Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders

Abstract

ObjectiveAccording to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patients with neurodevelopmental disorders from two unrelated Chinese pedigrees.MethodsFrom the 4 cases, the clinical data were collected. The potential pathogenic gene variations were analyzed by means of based-trio whole exome sequencing (Trio-WES) and then validated through Sanger sequencing in their respective pedigrees. Furthermore, both the in vitro minigene assay and the NMD assay were performed to evaluate the impact of splicing and frameshift variants.ResultsThe 4 patients displayed mild-to-severe intellectual developmental disorder, which was accompanied by speech delay, dysmorphic facies, and serious caries. In addition, the extended phenotype of developmental regression was observed in the proband from Family 1, which has been unreported previously. Molecular analysis was conducted to identify two novel heterozygous variants in the BCL11B gene: a maternal splicing variant c.427 + 1G > A in Family 1 and a de novo frameshift variant c.2461_2462insGAGCCACACCGGCG (p.Glu821Glyfs*28) in Family 2. As revealed by the in vitro minigene assay, the c.427 + 1G > A variant activated a new cryptic splice site. As confirmed by an overexpression assay, there was no significant difference in the level of mRNA and protein expression between the mutate-BCL11B (p.Glu821Glyfs*28) and the wild type. It confirms that p.Glu821Glyfs*28 variant could be an NMD escaping variant.ConclusionThe extended phenotype of BCL11B-related disorders is reported in this study to reveal the clinical and genetic heterogeneity of the disease. The study starts by identifying a splicing variant and a novel frameshift variant of the BCL11B gene, thus confirming its aberrant translation. The findings of this study expand the mutation spectrum of the genetic BCL11B gene, which not only improves the understanding of the associated neurodevelopmental disorders from a clinical perspective but also provides guidance on diagnosis and genetic counseling for patients.

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

“…Patients with autosomal dominant-negative BCL11B mutations patients develop combined immunodeficiency with syndromic features characterized by low peripheral T cell numbers, congenital abnormalities, and neurocognitive deficits(Alfei et al, 2022; Che et al, 2022; Lessel et al, 2018; Punwani et al, 2016; Tangye et al, 2022; Yang et al, 2020). Molecularly, the mutant protein was shown to form nonfunctional heterodimers with WT BCL11B, functionally resulting in BCL11B-deficiency(Lessel et al, 2018; Punwani et al, 2016).…”

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

“…Beyond that, the brain MRI revealed callosal agenesis, hippocampal malformations, parallel Although hematopoietic stem-cell transplantation was successful in treating the SCID, the patient later developed ID with spastic quadriplegia and seizures, which are welldescribed features of NDDs. To date, 16 additional articles have been published, covering a total number of 57 individuals with variations in the BCL11B gene loci [14,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The reported genetic variants and clinical symptoms make a systematic genetic/phenotypic correlation of the BCL11B gene more feasible.…”

“…Symptoms and their prevalence in patients with variations in BCL11B. Data condensed from[13,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76].…”

Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: a review of the BCL11B-associated phenotypes from the genetic perspective

“…The only splicing variant presented in this review, c.427+1G>A in exon 2 (observed in three patients from same family), produced the exon skipping during the splicing process, leading to the introduction of a premature stop codon at p.Val48Glyfs∗14, before C2H2-1 finger domain. The aberrant transcript caused by this variant was supposed to be degraded by NMD, but western blotting and immunofluorescence assays revealed normal expression and no significant changes in cell morphology or localization [ 49 ], suggesting the existence of post-transcriptional regulatory mechanisms affecting protein function as the disease-causing mechanism of the mutation.…”