Intellectual disability with persistence of fetal hemoglobin is caused by haploinsufficiency of BCL11A, on chromosome 2p16.1. Both heterozygous point mutations and whole gene deletions of variable size have been reported.
Molecular characteristics
Pathogenic variants in BCL11A include missense, nonsense, frameshift, and deletions. All the affected individuals described so far have a de novo variant. All the pathogenic variants lead to loss of function of the protein. Although genotype-phenotype correlations are not available due to the paucity of reported individuals, patients with missense mutations may have a milder phenotype, resulting from incomplete loss of function.
The protein encoded by BCL11A is highly expressed in B lymphocytes, the adult erythroid lineage, and the fetal brain. It acts as a transcriptional repressor of fetal hemoglobin, and is associated with the SWI/SNF chromatin remodelling complex. Pathogenic variants in BCL11A might, therefore, disrupt transcriptional regulation; heterozygous loss of BCL11A disrupts transcription in mouse brain.
The diagnosis of the intellectual disability with persistence of fetal hemoglobin syndrome (also known as Dias-Logan syndrome) is obtained when a pathogenic variant of BCL11A or a microdeletion encompassing BCL11A is detected. Patients with 2p16.1 microdeletion syndrome that encompasses BCL11A share clinical features, including intellectual disability and persistence of HbF, but usually have a more severe phenotype including brain and other congenital malformations. Targeted molecular analysis is technically feasible and should be phenotype-guided, but most patients have been identified through chromosomal microarray or whole exome sequencing. Elevation of HbF is indicative of decreased BCL11A-mediated repression of fetal hemogobin, and thus may aid in the classification of variants of unknown significance.