Dissection of partial 21q monosomy in different phenotypes: clinical and molecular characterization of five cases and review of the literature

Abstract

Background: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated with highly variable phenotypes, such as facial dysmorphic features, heart defects, seizures, psychomotor delay, and severe to mild intellectual disability, depending on the location and size of deletions. So far, three broad deletion regions of 21q have been correlated with the clinical phenotype.

Results: We described the clinical and genetic features of three family members (father and two siblings) and other two unrelated patients with very wide range in age of diagnosis. All of them showed intellectual disability with very variable symptoms, from mild to severe, and carried 21q interstitial deletions with different sizes and position, as detected by conventional karyotype and array-CGH.

Conclusions: Our study provided additional cases of partial 21q deletions, allowing to better delineate the genotype-phenotype correlations. In contrast to previous observations, we showed that deletions of the 21q proximal region are not necessarily associated with severe phenotypes and, therefore, that mild phenotypes are not exclusively related to distal deletions. To the best of our knowledge, this is the first report showing 21q deletions in adult patients associated with mild phenotypes, mainly consisting of neurobehavioral abnormalities, such as obsessive-compulsive disorders, poor social interactions and vulnerability to psychosis.

Keywords: Array Comparative Genomic Hybridization (array-CGH); BTG3 (BTG family; Behavioral disorders; DNA Copy Number Variations (CNVs); GRIK1 (glutamate receptor; Intellectual Disability (ID); Ionotropic; Kainate 1); Member 3); Partial 21q monosomy; RBM11 (RNA binding motif protein 11).

Fig. 1

Clinical features (a), G-banded karyotypes (b) and array-CGH profiles (c) of patients with chromosome 21q deletions. Chromosomes 21 shown in the red boxes (b) are enlarged in respect to the original karyograms. Parents of patient 4 denied permission to publish pictures

Fig. 2

Comparison of 21q deletion cases with mild (purple) and moderate/severe (green) phenotypes (behavioral disorders and intellectual disability, respectively). The protein-coding genes of 21q region are mainly grouped into two main clusters. The proximal cluster includes genes more likely involved in intellectual disability (BTG3 and RBM11), whereas the distal cluster mainly contains genes related to behavioral disorders, such as GRIK1 (almost completely deleted in the case reported by Haldeman-Englert et al., [13]). KKI-3, GM00137, and ECARUCA#4777 cases also had rearrangements involving chromosomes other than 21 (as reported in Table 1) that might contribute to the clinical severity

Fig. 3

Subsetting of the great 21q region 1 described by Lyle and colleagues in 2009 into two smaller subregions. Deletions in the subregion 1, from the centromere to ~ 21 Mb (including BTG3 and RBM11), are mainly associated with severe intellectual disability, whereas deletions of the subregion 2, until approximately 32 Mb (including GRIK1), are more tightly associated with milder neurobehavioral disorders, such as poor social interactions. Patients with a deletion overpassing the two subregions clinically manifested the most severe phenotype