Critical region in 2q31.2q32.3 deletion syndrome: Report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region

Abstract

Background: Standard cytogenetic analysis has revealed to date more than 30 reported cases presenting interstitial deletions involving region 2q31-q32, but with poorly defined breakpoints. After the postulation of 2q31.2q32.3 deletion as a clinically recognizable disorder, more patients were reported with a critical region proposed and candidate genes pointed out.

Results: We report two female patients with de novo chromosome 2 cytogenetically visible deletions, one of them with an additional de novo deletion in chromosome 20p12.2p12.3. Patient I presents a 16.8 Mb deletion in 2q31.2q32.3 while patient II presents a smaller deletion of 7 Mb in 2q32.1q32.3, entirely contained within patient I deleted region, and a second 4 Mb deletion in Alagille syndrome region. Patient I clearly manifests symptoms associated with the 2q31.2q32.3 deletion syndrome, like the muscular phenotype and behavioral problems, while patient II phenotype is compatible with the 20p12 deletion since she manifests problems at the cardiac level, without significant dysmorphisms and an apparently normal psychomotor development.

Conclusions: Whereas Alagille syndrome is a well characterized condition mainly caused by haploinsufficiency of JAG1 gene, with manifestations that can range from slight clinical findings to major symptoms in different domains, the 2q31.2q32.3 deletion syndrome is still being delineated. The occurrence of both imbalances in reported patient II would be expected to cause a more severe phenotype compared to the individual phenotype associated with each imbalance, which is not the case, since there are no manifestations due to the 2q32 deletion. This, together with the fact that patient I deleted region overlaps previously reported cases and patient II deletion is outside this common region, reinforces the existence of a critical region in 2q31.3q32.1, between 181 to 185 Mb, responsible for the clinical phenotype.

Figure 1

Conventional cytogenetic results: Ideogram of chromosome 2 locating the deletion (A), conventional GTG banded pair of chromosomes 2 from patients I (B) and II with the deleted chromosome on the right (C), ideogram of chromosome 20 locating the deletion (D) and pair of chromosomes 20 from patient II (E).

Figure 2

Oligoarray-CGH ratio profiles for chromosomes 2 and 20: chromosome 2 ideogram (A), Log2 ratio of chromosome 2 probes plotted as a function of chromosomal position for patients I (B) and II (C), genes involved in the 2q32deletion of patients I (D) and II (E); chromosome 20 ideogram (F), Log2 ratio of chromosome 20 probes plotted as a function of chromosomal position for patient II (G), genes involved in the 20p12 deletion of patient II (H). Each spot represents a probe, with the patient DNA labeled in red (Cy5) and the control DNA labeled in green (Cy3). Log2 ratios of zero represent equal fluorescence between both samples and the log2 ratio of -1 means copy number loss of the sample DNA.

Figure 3

Patients I and II chromosome 2 deletion compared to four previously reported patients. OMIM Morbid Map genes are in red and other genes discussed in the text are in green. The dotted black rectangle delimitates the common deleted region among the patients. Breakpoints mapped according to GRCh37, hg 19.