Phenotypic variability in a Hungarian patient with the 4q21 microdeletion syndrome

Abstract

BackgroundInterstitial deletions of 4q21 (MIM 613509) have already been reported in more than a dozen patients with deletions ranging from 2 to 15.1 Mb delineating a common phenotype including marked growth restriction, hypotonia, severe developmental delay with absent or delayed speech and distinctive facial features. A minimal critical region of 1.37 Mb accounting for the common features with 5 known genes (PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1) has been described so far.ResultsHere we report on a 5 year-old Hungarian girl presenting with severe developmental delay, good receptive language but absent spoken speech, short stature, dystrophy, hypotonia, distinctive facies including broad forehead, frontal bossing, downward slanting palpebral fissures, hypertelorism, hypoplastic ear-lobes, anteverted nostrils, short philtrum, small mouth, higharched palate, short, small hands and feet, distally narrowing fingers and clinodactyly. Cerebral MRI showed ventricular dilation and an increase in periventricular signal intensity. After extensive metabolic tests and exclusion of subtelomeric deletions array CGH analysis was performed using the Agilent Human Genome G3 SurePrint 8x60K Microarray (Agilent Technologies, USA), which detected a 4,85 Mb de novo interstitial deletion of 4q21.21-4q21.23. The clinical symptoms only partly overlap with reported 4q21 microdeletion cases. Among multiple annotated genes our patient is also haploinsufficient for the following genes: RASGEF1B being a strong candidate for the neurodevelopmental features and PRKG2 for severe growth delay.ConclusionThe first Hungarian case of 4q21 deletion adds to the phenotypic spectrum of this novel microdeletion syndrome and underlines the importance of array CGH to uncover the heterogeneous causes of intellectual disability.

Enolase-phosphatase 1 as a novel potential malignant glioma indicator promotes cell proliferation and migration

“…At present, the biological functions of ENOPH1 are still mainly not known. It has been revealed in a few recent studies that there is wide expression of ENOPH1 in the brain and it is related to neurodevelopmental disorders, anxiety behavior and BBB function integrity damage (10,21,28). The present study was the first investigation of the role of ENOPH1 in the pathophysiology of gliomas.…”

Cerebral Microvascular Endothelial Cell Apoptosis after Ischemia: Role of Enolase-Phosphatase 1 Activation and Aci-Reductone Dioxygenase 1 Translocation

“…Currently, the biological functions of ENOPH1 are largely unknown. A few recent studies have shown that ENOPH1 is widely expressed in the brain and is associated with neurodevelopmental disorders and anxiety (Barth et al, 2014 ; Komlósi et al, 2015 ). As the first study, here we investigated the role of ENOPH1 in ischemic stroke with a focus on the BBB.…”

Further defining the critical genes for the 4q21 microdeletion disorder

“…Severe growth retardation is a significant feature of 4q21 deletion syndrome. Previously, PRKG2 has been proposed as the candidate gene responsible for this phenotype [Komlosi et al, ]. Mutations in this gene cause dwarfism in beef cattle [Koltes et al, ], in rat [Chikuda et al, ; Tsuchida et al, ], and knockout mouse model [Pfeifer et al, ] but all in a recessive inheritance mode.…”

“…This is a non‐recurrent genomic disorder, presented with overlapping deletions of different size at 4q21 region. Currently, 48 cases (18 from literature [Bonnet et al, ; Dukes‐Rimsky et al, ; Tsang et al, ; Bhoj et al, ; Bartnik et al, ; Komlosi et al, ; Sakazume et al, ] and 30 cases from databases) with defined genomic coordinates have been reported and the majority of individuals with 4q21 deletion are characterized by neonatal hypotonia, intellectual disability, absent or delayed speech, marked progressive growth retardation, and variable degrees of brain malformation and facial dysmorphism.…”