Chromosome 15q11-Q13 Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome within the chromosome 15q11-q13 region (chr15:20.7-26.7 Mb, NCBI36). The 15q11-q13 region is also implicated in Angelman syndrome (AS; 105830) and Prader-Willi syndrome (PWS; 176270).

Description

The features of the chromosome 15q11-q13 duplication syndrome include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems (Bundey et al., 1994; Burnside et al., 2011).

See also chromosome 15q13.3 deletion syndrome (612001) and chromosome 15q11.2 deletion syndrome (615656).

For a discussion of genetic heterogeneity of autism, see 209850.

Clinical Features

Bundey et al. (1994) reported a boy with mental retardation, infantile autism, ataxia, and seizures, who had an extensive interstitial duplication of 15q11-q13, including the critical regions for PWS and AS on the maternally derived chromosome. Clayton-Smith et al. (1993) had earlier reported a patient with a less extensive duplication, which included the Angelman critical region, who had ataxia and moderate developmental delay, particularly of language, but neither epilepsy nor behavior problems.

Baker et al. (1994) reported 2 patients with an autistic disorder associated with duplication of chromosome 15q11-q13.

Flejter et al. (1996) reported 2 patients with mental retardation, seizures, autistic features, and mild hypotonia who both had supernumerary inv dup(15)(pter-q13::q13-pter) chromosomes. In both cases, the abnormal chromosome appeared to be derived from the mother.

In reviewing previous reports of individuals with autism and abnormalities of proximal 15q, Wolpert et al. (2000) suggested that there may be additional specific findings in these patients, including hypotonia, seizures, delayed motor milestones, and mental retardation.

Filipek et al. (2003) reported 2 autistic children who had a 15q11-q13 inverted duplication. Both had uneventful perinatal courses, normal electroencephalogram and MRI scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both children also had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting that candidate gene loci for autism within the critical region on chromosome 15 may affect pathways influencing mitochondrial function.

Thomas et al. (2003) reported 3 families with an interstitial duplication (15)(q11-q13), 2 of which demonstrated multigenerational maternal inheritance. Affected individuals had minor anomalies and developmental delay, and 4 of the 5 children examined either met criteria for a diagnosis of autism or were in the 'autistic range.'

Miller et al. (2009) identified 5 patients, including 2 sibs, with a chromosome 15q13.2-q13.3 microduplication identified by array comparative genomic hybridization (CGH). Four of 5 patients had diagnosis of autism; the fifth showed some repetitive behaviors and expressive language delay. Two other patients also had severe expressive language delay, but language testing results were not available on the remaining 2 patients. There was no consistent pattern of dysmorphology or seizures. Three patients, including the 2 sibs, inherited a duplication from an apparently unaffected mother. The duplications ranged in size from 0.50 to 1.98 Mb.

Orrico et al. (2009) reported a 33-year-old woman with profound mental retardation and hypotonia, poor motor skills, stereotyped movements, irregular breathing, absent language, and severe refractory seizures associated with a maternally derived microduplication of 15q11-q13. Although early growth and development were normal, at age 2.5 years she showed developmental regression, with progressive cognitive and behavioral decline. Learning and communication difficulties progressed to aphasia, poor motor coordination, reduction in social interaction, and repetitive stereotypic hand movements. She was diagnosed with pervasive developmental disorder, although a variant form of Rett syndrome (RTT; 312750) was suspected. Seizures included atypical absences, astatic, tonic, and complex partial seizures, sometimes evolving to status epilepticus. She often had periods of hyperventilation followed by apnea. At the age of 13 years, the patient could not longer speak, and motor and communication skills further declined. She had mild dysmorphic features including downslanting palpebral fissures, broad nasal bridge, epicanthal folds, short philtrum, and wide mouth with full lips. Brain MRI showed hypoplasia of the corpus callosum and moderate cortical atrophy. Array CGH detected a 4-Mb duplication of the 15q11.2-q13.1 region between BAC clones RP11-682C24 (22 Mb from the 15p telomere) and RP11-322N14 (25.9 Mb from the telomere); the duplication was in tandem. Orrico et al. (2009) postulated that her clinical deterioration, even as an adult, may have resulted from long-term epileptic encephalopathy due to intractable multiple intractable seizures that occurred on a daily basis her entire life.

