Intellectual disability with persistence of fetal hemoglobin is caused by a mutation in one of the 2 copies of the BCL11A gene or by the fact that a small part of chromosome 2 where this gene is located is missing (microdeletion). A gene is a piece of DNA that encodes for a protein that has a function in the organism. Deleterious changes in the BCL11A gene cause the formation of a protein that does not function properly.
The BCL11A protein regulates the activity of other genes. It is normally present in the fetal brain, and when there is only one normal copy (rather than two), this is likely sufficient to cause abnormal development. It is also responsible for making fetal haemoglobin, a form of haemoglobin present in developing babies in the womb and up to the first year of life. This is why fetal hemoglobin remains high when the protein does not function properly. We don’t expect any clinical problems because of persistent fetal haemoglobin.
Mutations in the BCL11A gene can be detected with sequencing of the gene, which looks at small changes at the nucleotide level, if the doctor suspects this condition. More often, the mutations are found using whole exome sequencing, which looks at the entire coding DNA. Deletions of the part of chromosome 2 containing BCL11A will be identified by chromosomal microarray analysis. Chromosomal microarray is able to find changes in the copy number, like microdeletions (pieces missing) and microduplications (pieces doubled).