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15q13.3 Microdeletion

, MD, PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD, PhD
Department of Human Genetics
Radboud University Nijmegen Medical Centre
Nijmegen, The Netherlands
, MD, PhD
Department of Pediatrics
Division of Genetic Medicine
University of Washington
Seattle, Washington
, MD, PhD
Department of Human Genetics
Radboud University Nijmegen Medical Centre
Nijmegen, The Netherlands

Initial Posting: .

Summary

Disease characteristics. Individuals with 15q13.3 microdeletion are at increased risk for a wide range of clinical manifestations including intellectual disability, cardiac malformations, seizures, autism, and schizophrenia; however, the deletion itself does not seem to lead to a clinically recognizable syndrome and a subset of persons with the deletion have no obvious clinical findings. Behavioral problems are common and mainly comprise poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior. Intellectual disability, observed in about half of the individuals with the common deletion at 15q13.3, is usually mild but can be moderate to severe.

Diagnosis/testing. 15q13.3 microdeletion is defined as the presence of a common 2.0-Mb deletion at the approximate position of 28.5-30.5 Mb in the reference genome, which includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications. No causative gene(s) have been identified within the common deletion. The microdeletion can be detected by any molecular method that determines the copy number of genomic sequences within the deleted region, including whole-genome analysis (e.g., chromosomal microarray [CMA], targeted approaches (e.g., fluorescence in situ hybridization [FISH], or multiplex ligation-dependent probe amplification [MLPA]).

Management. Treatment of manifestations: Ideally treatment is tailored to the specific needs of the individual. It is suggested that treatment for neurodevelopmental disability be based on a neuropsychological and/or developmental assessment by a clinical psychologist. Medical treatment for cardiac defects, epilepsy, autism, and schizophrenia should follow standard practice for these disorders, considering the age of the individual and the specific manifestations.

Surveillance: Close assessment/monitoring of developmental milestones is recommended during childhood, with referral to early intervention programs if required.

Genetic counseling. The 15q13.3 microdeletion is a contiguous gene deletion inherited in an autosomal dominant manner. Approximately 25% of 15q13.3 microdeletions occur de novo; approximately 75% are inherited. Offspring of an individual with the 15q13.3 microdeletion have a 50% chance of inheriting the deletion. Although prenatal testing is technically feasible, it is not possible to reliably predict the phenotype based on the laboratory finding of 15q13.3 microdeletion.

Diagnosis

Clinical Diagnosis

Individuals with the 15q13.3 microdeletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the deletion have no obvious clinical findings.

Individuals with 15q13.3 microdeletion are at increased risk for intellectual disability, cardiac malformations, seizures, autism, or schizophrenia. Some affected individuals have combinations of these findings, such as intellectual disability and seizures. Behavioral problems occur regularly and mainly comprise poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior.

The deletion is also present in a subset of unaffected individuals, implying that there is incomplete penetrance associated with the deletion.

Note: For this GeneReview, the 15q13.3 deletion is defined as the presence of a common 2.0-Mb deletion at the approximate position of 28.5-30.5 Mb in the reference genome, which includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications (NCBI Build [hg18]). A few individuals have deletions of chromosome 15q13.3 that are somewhat larger or smaller than the common 2.0-Mb deletion (see Genetically Related Disorders).

Testing

Cytogenetic testing. The 15q13.3 microdeletion is not detectable by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Molecular Genetic Testing

The diagnosis of 15q13.3 microdeletion is confirmed by detection of the 2.0-Mb heterozygous deletion at chromosome 15q13.3.

Several candidate genes (e.g., CHRNA) map to the 2.0-Mb common region, but no single gene in which mutation is causative has been identified in the region.

Clinical testing

  • Duplication/deletion analysis is testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA. The 2.0-Mb common region at 15q13.3 can be detected by any molecular method that determines the copy number of genomic sequences within the deleted region. Either whole-genome or targeted approaches can be applied (see Molecular Genetics for details of the deleted region):
    • Chromosomal microarray (CMA) analysis is the most appropriate test to identify the 15q13.3 deletion in a proband because the phenotype is nonspecific and genomic CMA can detect many chromosomal abnormalities that may be causal. CMA analysis using arrays of BACs, oligonucleotides, or SNPs can detect the 2.0-Mb deletion in a proband. The ability to determine that the deletion involves the 2.0-Mb critical region depends on both the type of microarray used and the density of probes in the 15q13 region. Depending on the resolution, some arrays used before 2008 may not have been effective in detecting this deletion.
    • Targeted deletion analysis. Targeted methods including fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) are useful for confirming the deletion after CMA analysis in the proband or for evaluating relatives of the proband for the presence of the deletion. Note: Targeted methods are not often used as the initial test method to find the deletion in the proband because the 15q13.3 microdeletion is not likely to be suspected based on clinical features alone.

