Familial 4p Interstitial Deletion Provides New Insights and Candidate Genes Underlying This Rare Condition

Abstract

Chromosome 4p deletions can lead to two distinct phenotypic outcomes: Wolf-–Hirschhorn syndrome (a terminal deletion at 4p16.3) and less frequently reported proximal interstitial deletions (4p11-p16). Proximal 4p interstitial deletions can result in mild to moderate intellectual disability, facial dysmorphisms, and a tall thin body habitus. To date, only 35 cases of proximal 4p interstitial deletions have been reported, and only two of these cases have been familial. The critical region for this syndrome has been narrowed down to 4p15.33-15.2, but the underlying causative genes remain unclear. In this study, we report the case of a 3-year-old female with failure to thrive, developmental and motor delays, and morphological features. The mother also had a 4p15.2-p14 deletion, and the proband was found to have a 13.4-Mb 4p15.2-p14 deletion by chromosome microarray analysis. The deleted region encompasses 16 genes, five of which have a high likelihood of contributing to the phenotype: PPARGC1A, DHX15, RBPJ, STIM2, and PCDH7. These findings suggest that multiple genes are involved in this rare proximal 4p interstitial deletion syndrome. This case highlights the need for healthcare providers to be aware of proximal 4p interstitial deletions and the potential phenotypic manifestations.

The Ca2+ Sensor STIM in Human Diseases

“…There are no more than 40 cases reporting interstitial deletions or duplications on the proximal short arm of chromosome 4 and few involving alterations in STIM2 alleles. The most prevalent phenotype associated with such chromosomal alterations is intellectual disability, presenting other clinical features to a minor degree, such as physical and facial dimorphism or congenital heart diseases [ 87 , 88 ]. For instance, two studies involving STIM2 allele duplication were reported.…”

“…The first study performed genetic analyses on a 3-year-old proband displaying physical and intellectual delay, microcephaly, diverse facial anomalies, anxiety, frequent laughing, and hypermobility of the elbows. A deletion of a region of 3.4 Mb in size was found at 4p15.2-p14, generating haploinsufficiency in STIM2 and 15 additional genes [ 87 ]. From those 16 genes, the authors restricted to five (DHX15, PCDH7, PPARGC1A, RBPJ, and STIM2) the major contributors to the phenotype.…”