Submission Details

Autosomal dominant

10/17/2019

The BCL11A gene is located on chromosome 2 at 2p16.1 and encodes BAF chromatin remodeling complex subunit BCL11A. BCL11A functions as a transcription factor and plays an important role in globin switching by repressing transcription of fetal hemoglobin. It is highly expressed in hemotopoietic cells as well as in the developing cerebral cortex. The BCL11A gene was first reported in relation to autosomal dominant BCL11A-related intellectual disability in 2016 (27453576: Dias et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique heterozygous variants (three missense, one predicted null, and four predicted premature truncations) identified in eight unrelated probands from four publications (27453576: Dias et al. 2016; 28589569: Yoshida et al. 2017; 28891213: Cai et al. 2017; 28960836: Soblet et al. 2018). All variants occurred de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency. This gene-disease relationship is supported by expression in the developing cerebral cortex and hematopoietic cells, functional alteration studies in non-patient cells demonstrating a consistent LOF effect of three missense variants on localization, dimerization, and transcriptional regulatory activity, and a haploinsufficiency mouse model showing microcephaly, narrow skull, behavioral evidence of memory impairment and altered social interactions, and altered transcriptional profiles in the cortex and cerebellum (27453576: Dias et al. 2016). In summary, there is strong evidence to support the relationship between BCL11A and autosomal dominant BCL11A-related intellectual disability. Additional reports in humans published three years from the first proposal of the association are needed to reach a definitive classification.

27453576 28589569 28891213 28960836 27453576