      Whether or not it is possible to confirm the 2.0 Mb size of the deletion depends on the number and distribution of probes tested in the 15q13.3 region. The size of a deletion cannot be determined with a single FISH or MLPA probe.

Table 1. Summary of Molecular Genetic Testing Used in 15q13.3 Microdeletion

Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
Chromosomal microarray (CMA)Copy number variants100% with appropriate BACs, oligonucleotides, or SNPs
Targeted deletion analysis Deletion of 2.0-Mb common region 2100% with appropriate probes

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Deletions identified by CMA can be confirmed by targeted deletion analysis using a variety of methods including FISH, MLPA, and quantitative PCR.

Testing Strategy

To confirm/establish the diagnosis in a proband requires detection of the15q13.3 microdeletion.

Evaluating at-risk relatives. Microarray, MLPA, FISH, or qPCR can be used to identify the 15q13.3 microdeletion in relatives of the proband, particularly in parents who may be phenotypically normal.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion in the proband. Whether prenatal diagnosis or PGD for the 15q13.3 microdeletion is warranted is uncertain given the wide clinical variability and difficulty in predicting the phenotype accurately.

Clinical Description

Natural History

The 15q13.3 microdeletion was first reported in nine individuals with intellectual disability [Sharp et al 2008]. Later studies reported not only a higher prevalence of this deletion in persons with intellectual disability (0.3%), but also in individuals with seizures (1%-2%), schizophrenia (0.2%) and autism (0.2%). In addition, the deletion has occasionally been found in healthy controls (0.02%) and frequently in healthy relatives of affected individuals [International Schizophrenia Consortium 2008, Sharp et al 2008, Stefansson et al 2008, Ben-Shachar et al 2009, Dibbens et al 2009, Helbig et al 2009, Miller et al 2009, van Bon et al 2009, de Kovel et al 2010, Masurel-Paulet et al 2010].

Intellectual disability and developmental delay. Intellectual disability has been observed in about half of the individuals with the 2.0-Mb common deletion at 15q13.3. This may represent an overestimate, reflecting a selection bias. Developmental delays are mainly delays in speech acquisition and cognitive function rather than motor disability. In the majority of individuals, cognitive impairment is mild. However, a subset of individuals with moderate to severe disability have been reported [Ben-Shachar et al 2009, van Bon et al 2009].

Epilepsy. The 15q13.3 microdeletion has been shown to represent a major risk factor for epilepsy, found in 1%-2% of individuals with generalized epilepsy. Epilepsy has been described in almost one third of individuals reported to have the 15q13.3 microdeletion.

However, this percentage may be an overestimate resulting from ascertainment bias because the percentage of individuals with epilepsy derived from different cohorts (e.g., intellectual disability, schizophrenia, or autism) is relatively low. The types of epilepsy include juvenile myoclonic epilepsy, childhood absence epilepsy, and juvenile absence epilepsy [Dibbens et al 2009, Helbig et al 2009, de Kovel et al 2010, Mefford et al 2010]. Seizure types include typical absence seizures, myoclonic seizures, and primary generalized tonic-clonic seizures. The 15q13.3 microdeletion has not been found in individuals with a primary diagnosis of partial epilepsy [Heinzen et al 2010].

Neuropsychiatric disorders. Behavioral problems are relatively common and mainly include poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior.

In two studies, 15q13.3 microdeletions were found to be enriched in large cohorts of individuals with schizophrenia compared to controls [Stefansson et al 2008, International schizophrenia consortium 2008]. So far, schizophrenia has not been reported in any of the persons with the microdeletion originating from cohorts ascertained for intellectual disability, autism, or epilepsy or in family members who also have the microdeletion. Bipolar disorder with mild learning disability was diagnosed in the parents of two probands with intellectual disability [Ben-Shachar et al 2009].