Piard et al. (2010) reported a large 3-generation family in which 12 individuals had an interstitial duplication of chromosome 15q11-q13. There was a wide range of cognitive impairment, but no patient met the criteria for autism. Psychologic evaluations showed low IQ, deficits in attention, concentration, memory, visual spatial abilities, and adaptive skills, with considerable variation. Some patients had speech delay, and some had delayed motor development and deficits in fine motor skills. Several had psychiatric disturbances, such as depression, anxiety, emotional lability, and shyness. One patient had seizures, 1 had febrile seizures as an infant, and none had dysmorphic features. Ten individuals with maternal origin of the duplication demonstrated some variation of the phenotype, whereas the 2 females with paternal origin of the duplication had no demonstrable abnormalities. The minimal size of the duplication was 5.68 Mb and included more than 30 genes.

Among 17,000 subjects referred for microarray analysis, Burnside et al. (2011) found that 69 (0.41%) had deletions (615656) and 77 (0.45%) had duplications of BP1-BP2 on proximal 15q. Phenotypic information was available for 56 cases with deletions and 49 with duplications. Phenotypic features enriched in these individuals (occurring in approximately 20 to 60%) included autism, developmental delay, motor and language delays, and behavioral problems, consistent with a spectrum of neurologic impairment. Parental studies showed phenotypically normal carriers in many cases, complicating phenotypic association and/or causality. Secondary genomic alterations were detected in 22.6% of the cases. Burnside et al. (2011) concluded that copy number variation of BP1-BP2 is not sufficient to cause a phenotype, but may increase susceptibility to neurodevelopmental problems.

Cytogenetics

The duplication of chromosome 15q11-q13 identified by Bundey et al. (1994) in a boy with mental retardation, infantile autism, ataxia, and seizures occurred on the maternally derived chromosome. Analysis by FISH and conventional Southern blot analysis, as well as genotyping for (CA)n repeat markers by PCR amplification, demonstrated duplication of all markers from D15S11 to D15S24. Among the duplicated genes were GABRA5 (137142) and GABRB3 (137192), and the authors speculated that these duplications may have contributed to the phenotype.

Cook et al. (1997) reported a family in which 2 children with autism, 1 of whom had a milder form, had maternal inheritance of a 15q11-q13 duplication. Microsatellite and methylation analysis showed that the unaffected mother inherited the 15q11-q13 duplication from her father. A third unaffected child did not inherit the duplication. Cook et al. (1997) noted that the findings in this family emphasized the significance of parental origin for duplications of 15q11-q13; paternal inheritance led to a normal phenotype, whereas maternal inheritance led to autism or atypical autism. The authors suggested that the percentage of autistic patients who have large, cytologically detectable abnormalities in the critical 15q11-q13 region is likely to be small (less than 3% of cases in their clinic). Nonetheless, among those remaining autistic cases it is possible that a larger percentage have mutations of an autism susceptibility gene(s) within this region.

In 4 of 100 patients with autism, Schroer et al. (1998) identified abnormalities in proximal 15q: 1 patient had 4 copies of proximal 15q, 2 patients had 3 copies, and 1 patient had 1 copy. All of the chromosome 15 abnormalities were inherited from the mother.

Philippe et al. (1999) presented evidence suggesting a potential autism susceptibility region that overlapped with a 15q11-q13 region identified in previous candidate gene studies (Pericak-Vance et al., 1997). Wolpert et al. (2000) reported 3 unrelated autistic patients with isodicentric chromosomes that encompassed the proximal region of 15q11.2. All 3 abnormal chromosomes were of maternal origin.

Shao et al. (2003) used a novel statistical method, ordered subset analysis, to identify a homogeneous subset of families that contribute to overall linkage at chromosome 15. Data from 221 patients with autism were used as a covariate, yielding evidence for linkage to 15q11-q13 with an increase in the lod score from 1.45 to 4.71. The authors noted that the candidate region includes the gamma-aminobutyric acid receptor beta-3 gene (GABRB3; 137192).

