2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment

Abstract

Key Points Elevation of HbF in 3 patients heterozygous for distinct 2p15-p16.1 syndrome microdeletions affecting BCL11A. Identification of novel, putative regulatory elements downstream of BCL11A that govern its expression in erythroid cells.

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…All of the patients had substantial persistence of HbF ranging between 15-30% in the setting of BCL11A mRNA haploinsufficiency, without observable abnormalities in either other blood or immune cell phenotypes. Similar findings have also been reported in subsequent follow-up studies (41). Importantly, we could demonstrate using a variety of orthogonal genetic datasets that BCL11A had a key role in human neurodevelopment, suggesting the importance of careful phenotypic assessment with any potential BCL11A-targeting therapies that may be developed in the future (40).…”

Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors

“…This raises the issue of safety in terms of neurogenesis, because patients with deletions in BCL11A appear prone to schizophrenia and autism spectrum disorders. 40,41 However, in preliminary studies, pomalidomide was added to human neuronal cell lines, and there was no change in the expression levels of BCL11A (supplemental Figure 6). In addition, pomalidomide induces less neuropathy than thalidomide.…”

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

“…Patients with missense and LoF mutations (Dias et al, 2016), or BCL11A encompassing 2p15p16 microdeletions (Basak et al, 2015; Funnell et al, 2015) were shown to have elevated fetal hemoglobin levels, ranging from 3.1% (Dias et al, 2016) to 29.7% (Basak et al, 2015). Our patient value of 4.5% of HbF is thus in accordance with reported cases and constitutes additional evidence for the pathogenic nature of the LoF variant observed in our patient.…”

“…BCL11A has been shown to be a critical modulator of hemoglobin switching and HbF silencing (Basak et al, 2015; Funnell et al, 2015; Guda et al, 2015; Xu et al, 2013). In the murine brain, Bcl11a controls cell polarity, radial migration of upper cortical neurons, axon branching, and dendrite outgrowth (Kuo, Chen, & Hsueh 2010; Kuo, Hong, & Hsueh, 2009; Kuo, Hong, Chien, & Hsueh, 2010; Wiegreffe et al, 2015).…”

“…Microcephaly, autism spectrum disorder, and mild dysmorphism can be present and the level of fetal Hb is raised. In addition, BCL11A is included in most CNVs reported as the 2p15‐p16.1 microdeletion syndrome (OMIM #612513), characterized by developmental delay, intellectual disability, hypotonia, poor verbal skills, craniofacial and skeletal features, digital anomalies, and fetal hemoglobin persistence (Basak et al, 2015; Funnell et al, 2015). When described, patients with 2p15p16 microdeletion encompassing BCL11A show delayed receptive and expressive language skills (Hancarova et al, 2013; Piccione et al, 2012; Rajcan‐Separovic et al, 2007), language delay (Balci, Sawyer, Davila, Humphreys, & Dyment, 2015; Felix, Petrin, Sanseverino, & Murray, 2010), language restricted to a few single words and signing (Florisson et al, 2013), or absence of language (Florisson et al, 2013; Hucthagowder et al, 2012).…”