Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome

Abstract

BackgroundChromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature.MethodsMolecular analysis was performed using microarray‐based comparative genomic hybridization (array CGH). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed.ResultsWe identified four patients with ID, neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL11A,PAPOLG, and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons.ConclusionThe zinc finger transcription factor BCL11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL11A haploinsufficiency is closely related to cerebellar abnormalities.

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

“…Many genomic disorders intersect with a single DNM-enriched gene, confirming a known CNV gene association, including KANSL1 (Koolen-de Vries) 50 , SHANK3 (Phelan-McDermid) 51 , RAI1 (Smith-Magenis) 52 , NSD1 (Sotos) 53 , WHSC1 (Wolf-Hirschhorn) 54 , BCL11A (2p15-16.1 microdeletion) 55 , EHMT1 (9q34 deletions / Kleefstra syndrome) 56 , and CREBBP (Rubinstein-Taybi) 57 (Table 3, Supplementary Table 2). In addition, this analysis also highlights genes that have been implicated as candidates by case reports, functional studies, or smaller CNVs (Table 3, Supplementary Table 2).…”

“…The 2q33.1 region contains several potentially high-impact candidates, including HECW2 , which has been linked to neurodevelopmental delay, ID and epilepsy by missense mutations 27,76 ; SATB2 , which has been independently identified by focal CNVs 18,71 ; ABI2 , which is a candidate for autosomal recessive ID 77 ; and SF3B1 , which interacts directly with the ID gene PQBP1 78 . Similarly, in the 2p15-p16.1 deletion region we identify both the primary gene BCL11A 55 as well as a second candidate gene in the minimal critical region, PAPOLG 79 , which is enriched for severe missense DNM. Finally, in the 2q11.2q13 deletion region we identify both POU3F3 , which has been linked to ID and dysmorphic features by focal deletions 80 , and RFX8 , which has limited functional information in the literature.…”

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

“…Many genomic disorders intersect with a single DNM-enriched gene, confirming a known CNV gene association, including KANSL1 (Koolen-de Vries) 57 , PAFAH1B1 aka LIS1 (Miller-Dieker) 58 , SHANK3 (Phelan-McDermid) 59 , RAI1 (Smith-Magenis) 60 , NSD1 (Sotos) 61 , WHSC1 (Wolf-Hirschhorn) 62 , BCL11A (2p15-16.1 microdeletion) 63 , and CREBBP (Rubinstein-Taybi) 64 (Table 3). In addition, this analysis also highlights genes that have been implicated as candidates by case reports, functional studies, or smaller CNVs (Table 3).…”

Duplication 2p16 is associated with perisylvian polymicrogyria

“…Mutations in some of these genes are known to be associated with neurodevelopmental disorders. CCDC88A mutations cause progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO)‐like syndrome (Nahorski et al, ), VRK2 is associated with autism and neuroectodermal developmental disorders in the 2p15‐p16.1 deletion syndrome (Chabchoub, Vermeesch, de Ravel, de Cock, & Fryns, ; de Leeuw et al, ; Rajcan‐Separovic et al, ), BCL11A haploinsufficiency can be associated with intellectual developmental disorders and cerebellar hypoplasia (Shimbo et al, ) as well as hypoplasia of the corpus callosum and a simplified cortical gyral pattern (Balci, Sawyer, Davila, Humphreys, & Dyment, ) or a severe speech sound disorder (Peter, Matsushita, Oda, & Raskind, ). In the 2p16.1p15 microduplication, BCL11A and VRK2 duplications are thought to be implicated in the observed intellectual deficiency, but no information is provided regarding a possible associated malformation of cortical development (Chen et al, ; Mimouni‐Bloch, Yeshaya, Kahana, Maya, & Basel‐Vanagaite, ).…”