Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects

Abstract

Background: Genomic imbalances of the 12q telomere are rare; only a few patients having 12q24.31-q24.33 deletions were reported. Interestingly none of these were mosaic. Although some attempts have been made to establish phenotype/genotype interaction for the deletions in this region, no clear relationship has been established to date.

Results: We have clinically screened more than 100 patients with dysmorphic features, mental retardation and normal karyotype using high density oligo array-CGH (aCGH) and identified a ~9.2 Mb hemizygous interstitial deletion at the 12q telomere (Chromosome 12: 46,XY,del(12)(q24.31q24.33) in a severely developmentally retarded patient having dysmorphic features such as low set ears, microcephaly, undescended testicles, bent elbow, kyphoscoliosis, and micropenis. Parents were found to be not carriers. MLPA experiments confirmed the aCGH result. Interphase FISH revealed mosaicism in cultured peripheral blood lymphocytes.

Conclusions: Since conventional G-Banding technique missed the abnormality; this work re-confirms that any child with unexplained developmental delay and systemic involvement should be studied by aCGH techniques. The FISH technique, however, would still be useful to further delineate the research work and identify such rare mosaicism. Among the 52 deleted genes, P2RX2, ULK1, FZD10, RAN, NCOR2 STX2, TESC, FBXW8, and TBX3 are noteworthy since they may have a role in observed phenotype.

Figure 1

Patient photos. Photos showing the patient and clinical phenotypes: A) Left arm showing bent elbow, B) Face indicating long philtrum of upper lip, C) Right arm with bent elbow, D) Facial features including small ear lobe from left side, E-F) Full body indicating scoliosis, short stature, micro-retrognathia, respectively.

Figure 2

Family pedigree, aCGH data and FISH results. Panel I is presenting the family pedigree and aCGH data analysis results. A. The pedigree indicates presence of two miscarriages, six healthy family members (two girls and four boys) and one affected boy B. aCGH data showing the largest deletion found on chromosome 12q telomere. The deletion is nearly 9.2 Mb in size and starts from bases of 123097890 and extends to the near end of the chromosome 12 and therefore, is considered as a novel telomeric deletion. Similar deletions limited to a few patients were previously reported but the breakpoints and sizes are different. Panel II is depicting three different cells based on interphase FISH results. A. Interphase FISH showing the wild type cell with four signals (two telomeric red and two centromeric green signals). B. A cell with hemizygosity indicated by three signals based on the FISH experiments. C. The FISH result depicting only two green signals in a cell indicating nullisomy for chromosome 12q24.31-q24.33.