Intellectual Developmental Disorder With Persistence Of Fetal Hemoglobin

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with persistence of fetal hemoglobin is caused by heterozygous mutation in the BCL11A gene (606557) on chromosome 2p16.

Description

Intellectual developmental disorder with persistence of fetal hemoglobin is characterized by delayed psychomotor development, intellectual disability, variable dysmorphic features, including microcephaly, downslanting palpebral fissures, strabismus, and external ear abnormalities, and asymptomatic persistence of fetal hemoglobin (HbF) (summary by Dias et al., 2016).

Many of these features overlap with chromosome 2p16.1-p15 deletion syndrome (612513).

Clinical Features

Dias et al. (2016) reported 9 patients with global developmental delay and intellectual disability associated with persistence of HbF. Cognitive dysfunction varied from mild to severe, and about 30% of patients had autism spectrum disorder. The patients also had variable dysmorphic features, including joint laxity (87%), strabismus (100%), microcephaly (55%), downslanting palpebral fissures, thin upper lip, everted lower lip, flat midface, small nares, and external ear abnormalities. Three had blue sclerae in infancy. Brain imaging, performed in 6 patients, showed small cerebellar vermis in 2, mild hypoplasia of the corpus callosum in 1, and slightly reduced white matter volume in 1. Laboratory studies showed increased HbF (range 3.1 to 26.3%). Several of these patients were identified through the Deciphering Developmental Disorders Study (2015). Two additional patients with truncating BCL11A mutations ascertained from other studies of patients with autism spectrum disorder (e.g., Iossifov et al., 2012) were also described: they had global developmental delay, including speech and language delay.

Molecular Genetics

In 9 unrelated patients with intellectual developmental disorder with persistence of fetal hemoglobin, Dias et al. (2016) identified 9 different de novo heterozygous mutations in the BCL11A gene (see, e.g., 606557.0001-606557.0006). The mutations, which included 3 missense and 6 truncating mutations, were found by exome sequencing. In vitro functional expression assays showed that all 3 missense mutations occurred in the N-terminal region, which encodes a dimerization site, and resulted in defective dimerization, localization, and transcriptional activity, consistent with a loss of function. The overall findings suggested that the disorder results from haploinsufficiency. The findings also showed the importance of BCL11A for transcriptional repression of HbF.

Animal Model

Dias et al. (2016) found that haploinsufficiency of Bcl11a in the mouse resulted in microcephaly with decreased brain volume, particularly affecting the limbic system, and abnormal behavior, including impaired long-term social memory and increased locomotion. Haploinsufficient mice also showed significant transcriptional deregulation in the cortex and hippocampus, with effects on genes involved in ion transport, membrane trafficking, and neuronal signaling.