Clinical characteristics.

Individuals with the 15q13.3 microdeletion are at increased risk for a wide range of clinical manifestations including intellectual disability, seizures, autism spectrum disorders, and schizophrenia; however, the microdeletion itself does not appear 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 this recurrent deletion, is usually mild but can be moderate to severe.

Diagnosis/testing.

The 15q13.3 microdeletion is defined as the presence of a common 2.0-Mb deletion at the approximate position of 30.5-32.5 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 single gene within the deletion has been associated with disease findings. Genomic testing methods that determine the copy number of sequences, such as chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays, can detect the 15q13.3 microdeletion in a proband.

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 spectrum disorders, 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 15% are de novo and approximately 85% are inherited. Offspring of an individual with this deletion 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 the 15q13.3 microdeletion.

Suggestive Findings

15q13.3 microdeletion should be considered in individuals with the following clinical findings:

• Intellectual disability
• Speech delay
• Seizures
• Autism
• Schizophrenia
• Behavioral problems (poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior)

Some affected individuals have combinations of these findings, such as intellectual disability and seizures.

Establishing the Diagnosis

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

For this GeneReview, the 15q13.3 microdeletion is defined as the presence of a recurrent 2.0-Mb deletion at the approximate position of 30.5-32.5 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 [hg38]).

Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 15q13.3 microdeletion (see Genetically Related Disorders).

Although several genes of interest (e.g., CHRNA) are within the 2.0-Mb deletion, no single gene has been associated with the disease findings (see Molecular Genetics for genes of interest in the deleted region).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH) or multiplex ligation dependent probe amplification (MLPA). Note: The 15q13.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

• Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the common deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q13.3 region.
  Note: (1) Most individuals with the 15q13.3 microdeletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected this deletion.
• Targeted deletion analysis. FISH analysis and MLPA may be used to test at-risk relatives of a proband known to have the 15q13.3 microdeletion.
  Note: (1) Targeted deletion testing by FISH or MLPA is not appropriate for an individual in whom the microdeletion was not detected by CMA designed to target 15q13.3. (2) It is not possible to size the microdeletion routinely by use of FISH or MLPA.

Evaluating at-risk relatives. FISH can be used to identify 15q13.3 microdeletion in at-risk relatives of the proband. Testing of parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

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 microdeletion in persons with intellectual disability (0.3%), but also in individuals with seizures (1%-2%), schizophrenia (0.2%), and autism spectrum disorders (0.2%). In addition, the microdeletion 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].

Data on 23,838 adult controls detected no 15q13.3 microdeletions [Lowther et al 2015]. However, another study reporting on a population-based sample (n=101,655) identified 25 such microdeletions (0.025%) [Stefansson et al 2014].

Intellectual disability and developmental delay. Accounting for ascertainment, intellectual or developmental disability has been observed in 58% of the individuals with the 15q13.3 microdeletion [Lowther et al 2015]. 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 has been reported [Ben-Shachar et al 2009, van Bon et al 2009, Lowther et al 2015].

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. Accounting for ascertainment, epilepsy/seizures are present in 28% of individuals [Lowther et al 2015].

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. 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 (35%) and mainly include poor attention span, hyperactivity, mood disorder, self-mutilation and aggressive and/or impulsive behavior. Accounting for ascertainment, ADHD is present in 6.5% of individuals [Lowther et al 2015].

In three studies, the 15q13.3 microdeletion was found to be enriched in cohorts of individuals with schizophrenia compared to controls [International Schizophrenia Consortium 2008, Stefansson et al 2008, Lowther et al 2015]. Accounting for ascertainment bias, schizophrenia could be diagnosed in 11% of individuals and mood disorder in 10% of individuals [Lowther et al 2015].

Autism spectrum disorder has been reported in 11% of persons with the 15q13.3 microdeletion and can be present in both intellectually disabled and non-disabled individuals [Lowther et al 2015]. Non-disabled individuals with the 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 specific pattern of dysmorphic features.

Although cardiac defects were previously reported in a subset of individuals with the microdeletion [Sharp et al 2008, van Bon et al 2009, Masurel-Paulet et al 2010], a recent systematic review including all currently reported cases (n=246), emphasized the low penetrance (2.4%) for structural cardiac defects. No other frequently occurring congenital anomalies have been reported.

Genotype-Phenotype Correlations

No phenotype-genotype correlations are known as the phenotypic findings in individuals with the 15q13.3 microdeletion ranges from normal to significantly impaired.

Penetrance

The penetrance of the 15q13.3 microdeletion is highly variable.

