Chromosome 2p16.1-P15 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr2:59.0-61.5 Mb; involving chromosome 2p16.1-p15).

Description

Chromosome 2p16.1-p15 deletion syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and variable but distinctive dysmorphic features, including microcephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and high palate. Many patients have behavioral disorders, including autistic features, as well as structural brain abnormalities, such as pachygyria or hypoplastic corpus callosum. Those with deletions including the BCL11A gene (606557) also have persistence of fetal hemoglobin (HbF), which is asymptomatic and does not affected hematologic parameters or susceptibility to infection (summary by Funnell et al., 2015).

Point mutation in the BCL11A gene causes intellectual developmental disorder with persistence of fetal hemoglobin (617101), which shows overlapping features.

See also fetal hemoglobin quantitative trait locus-5 (HBFQTL5; 142335).

Clinical Features

Rajcan-Separovic et al. (2007) reported 2 unrelated children, a boy and a girl, with a de novo interstitial microdeletion at chromosome 2p16.1-p15 associated with a similar phenotype characterized by mental retardation, autistic features, and dysmorphic features. Dysmorphic craniofacial features included progressive microcephaly, flat occiput, bitemporal narrowing, widened inner canthal distance, small palpebral fissures, ptosis, downslanting palpebral fissures, long and straight eyelashes, broad and high nasal root, wide and prominent nasal tip, elongated smooth philtrum, high palate, large ears, and everted lower lips. Additional features included optic nerve hypoplasia, hydronephrosis, digital camptodactyly, widely spaced nipples, and lower limb spasticity. Brain MRI showed cortical dysplasia/pachygyria.

De Leeuw et al. (2008) reported an additional male patient with 2p16.1-p15 deletion syndrome. He had delayed psychomotor development, mental retardation, optic nerve hypoplasia, a narrow receding forehead, widened inner canthal distance, short and downslanting palpebral fissures, high nasal bridge, low-set large ears, and small mouth with high palate. The thorax was broad with increased internipple distance. Renal ultrasound showed multiple cysts.

Chabchoub et al. (2008) reported a 16-year-old Belgian boy with 2p16.1-p15 deletion syndrome. He had mild mental retardation without autistic features. Dysmorphic features included high forehead, downslanting palpebral fissures, large ears, broad nasal root with prominent tip, and a smooth upper vermilion border of the mouth with everted upper lip. Other features included pectus excavatum, small testes, arachnodactyly, and mild kyphoscoliosis. He also had multiple cardiac valvular defects.

Liang et al. (2009) reported a 4.5-year-old Japanese girl with 2p16.1-p15 microdeletion syndrome. She showed intrauterine and postnatal growth retardation and severely delayed psychomotor development with an IQ of about 20. Short stature and microcephaly were noted. Dysmorphic facial features included hypertelorism, epicanthal folds, broad nasal bridge, retrognathia, and low-set ears. She had generalized hypotonia, spasticity, attention deficit, metatarsus adductovarus, and bilateral optic atrophy. Brain imaging showed no abnormalities. Comparative genomic hybridization array analysis showed a de novo heterozygous 3.2-Mb deletion at chromosome 2p16.1-p15 on the paternally-derived chromosome.

Felix et al. (2010) reported a 4-year-old girl with a de novo heterozygous 3.35-Mb deletion at 2p16.1-p15 on the paternal chromosome. She had pre- and postnatal growth deficiency, microcephaly, and developmental delay. Dysmorphic features included micrognathia, high and broad nasal root, smooth philtrum, long eyelashes, high palate, and camptodactyly. She also had gastroesophageal reflux and 2 febrile seizures. Brain imaging was normal.

Prontera et al. (2011) and Piccione et al. (2012) independently reported a total of 3 children with developmental delay and dysmorphic features associated with variable de novo heterozygous deletions of 2p16.1-p15. Each patient also had additional copy number variations of other chromosomes that may have contributed to the phenotype. Dysmorphic features were variable, but included flat facial profile, trigonocephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, strabismus, epicanthal folds, large, low-set, or posteriorly rotated ears, thin upper lip, everted lower lip, and high palate. Other features included short stature, hypotonia, and hypogonadism. One patient had cerebral atrophy and hypoplasia of the corpus callosum on brain imaging. Funnell et al. (2015) found that the 3 patients reported by Prontera et al. (2011) and Piccione et al. (2012) had increased fetal hemoglobin levels (7.3%, 4.8%, and 6.2%, respectively) compared to controls, although additional hematologic parameters in these patients were largely normal.

