BCL11A

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: ClinGen

Variants in BCL11A were first reported in association with Dias-Logan syndrome in 2016, at which time Dias et al. (PMID: 27453576) described nine individuals with similar phenotypes, all of which had predicted LOF variants in BCL11A. All individuals had neurodevelopmental concerns, such as intellectual disability and developmental delay, and persistent fetal hemoglobin. At the time of curation, 27 pathogenic/likely pathogenic variants have been reported in humans, predominantly frameshift variants, though nonsense and pathogenic missense variants have also been observed. Dias-Logan syndrome (also known as Intellectual disability with persistence of fetal hemoglobin) is characterized by developmental delay/intellectual disability, and fetal hemoglobin that remains high in childhood (wheras is normally low after birth), infantile hypotonia, and distinctive but variable facial features. Other features such as language delay, microcephaly, and autism spectrum disorder are also associated with this syndrome. Summary of Case Level Data: Variants in this gene have been reported in a number of individual probands since 2007, when Rajcan-Separovic et al. (PMID: 16963482) first described a neurodevelopmental syndrome associated with deletions in 2p15-16.1. This group of features was formally labeled Dias-Logan syndrome by Dias et al. in their 2016 publication, which included robust experimental evidence supporting the pathogenic nature of BCL11A haploinsufficiency. Note that two probands, subjects 5 and 7, could not be entered in the gene curation interface, but were counted towards the scoring total. These subjects both had de novo frameshift variants, and were given scores of 2 and 1.5, respectively (second score downgraded due to lack of information about fetal hemoglobin levels). The phenotypic spectrum for BCL11A continues to expand, with features such as seizures being reported in more recent cases, along with the typical presentation of Dias-Logan syndrome (e.g. Soblet et al., 2018 (PMID: 28960836); Yoshida et al., 2018 (PMID:28589569)). Most recently, a case was reported by Korenke et al. (2020) of a 13 year old male patient with classic features of Dias-Logan syndrome. Experimental Evidence: Non-human model organisms and cell models have been used to investigate the effect of BCL11A haploinsufficiency on brain function, and behaviours related to Dias-Logan syndrome. In this curation, one strong example is presented from Dias et al. (2016), whereby BCL11A haploinsufficient mouse models were found to have brain and behavioral abnormalities in line with features observed in human Dias-Logan syndrome patients (e.g. microcephaly, impaired cognition, abnormal social behavior). Based on the presented evidence, default points for a non-human model organism (2 points) were awarded. This study also demonstrated (using cell models) that the same three missense variants observed in their described subjects disrupted protein localization, dimerization, and transcriptional regulation, consistent with a LOF effect. This evidence was used to award default points to the de novo missense variants in this curation’s genetic evidence section. In summary, at present there is an abundance of evidence to support a definitive classification for this gene-disease relationship. Future recurations will likely continue to support this recently described syndromic condition, and may expand the phenotypic spectrum of Dias-Logan syndrome further.

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014914

Submitter: Labcorp Genetics (formerly Invitae)