Submission Details

BCL11B was first reported in relation to autosomal dominant BCL11B-related BAFopathy in 2016 (Punwani et al., PMID: 27959755). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Immunodeficiency 49, severe combined (OMIM:617237) and Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (OMIM:618092). Affected individuals have delayed psychomotor development, intellectual disability, speech delay, dysmorphic features, dental anomalies, recurrent infections, low or poor proliferation of T-cells, and allergic disease in some. 15 variants (missense, nonsense, and frameshift) that have been reported in 15 probands in four publications (PMIDs: 27959755, 29985992, 37860968, 33194885) are included in this curation. All of variants occurred likely de novo with confirmed parental relatedness and 12 of the 13 truncations occurred in the last exon. The mechanism of pathogenicity is known to be loss of DNA binding function either by dominant negative or haploinsufficiency. This gene-disease relationship is also supported by animal models, rescue studies, expression studies, and functional alteration studies (PMIDs: 27959755, 22588081, 20538915, 28951542). BCL11B is expressed in T-cells and is required for T-cell development. Knockout mice have reduced neuronal progenitor cell proliferation and impaired neuronal differentiation. Introduction of human BCL11B rescued the arrest in T-cell development and corrected the craniofacial abnormalities caused by bcl11ba knockdown in Zebrafish. BCL11B forms a homodimer and a heterodimer with BCL11A. BCL11B pathogenic variants interfere with the function of both BCL11A and BCL11B in suppressing NK cell-related gene expression. In summary, there is definitive evidence supporting the relationship between BCL11B and autosomal dominant BCL11B-related BAFopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen SCID-CID GCEP on the meeting date December 19, 2024 (SOP Version 11).