Basak et al. (2015) reported 3 unrelated children with 3 different de novo heterozygous deletions at 2p16.1-p15 (440 kb, 1 Mb, and 874 kb, respectively) that commonly deleted only the BCL11A gene. All children had a neurodevelopmental disorder characterized by moderate to severe developmental delay, autism spectrum disorder, hypotonia, and dysmorphic facial features. Two had microcephaly and normal brain structure, whereas the third had a normal head circumference with a posterior fossa malformation. In addition, all 3 patients had persistence of fetal hemoglobin (HbF), which was elevated at 23.8%, 16.1%, and 29.7%, respectively. None had changes in any hematologic parameters or evidence of impaired immune function. Mononuclear cells from 2 of the patients showed haploinsufficiency for BCL11A and increased mRNA levels of the HbF-encoding genes HBG1 (142200) and HBG2 (142250) compared to controls. The findings implicated BCL11A as a key neurodevelopmental gene in addition to its role in silencing HbF. Moreover, Basak et al. (2015) concluded that the findings demonstrated that haploinsufficiency of BCL11A may be sufficient to allow persistence of HbF at a high enough level to ameliorate beta-thalassemia (613985) or sickle cell disease (603903).

Balci et al. (2015) reported a 3-year-old girl with moderate developmental delay and dysmorphic features associated with a heterozygous de novo 0.875-Mb deletion at 2p16.1 including the BCL11A gene. In addition to characteristic dysmorphic features observed with this disorder, she also had brain malformations, including cerebral atrophy, enlarged ventricles, and hypoplasia of the corpus callosum, amygdala, pons, and cerebellum.

Mapping

Rajcan-Separovic et al. (2007) found that the 2p16.1-p15 deletion in 2 affected individuals measured 4.5 Mb and 5.7 Mb, respectively. In another patient, De Leeuw et al. (2008) narrowed the candidate region to a 3.9-Mb interval within the deletion regions described by Rajcan-Separovic et al. (2007).

In a patient with dysmorphic facial features and mild mental retardation, Chabchoub et al. (2008) identified a 570-kb deletion at chromosome 2p15. Compared with previously reported cases, the authors concluded that a candidate gene(s) in the 570-kb region was most likely responsible for the facial dysmorphism features and proposed a role for the VRK2 gene (602169) on chromosome 2p16.1 for autism and neuroectodermal developmental disorders in the patients of Rajcan-Separovic et al. (2007).

In an affected girl, Felix et al. (2010) was able to refine the critical region for the 2p16.1-p15 deletion syndrome to a 3.35-Mb region (chr2:59.13-62.48) that did not include the VRK2 gene. The girl had facial dysmorphism and developmental delay, but MRI did not show brain abnormalities, such as cortical dysplasia.

Cytogenetics

Peter et al. (2014) reported an 11-year-old boy with mild intellectual disability and a severe speech sound disorder associated with a de novo heterozygous 203-kb deletion at 2p16.1 including only the BCL11A gene (606557). It was the smallest deletion of this region yet reported. He had some features associated with larger deletions of 2p16-p15, including abnormal muscle tone and delayed motor development, but lacked other significant features, such as craniofacial or skeletal anomalies and optic nerve impairment. His language difficulties were significant and included poor expressive speech, dysarthria in the orofacial region, and childhood apraxia of speech. Peter et al. (2014) suggested a specific role for the BCL11A gene in language development, and noted that this gene falls within a locus for susceptibility to dyslexia (DYX3; 604254) on chromosome 2p16-p15. The patient also had a 343-kb duplication on 2q13 and an 80-kb duplication on 6p25.3.

Molecular Genetics

Funnell et al. (2015) concluded that increased HbF in patients with 2p16.1-p15 deletion syndrome is due to haploinsufficiency of the BCL11A gene. Erythroblasts from these patients had significantly reduced BCL11A transcript levels. Funnell et al. (2015) noted that the patient reported by Prontera et al. (2011) had a 3.5-Mb deletion that was downstream of the BCL11A gene; however, BCL11A expression was significantly decreased in patient cells, suggesting that there are downstream regulatory elements within the deleted region that are required for full gene expression.