Autism or autistic behavior has been reported in over 10% of persons with the 15q13.3 microdeletion and can be present in both intellectually disabled and non-disabled individuals. Non-disabled individuals with the 15q13.3 microdeletion with an autism spectrum disorder may show impaired expressive and written language, poor eye contact, repetitive movements, obsessive and hyperactive behavior, and disturbed social interactions [Miller et al 2009, Pagnamenta et al 2009].

Dysmorphisms and congenital anomalies. In general, individuals with the 15q13.3 microdeletion have no or only mild dysmorphic features. In three reports cardiac defects were noted in 7%-17% of individuals with the deletion [Sharp et al 2008, van Bon et al 2009, Masurel-Paulet et al 2010] whereas cardiac evaluation of persons with the deletion was not mentioned in other reports. Whether 15q13.3 deletions are associated with isolated cardiac defects is still uncertain.

Other frequently occurring congenital anomalies have not been reported.

Genotype-Phenotype Correlations

No phenotype-genotype correlations are known as the phenotypic findings in individuals with the recurrent 2.0-Mb deletion in the 15q13.3 region ranges from normal to significant impairment.

Penetrance

The penetrance of 15q13.3 microdeletions is highly variable. Because of ascertainment bias for intellectual disability, epilepsy, schizophrenia, and autism, the frequencies of several phenotypic features may be overestimated, particularly because family members who have the same deletion as the affected proband are in general only mildly affected or apparently unaffected [van Bon et al 2009].

Anticipation

To date, anticipation has not been observed. In cases of an inherited deletion, parental break points appear similar to those of the proband at the level of resolution of oligonucleotide aCGH.

Nomenclature

Owing to the lack of a recognizable phenotype in persons with a 15q13.3 microdeletion, it has not been described eponymously. Although the 15q13.3 region includes other segmental duplication break points [Makoff & Flomen 2007, Shinawi et al 2009], the 15q13.3 deletion specifically refers to deletion of the 2.0-Mb common region at the approximate position of 28.5-30.5 Mb in the reference genome (NCBI Build [hg18]).

Prevalence

Estimates of prevalence depend on the subset of individuals tested. In control cohorts, the recurrent 2.0-Mb microdeletion at 15q13.3 has been found in 0.02% of individuals. In addition, it has been found in approximately 0.3% of individuals with intellectual disability, 1%-2% of persons with epilepsy, approximately 0.2% of individuals with schizophrenia, and approximately 0.2% of persons with autism.

Differential Diagnosis

The differential diagnosis of 15q13.3 deletion comprises an extensive and broad spectrum of diseases. It includes any cause of developmental delay, schizophrenia, autism spectrum disorders, and epilepsy without additional distinguishing clinical features. (See Autism Spectrum Disorders.)

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a 15q13.3 microdeletion, the following evaluations are recommended:

  • General clinical examination
  • Cardiac ultrasound evaluation
  • Cognitive assessment
  • Neuropsychological and developmental evaluation by a clinical psychologist to help determine needs for subsequent treatment
  • EEG if epilepsy is suspected

Treatment of Manifestations

Ideally treatment is tailored to the specific needs of the individual. Because of the high incidence of neurodevelopmental disability, referral to a clinical psychologist for neuropsychological and/or developmental assessment for treatment recommendations is suggested.

Medical treatment for persons with cardiac defects, epilepsy, autism, and schizophrenia should follow standard practice for these disorders, considering the age of the patient and the specific manifestations.

Additional management in healthy adults who have the 15q13.3 microdeletion is not necessary, although their medical care providers may benefit from being alerted to the possible increased risk for late-onset manifestations (e.g., schizophrenia).

Surveillance

Close assessment/monitoring of developmental milestones is recommended during childhood for all children who have the 15q13.3 microdeletion, with referral to early intervention programs if required.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The 15q13.3 microdeletion is a contiguous gene deletion inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 25% of 15q13.3 microdeletions occur de novo.
  • Approximately 75% of 15q13.3 microdeletions have been inherited. A parent-of-origin bias has not been reported.
  • Evaluation of the parents by CMA analysis, MLPA, or FISH is recommended. Although it has not been described for 15q13.3 microdeletions as yet, parents of an affected proband could have somatic mosaicism.

