síndrome de duplicación cromos

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#608636

CHROMOSOME 15q11-q13 DUPLICATION SYNDROME

Alternative titles; symbols

DUPLICATION 15q11-q13 SYNDROME

Other entities represented in this entry:

AUTISM, SUSCEPTIBILITY TO, 4, INCLUDED; AUTS4,

INCLUDED

Gene Phenotype Relationships

Phenotypic Series

Clinical Synopsis

TEXT

A number sign (#) is used with this entry because a phenotype that includes features of

autism, mental retardation, ataxia, and seizures is caused by duplication of one or more

genes within the chromosome 15q11-q13 region. The 15q11-q13 region is also

implicated in Angelman syndrome (AS; 105830) and Prader-Willi syndrome (176270).

For a phenotypic description and a discussion of genetic heterogeneity of autism, see

209850.

See also chromosome 15q13.3 deletion syndrome (612001).

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

Location Phenotype PhenotypeMIM number

15q11 {Autism susceptibility 4} 608636

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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 withduplication 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 ofproximal 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. Theduplications ranged in size from 0.50 to 1.98 Mb.





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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 includingdownslanting 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.

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





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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 amilder 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 than3% 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 publisheddata from affected individuals in 9 genomewide studies of schizophrenia, autism, and

mental retardation. They found evidence to support the association of duplication at





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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 mentalretardation.

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 puretrisomy. 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.

REFERENCES

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2. Bonati, M. T., Finelli, P., Giardino, D., Gottardi, G., Roberts, W., Larizza, L.





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chromosome 15 in autistic disorder (AUT). (Abstract) Am. J. Hum. Genet. 61

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Contributors: Cassandra L. Kniffin - updated : 1/10/2011

Creation Date: Cassandra L. Kniffin : 5/4/2004

Edit History: wwang : 01/28/2011



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