To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of duplication at chromosome 15q11-q13 with autism, mental retardation, and schizophrenia (locus P = 1.54 x 10(-7)). They identified 58 CNVs in this region; 45 of these were disease-associated.

Van Bon et al. (2009) reported 4 probands with chromosome 15q13 duplication, including 3 with duplication involving breakpoints 4 and 5 (BP4-BP5) and 1 with duplication of BP3-BP5. One of the duplications was de novo, 1 was inherited from an unaffected father, and the inheritance of the remaining 2 could not be determined. All patients had mild to severe mental retardation, and other common features present in at least 2 of the 4 included autism, obesity, hypotonia, and recurrent ear infections. Both parents of 1 patient had psychiatric illness (depression/personality disorder and schizophrenia, respectively), but neither parent could be studied for the duplication. Van Bon et al. (2009) suggested that the duplication may contribute to mental retardation.

Of 1,035 individuals carrying copy number variants associated with schizophrenia, Sahoo et al. (2011) identified 63 individuals with microduplication at 15q11.2. Indications for study in these 63 individuals included developmental delay, dysmorphic features, autism, and seizures. Sahoo et al. (2011) concluded that these and other results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.

Girirajan et al. (2012) analyzed the genomes of 2,312 children known to carry a copy number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Among the affected children, 10.1% carried a second large copy number variant in addition to the primary genetic lesion. Girirajan et al. (2012) identified 7 genomic disorders, each defined by a specific copy number variant, in which the affected children were more likely to carry multiple copy number variants than were controls. These included the 16p12.1 deletion (136570), the 16p11.2 duplication (614671), and the 15q11.2 deletion. They found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy number variants and whether the variants are inherited or de novo. Children who carried 2 large copy number variants of unknown clinical significance were 8 times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11 x 10(-38)). Among affected children, inherited copy number variants tended to co-occur with a second-site large copy number variant (Spearman correlation coefficient, 0.66; P less than 0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P less than 0.001), and mothers were more likely than fathers to transmit second-site copy number variants to their offspring (P = 0.02). Girirajan et al. (2012) concluded that multiple, large copy number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy number variants are preferentially transmitted from maternal carriers.

Heterogeneity

In addition to the chromosome 15q11-q13 duplication, Bonati et al. (2005) presented evidence pointing to a more distal region of 15q having a role in autism. They reported the case of a male child with autistic disorder, postnatal overgrowth, and a minor brain malformation. Karyotyping and FISH analysis showed the presence of an extra copy of the distal portion of 15q (15q25.2-qter) transposed to 15p, leading to 15q25.2-qter pure trisomy. This karyotype-phenotype study further supported the evidence for a specific phenotype related to trisomy 15q25 or 15q26-qter and suggested that distal 15q may be implicated in specific behavioral phenotypes.

Molecular Genetics

Among 166 unrelated Japanese patients with autism and 412 controls, Tochigi et al. (2007) found no association with SNPs in 2 of the GABA receptor genes mapping to chromosome 15q11-q13: GABRA5 (137142) and GABRG3 (600233). However, there was evidence for association with SNP (rs3212337) near microsatellite 155CA-2 in the GABRB3 gene (137192) (p = 0.029 after Bonferroni correction) at 15q11.2-q12.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 15q11.2-q13 duplication was identified in 35 cases and no controls for a p value of 4.57 x 10(-8) and a frequency of 1 in 450 cases.

Mapping

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variants of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2, 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (192430, 608363). A microduplication at 15q11.2 was observed in 63 of 1,035 individuals; inheritance was unknown in 61 of the 63. Average age at diagnosis was 8.2 years. Sahoo et al. (2011) found the 15q11.2 microduplication in 83 of 13,670 cases for a frequency of 0.61%, and not at all among the 5,674 controls studied by Itsara et al. (2009) (p less than 0.0001). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.