Chromosome 15q11.2 Deletion Syndrome
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome involving chromosome 15q11.2. The deleted region spans approximately 300 to 500 kb between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi (PWS; 176270)/Angelman syndrome (AS; 105830) critical region. The deletion region between BP1 and BP2 contains 4 genes that are not imprinted: TUBGCP5 (608147), NIPA1 (608145), NIPA2 (608146), and CYFIP1 (606322).
DescriptionA heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011).
See also chromosome 15q11.2 duplication syndrome (608636).
Clinical FeaturesMurthy et al. (2007) reported a 3.5-year-old boy with mental retardation who was found to carry a heterozygous 253-kb deletion of chromosome 15q11.2 between BP1 and BP2. The patient was haploinsufficient for 4 genes: TUBGCP5, NIPA1, NIPA2, and CYFIP1. The parents were related as second cousins. The child had cleft palate, delayed motor development, delayed speech, and attention deficit-hyperactivity disorder. He also had hypotonia with brisk reflexes, wide-based gait, and happy appearance. He did not have seizures. The deletion was inherited from the patient's father, who had similar, but less severe, features. A half sister of the proband reportedly had severe mental retardation, cleft palate, and seizures.
Doornbos et al. (2009) reported 9 unrelated patients who were found to have a heterozygous 340-kb microdeletion between BP1 and BP2 on chromosome 15q11.2. These patients were identified from a larger cohort of 1,576 patients referred for microarray analysis because of mental retardation or multiple congenital anomalies. The 9 patients did not have Prader-Willi or Angelman syndrome. Eight had overlapping and variable features, including general, speech, or motor developmental delay, and abnormal behavior such as autism spectrum disorder, obsessive-compulsive disorder, attention deficit-hyperactivity disorder, and happy demeanor. Many patients had dyspraxia, and 2 had seizures. Dysmorphic features were present in some patients and included plagiocephaly, broad forehead, hypertelorism, dysmorphic ears, cleft palate, and slender fingers. One patient with the deletion had normal psychomotor development and was not dysmorphic; he was referred for a complex congenital heart defect. The deletion was not found in 350 healthy unrelated controls.
In a study focusing on recurrent microdeletions in idiopathic generalized epilepsy (EIG; 600669), de Kovel et al. (2010) identified 15q11.2 microdeletions in 12 (1%) of 1,234 EIG patients and in 6 (0.2%) of 3,022 controls (odds ratio of 4.9, p = 4.2 x 10(-4)). Analysis of the 4 cases in which parental DNA was available showed that 3 of the mutations were inherited from the mother and 1 from the father; 3 parents were unaffected, whereas 1 mother had a history of febrile seizures. There were also several affected family members who did not carry the deletion. Cosegregation of the microdeletion and the phenotype was not consistent in 3 large families. None of the deletion carriers were noted to have intellectual disabilities. De Kovel et al. (2010) suggested that the 15q11.2 microdeletions may contribute to epileptogenesis.
Burnside et al. (2011) identified heterozygous, approximately 500-kb deletions of BP1-BP2 in 69 (0.41%) of about 17,000 individuals referred for microarray analysis. Clinical information was available for 56 of these patients. Developmental delay and motor delay were found in 59% and 36% of all patients, respectively. Among those older than 1 year of age, 90% had speech delay. Most patients (67%) with the deletion had some sort of behavioral or neurologic problem, such as ataxia or dyspraxia, hypotonia, tantrums, obsessive-compulsive disorder, abnormal brain MRI or EEG, or sleep problems. Fourteen (25%) had seizures. Seventeen patients had additional secondary copy number alterations. Burnside et al. (2011) hypothesized that BP1-BP2 copy number changes may increase susceptibility to neuropsychiatric or neurodevelopmental disorders.
Von der Lippe et al. (2011) reported 7 patients from 6 families with the same 350-kb deletion of chromosome 15q11.2 reported by Doornbos et al. (2009) that included the TUBGCP5, NIPA1, NIPA2, and CYFIP1 genes. The deletion occurred between BP1 and BP2 in the PWS region. The patients ranged in age from 9 to 24 years, and all had some type of delayed psychomotor development, often with autistic features or other behavioral problems. Some patients had dysmorphic features, including small face, micrognathia, irregular teeth, strabismus, or bulbous nose. Six of the deletions were inherited from a parent, and 3 of the deletions were also identified in a grandparent. Some carrier parents showed learning difficulties, but carrier grandparents did not have significant problems.
From a sample of 101,655 genotyped individuals representing approximately one-third of the Icelandic population, Stefansson et al. (2014) recruited control carriers of neuropsychiatric copy number variants (CNVs), controls carrying other CNVs not known to be associated with schizophrenia or autism, controls without large CNVs, and schizophrenia patients. In 47 control subjects carrying the 15q11.2(BP1-BP2) deletion, there was significant association with lower general assessment of function (GAF) score (0.66 s.d., p = 9.9 x 10(-5)) and history of learning difficulties as evaluated by the adult reading history questionnaire (ARHQ) (0.70 s.d., p = 1.9 x 10(-4)) and the adult mathematical history questionnaire (AMHQ) (0.78 s.d., p = 2.3 x 10(-5)). The 15q11.2(BP1-BP2) deletion was associated with dyslexia with an odds ratio of 3.18 (p = 0.0017) and with dyscalculia (odds ratio 3.91, p = 0.00011). The associations with ARHQ and AMHQ scores were only slightly weakened when conditioned on IQ, with the association of AMHQ score remaining the most significant (0.70 s.d., 2.3 x 10(-4)). Stefansson et al. (2014) performed structural magnetic resonance imaging (MRI) in 15 control carriers of the 15q11.2(BP1-BP2) deletion, 55 carriers of the reciprocal duplication (608636), and 201 population controls. They found that the 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia. For both gray and white matter, 15q11.2(BP1-BP2) duplication carriers always showed reciprocal changes in exactly the same regions altered in deletion carriers, demonstrating allele dose-dependent effects of CNVs on the structure of the human brain.
InheritanceOf the BP1-BP2 deletions found in 9 unrelated patients, Doornbos et al. (2009) determined that 2 occurred de novo and were on the maternal chromosome, 3 were inherited from the mother, and 4 were inherited from the father. Only 1 of 7 parents who carried the deletion was affected, indicating incomplete penetrance.