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.
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].
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.