Microdeletion Syndrome on Chromosome 15q13.3

15q13.3 Microdeletion

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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.

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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 aproband 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 theproband 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 Method	Mutations Detected	Mutation Detection Frequency by Test Method 1
Chromosomal microarray (CMA)	Copy number variants	100% with appropriate BACs, oligonucleotides, or SNPs
Targeted deletion analysis	Deletion of 2.0-Mb common region 2	100% 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 thedeletion 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.

Genetically Related (Allelic) Disorders

15q13.3 microduplication. Only eight individuals with the reciprocal duplication in the 15q13.3 region have been reported [van Bon et al 2009, Szafranski et al 2010]; therefore, the clinical significance of the microduplication is still uncertain. Phenotypic features of reported individuals include intellectual disability, behavioral problems, autism, hypotonia, obesity, and recurrent ear infections. No distinctive features, structural brain anomalies, or epileptic seizures were noted. The duplication can occur de novo but can also be inherited from an apparently unaffected parent.

Note: (1) 15q13.3 recurrent duplications are detectable by the same methods that detect the 15q13.3 deletion (see Molecular Genetic Testing). (2) Routine metaphase FISH analysis cannot detect duplication of the 2.0-Mb common region of 15q13.3 because duplications (or greater intensity of the signal) cannot be recognized. Thus, a normal metaphase FISH study does not exclude 15q13.3 duplication. Interphase FISH can detect the duplication.

15q13.3 microdeletions that overlap the 2.0-Mb common region. A few individuals with large overlapping deletions (~4 Mb) have been reported [Sharp et al 2008, van Bon et al 2009]. Although the number of individuals reported with these larger deletions is relatively small, their phenotype does not seem to differ clinically from persons with the 15q13.3 microdeletion resulting from the common 2.0-Mb deletion.

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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 theproband 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.

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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.)

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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.

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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 a="" aria-expanded="false" aria-haspopup="true" because="" but="" class="def" general="" greater="" have="" href="http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline-mosaicism/" may="" nbsp="" of="" parent="" population="" role="button" style="color: #642a8f; cursor: help;" than="" that="" the="">germline mosaicism

 or low-levelsomatic 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.

And here's the link. 

Aria's Deletion

As many of yo already know, our sweet little Aria has Microdeletion Syndrome. What this means is that her 15th chromosome is missing some genetic material. Try not to focus on that word syndrome, syndrome sounds very scary and life threatening. All syndrome means is that medical professionals have grouped a number of symptoms and have lumped them into the same condition. This particular syndrome has the potential to be life threatening or it's even possible that Aria is just missing some DNA and it won't effect her one bit. We just don't know and that's why we're meeting with all of these specialists. This little sweet girl is the world to us and we're going to do anything and everything it takes to figure out this little body of hers.

So here's a run down of all the specialists she has and will be meeting with:

Neurologist: Met with the neurologist last week and Aria cognitively is doing so great! She is just so smart. I had no doubt about it. I can just look at her sweet face and I know that she is all there and I know that she is so bright. She is such a little copy cat. She can just watch someone do something just once and pick it up just like that and do it herself. She also is getting so great with her words, I'm not sure she knows what they mean, but she can just repeat so many things. She's learning 5 new words each week. The neurologist says that Aria is although really struggling with muscle tension and he really wants to see some major improvements. If there aren't any improvements in the next 4 weeks we'll have to take her in for an EEG. This has been the scariest aspect for me because to be able to do this they would have to put Aria to sleep. This was all before her blood tests results came back with the Microdeletion Syndrome. A symptom of this syndrome could be seizures and because of this they'll definitely have to do the EEG. We'll go back in a few weeks for that and to follow up with blood tests that they did about a week and a half ago.

Early Intervention Specialist: Met with these lovely ladies this week. With Aria's blood test results, medically she qualified by those results alone. Based on her development and age she qualified as well. We're just happy that she will be getting the help that she needs. We've got a very positive outlook that she'll be able to catch up and hopefully have that normal life that every parent hopes for their children. I know that no matter what happens, Aria will always be "normal" to us. She already is. Everything that she has gone through so far we've adapted to and it's just another piece of her that makes her wonderful and unique.

Audiologist: We haven't met with the audiologist yet, that will be next week. I don't really think that we have anything to worry about when it comes to Aria's hearing, but I would rather be safe than sorry. That has been my philosophy through this whole ordeal. I really didn't think anything was wrong with Aria at all, but decided to go through with all of these blood tests for peace of mind in knowing. And I can say that I am glad we did, and although I don't think anything is wrong with her hearing, you just never know.

Geneticist: We'll meet with the geneticist and the genetics counselor on April 4th. They'll draw more blood from Aria and quite possibly from Chris and I as well. There is a 75% chance that one of us past this down to her with out even knowing about it ourselves. She also has a 50% chance of passing it down to her children. Hopefully we can find out more about what this deletion is going to mean for Aria and life soon.

Cardiologist: I took Aria to see the cardiologist this morning and I was so nervous, but it went great!! Aria has a perfect healthy heart. Sure she has a hole in her heart, but they say that's normal. A hole in the heart can be a precursor to genetic issues, but majority of the time these holes close on their own  by the time the child is 2 years old.

What is all of this going to mean for Aria? Well, like I said before, it could just mean that she's missing some genes and she'll be perfectly fine with out them. That's the hope, but with all of the issues Aria has had in her life so far and new tests results from today, that's highly unlikely. All of Aria's weight gain issues and developmental delays can be traced back to this deletion. Some other symptoms of this deletion are autism, anger, rage, aggression, schizophrenia, heart defects, facial abnormalities, behavior issues, developmental delays, intellectual delays, epilepsy, and ADHD. I'm sure there are some others not listed. This syndrome effects about 1 in ever 40,000 people. I think I read somewhere that the first documented case was in 2008 and there have only been about 150 documented cases since then, so this is still pretty rare. I'm almost positive that there are quite a few that are just undocumented.

We have such a positive outlook for our sweet Aria. Everyone that I've spoken to, I've had to remind, this is our little girl and she is just fine. She is no different today with these results than she was 2 weeks ago. She is so great and has been making some great improvements these last couple of weeks. If we could only get her walking, and I'm sure that will come with time, along with everything else.