Sibs of a proband. The risk to sibs of a proband depends on the deletion status of the parents.

  • If the parents of an individual with a 15q13.3 microdeletion have normal CMA, MLPA, or FISH studies, the risk to sibs is low (<1%) but greater than that of the general population because a parent may have germline mosaicism or low-level somatic mosaicism for the deletion.
  • If a parent has the 15q13.3 microdeletion, the risk to each sib is 50%.

Offspring of a proband. Offspring of an individual with the 15q13.3 microdeletion have a 50% chance of inheriting the deletion.

Other family members. The risk to other family members depends on the genetic status of the proband’s parents. If a parent has the 15q13.3 microdeletion, his or her family members may also have the deletion.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 microdeletion.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at about 15 to18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using interphase FISH, MLPA, or CMA, in the manner described in Molecular Genetic Testing.

However, it is not possible to reliably predict the phenotype from a laboratory finding of 15q13.3 microdeletion.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the diagnosis of 15q13.3 microdeletion has been established in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Chromosome Disorder Outreach (CDO)
    PO Box 724
    Boca Raton FL 33429-0724
    Phone: 561-395-4252 (Family Helpline)
    Email: info@chromodisorder.org
  • Unique: The Rare Chromosome Disorder Support Group
    PO Box 2189
    Caterham Surrey CR3 5GN
    United Kingdom
    Phone: +44 (0) 1883 330766
    Fax: +44 (0) 1883 330766
    Email: info@rarechromo.org; rarechromo@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. 15q13.3 Microdeletion: Genes and Databases

Gene SymbolChromosomal LocusProtein Name
Not applicable15q13​.3Not applicable

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for 15q13.3 Microdeletion (View All in OMIM)

612001CHROMOSOME 15q13.3 DELETION SYNDROME

Molecular Genetic Pathogenesis

The proximal 15q region is characterized by a high density of low copy repeats [Bailey et al 2002, Makoff & Flomen 2007, Sharp et al 2008] and therefore susceptible to several genomic rearrangements leading to partial aneuploidy. The breakpoints (BPs) of such rearrangements cluster in the low copy repeats. So far, six BPs have been characterized in the chromosome 15q11q14 region [Mignon-Ravix et al 2007]. The 2.0-Mb common region on chromosome 15q13.3 occurs between the breakpoints designated as BP4 and BP5 [Sharp et al 2008]. The 2.0-Mb deletions arise when the flanking low copy repeats are positioned in a direct orientation, most probably through an inversion polymorphism of the BP4-BP5 region, which generates a configuration predisposing to non-allelic homologous recombination (NAHR) [Sharp et al 2008].

The recurrent 2.0-Mb deletion results in the loss of six known genes: MTMR15, TRPM1, MTMR10, KLF13, OTUD7A, and CHRNA7. How deletion of these genes results in the clinical findings of the syndrome is unknown, but ongoing investigations may identify one or more genes as responsible for the phenotypic features. There are a few individuals who have a 680-kb deletion, comprising only CHRNA7 and OTUD7A, within the 2.0-Mb common 15q13.3 region [Shinawi et al 2009]. The neurobehavioral phenotype in these individuals is similar to that seen in persons with the 15q13.3 microdeletion resulting from the common 2.0-Mb deletion, suggesting that haploinsufficiency of CHRNA7 (or OTUD7A) is causative for the majority of neurodevelopmental phenotypes observed with the 15q13.3 microdeletion [Shinawi et al 2009].

CHRNA7 encodes a synaptic ion channel protein mediating neuronal signal transmission and has been suggested to be a possible candidate gene in the pathogenesis of epilepsy, schizophrenia, and bipolar disorder [Taske et al 2002, Hong et al 2004, Leonard & Freedman 2006, Iwata et al 2007]. So far, no persons with mutations in CHRNA7 have been reported.

KLF13 encodes a member of the Kruppel-like family of zinc-finger proteins and is a regulator of cardiac gene expression and heart morphogenesis [Lavallée et al 2006]. This gene may be implicated in cardiac disease noted in a small subset of persons with the 15q13.3 microdeletion.

References

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Chapter Notes

Revision History

  • 23 December 2010 (me) Review posted live
  • 18 May 2010 (bwmvb) Original submission
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