Possible genes responsible for developmental delay observed in patients with rare 2q23q24 microdeletion syndrome: Literature review and description of an additional patient

Abstract

Cases of 2q23q24 microdeletion syndrome are rare. Patients with chromosomal deletions in this region often show language impairment and/or developmental delay of variable severity. Previous genotype-phenotype correlation study suggested GALNT13 and KCNJ3 as possible candidate genes for such phenotypes. We identified a new overlapping deletion in a patient with severe developmental delay. The identified deletion extended toward the distal 2q24.1 region, and more severe phenotypes in the present patient were considered to be related to the additionally deleted genes including NR4A2 and GPD2. Previously reported chromosomal translocation and the mutation identified in GPD2 suggested that this gene would be responsible for the developmental delay. Re-evaluation for the critical region for behavior abnormalities commonly observed in the patients with overlapping deletions of this region suggested that KCNJ3 rather than GALNT13 may be responsible for abnormal behaviors, although there was phenotypic variability. Combinatory deletions involving KCNJ3 and GPD2 may lead to more severe developmental delay. Further studies would be necessary to establish clearer genotype-phenotype correlation in patients with 2q23q24 microdeletion syndrome.

Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment

“…To our knowledge, this is the first time a point mutation leading to loss of function in NR4A2 is reported. Our patient's phenotype is similar to the previously described in individuals with de novo microdeletions encompassing NR4A2 at the 2q24.1 region and whose clinical manifestations were mainly characterized by language and cognitive delay . Our patient also presented focal motor seizures in the rolandic epilepsy spectrum, which expands the clinical manifestations related to NR4A2 haploinsufficiency and reinforces the predominance of language impairment associated with this condition.…”

“…Barge‐Schaapveld et al and Shimojima et al suggested previously that GPD2 haploinsufficiency was the most likely to be responsible for the 2q23q24 microdeletion phenotype. However, GPD2 probability of loss‐of‐function intolerance (pLi) is zero and over 100 loss‐of‐function variants are reported in ExAC,on the other hand, NR4A2 has a pLi = 1 and no loss‐of‐function variants in ExAC .…”

NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder

“…Among larger deletions, Leppa et al also reported 2 2q24.1 deletions (3.3 and 1.1 Mb) in patients with autism spectrum disorder (ASD), language delay and ID based on analysis of families from the Autism Genetic Resource Exchange project (AGRE) . Shimojima et al described a patient harboring a 4.5‐Mb 2q23.3q24.1 microdeletion with severe ID . These articles narrowed the critical region of overlap for ID, developmental delay (DD), ASD and language delay to NR4A2 and GPD2 genes .…”

“…5 Shimojima et al described a patient harboring a 4.5-Mb 2q23.3q24.1 microdeletion with severe ID. 6 These articles narrowed the critical region of overlap for ID, developmental delay (DD), ASD and language delay to NR4A2 and GPD2 genes. [4][5][6] Recently, Reuter et al reported the first patient with prominent language delay and mild cognitive impairment associated with a de novo deletion encompassing only NR4A2 gene.…”

Developmental delay and dysmorphic features in a girl with a de novo 5.4 Mb deletion of 13q12.11‐q12.13

“…Exome sequencing could identify further additional variants associated with the phenotypes of the patient. Haploinsufficiency of a combination of genes in this region could lead to the developmental delay and dysmorphic facial appearance of the reported patients . Further analysis with animal models and a patient cohort could provide an insight to the underlying mechanism.…”