In total, 80.5% of individuals with the microdeletion have at least one of the following neurodevelopmental or neuropsychiatric diagnoses: intellectual disability/developmental delay, speech problems, epilepsy, autism spectrum disorder, schizophrenia, mood disorder, and ADHD [Lowther et al 2015].

Nomenclature

Owing to the lack of a recognizable phenotype in persons with the 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 microdeletion specifically refers to deletion of the 2.0-Mb region at the approximate position of 30.5-32.5 Mb in the reference genome (NCBI Build [hg38]).

Prevalence

Estimates of prevalence depend on the subset of individuals tested.

In control cohorts, the 15q13.3 microdeletion has been found in 0.02% of individuals.

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.

Evaluations Following Initial Diagnosis

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

• General clinical examination
• Cognitive assessment including speech assessment
• Neuropsychological and developmental evaluation by a clinical psychologist to help determine needs for subsequent treatment
• EEG and neurologic examination if epilepsy is suspected
• Cardiac ultrasound evaluation
• Consultation with a clinical geneticist and/or genetic counselor

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 spectrum disorders, 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 neurocognitive development and developmental milestones are recommended during childhood for all children who have the 15q13.3 microdeletion, with referral to early intervention programs if required.

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

Agents/Circumstances to Avoid

About 10% of the individuals with the 15q13.3 microdeletion develop schizophrenia. The use of cannabis has been reported as a risk factor for development of schizophrenia. Although no studies have been performed on the possible additional risk of the use of cannabis by persons with the 15q13.3 microdeletion, discouraging the use of cannabis may be considered.

Evaluation of Relatives at Risk

Using genomic testing that will detect the 15q13.3 microdeletion found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

The 15q13.3 microdeletion is inherited in an autosomal dominant manner; approximately 15% of deletions occur de novo and 85% are inherited from a parent.

Risk to Family Members

Parents of a proband

• Evaluation of the parents by genomic testing that will detect the 15q13.3 microdeletion present in the proband is recommended.
• Although not described to date, one of the parents of a proband could have somatic mosaicism (which also includes the germline) for the 15q13.3 microdeletion.

Sibs of a proband

• The risk to sibs of a proband depends on the genetic status of the parents.
• If the 15q13.3 microdeletion identified in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the microdeletion.
• If one of the parents has the 15q13.3 microdeletion, the risk to each sib of inheriting the microdeletion is 50%. However, it is not possible to reliably predict the phenotype of the individual.

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

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 microdeletion.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, gene variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Pregnancies known to be at increased risk for the 15q13.3 microdeletion. Prenatal testing using genomic testing that will detect the 15q13.3 microdeletion found in the proband may be offered when:

• A parent has the microdeletion.
• The parents do not have the microdeletion but have had a child with microdeletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably less than 1%.

Pregnancies not known to be at increased risk for the 15q13.3 microdeletion. CMA performed in a pregnancy not known to be at increased risk may detect the microdeletion.

Note: Phenotype cannot be reliably predicted on the basis of a prenatal test finding of the 15q13.3 microdeletion (see Penetrance).

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the microdeletion has been identified.

Molecular Genetic Pathogenesis

Deletion mechanism. 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 is therefore susceptible to several genomic rearrangements leading to partial aneuploidy. The breakpoints (BPs) of such rearrangements cluster in the low copy repeats. To date, six BPs have been characterized in the 15q11q14 region [Mignon-Ravix et al 2007]. The recurrent 2.0-Mb 15q13.3 microdeletion occurs between the breakpoints designated as BP4 and BP5 [Sharp et al 2008].

The 2.0-Mb microdeletion arises when the flanking low copy repeats are positioned in a direct orientation, most probably through a common inversion of the BP4-BP5 region, which generates a configuration predisposing to non-allelic homologous recombination [Sharp et al 2008].

Genes of interest in this region. The 2.0-Mb microdeletion 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.

Smaller 15q13.3 deletions overlapping only CHRNA7 have been found in individuals with developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia (see Genetically Related Disorders), thus implicating CHRNA7 as the main candidate gene for the neuropsychiatric manifestations of the 15q13.3 microdeletion. CHRNA7 encodes a synaptic ion channel protein mediating neuronal signal transmission [Taske et al 2002, Hong et al 2004, Leonard & Freedman 2006, Iwata et al 2007]. No individuals with a pathogenic loss-of-function variant in CHRNA7 have been reported to date.

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Author Notes

15q13.3 Research Project

The aim of the 15q13.3 research project is to gain more understanding of the great variabilty in the clinical spectrum associated with this deletion.

Revision History

• 23 July 2015 (me) Comprehensive update posted live
• 23 December 2010 (me) Review posted live
• 18 May 2010 (bwmvb) Original submission