicated the likelihood of BMP4 as a candidate disease gene in anophthalmia (Nolen et al, 2006). BMP4 is a member of the transforming growth factor-β1 superfamily of secretory signalling molecules.…”

“…Analysis of patients with interstitial deletions of 14q22-23 and a t(3;14)(q28;q23.2) patient led to the identification of OTX2 as a candidate disease gene in anophthalmia (Bennett et al, 1991;Elliott et al, 1993;Lemyre et al, 1998;Nolen et al, 2006). OTX2 is a bicoid-type homeodomain transcription factor important in retinal differentiation and fore and midbrain development (Bovolenta et al, 1997;Simeone et al, 1993).…”

“…Standard karyotypic analyses, while valuable in detecting balanced chromosomal translocations and inversions, are limited in their resolution of duplications or deletions to about 5 to 10 Mb. CGH microarrays provide the means for disease gene identification at a greater resolution in whole genome analysis (Bakrania et al, 2008;Nolen et al, 2006;Vissers et al, 2004). In CGH microarray, genomic DNA from the patient and a control case are labeled with two different fluorescent dyes and then co-hybridized to the array slide, which is imprinted with a DNA probe set, arrayed as many thousands of discrete spots.…”

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

“…1,2 In some cases, molecular diagnosis may be aided by syndrome identification or a chromosomal anomaly may be revealed. 3 For isolated cases, which are the majority, molecular diagnosis is challenging, as the required sequential sequencing for identification of underlying mutation/s is rarely completed owing to the lack of an available panel covering all the known genes.…”

Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

“…We reviewed the available brain MR midline sagittal images including the posterior cranial fossa of previously reported patients with Otx2 mutations [35][36][37][38] or chromosome 14 deletions including Otx2, [39][40][41][42][43] and we recognized a similar midbrain hypoplasia with a long pons and large superior vermis in 5 patients. 35,36,40,41,43 We therefore suggest that MH abnormalities may have been underestimated in patients with Otx2 mutations or deletion; further studies on larger series are awaited to address this hypothesis. This study has several limitations, mainly including its retrospective design, the relatively small sample size, and the incomplete genetic assessment.…”