Date of Award


Document Type

Thesis - Open Access

Degree Name

MS Human Genetics


Human Genetics Graduate Program


Advanced genetic testing has enabled detection of copy number variations (CNVs) which were previously undetectable. The 15q11.2 microdeletion is an example of this sort of CNV. Chromosome 15q11 to q13 is known to be a highly unstable region and therefore associated with high frequency of mutation (Murthy et al, 2007). Specifically, the presence of repeat sequences in low copy numbers at some regions within 15q11 to q13 has created common break point regions including BP1, BP2, and BP3 (Murthy et al, 2007). 15q11.2 microdeletions encompass a lost copy from BP1 to BP2. The four genes in this region are NIPA1, NIPA2, CYFIP1, and TUBGCP5 (De wolf et al, 2013), and the deletion spans from 20,306,549bp to 20,777,695bp on chromosome 15, or approximately about 470 kb (Stefansson et al, 2008). Although 15q11.2 is next to the region associated with Prader-Willi syndrome and Angelman syndrome, it is not overlapping. These two conditions are related specifically to the region between BP2 and BP3. None of the four genes in 15q11.2 region are known to be imprinted, in contrast to some genes in adjacent bands. Deletions in 15q11.2 are known to increase the risk of neurodevelopmental disorders. Specifically, 15q11.2 deletions have been associated with conditions such as developmental delay, autism spectrum disorder, schizophrenia, epilepsy, dyslexia, and dyscalculia (Burnside et al, 2011; Cooper et al, 2011; De Kovel et al, 2010; De wolf et al, 2013; Doornbos et al, 2009; Murthy et al, 2007; Stefansson et al, 2008; Stefansson et al, 2014; Von der Lippe et al, 2010). However, like many other recently detected CNVs, 15q11.2 deletions lack phenotypic specificity. This deletion can manifest with different symptoms in different individuals. To further complicate the matter, 15q11.2 deletions, like many other newly detectable CNVs, are present in the population among those who do not present with any clinically significant symptoms (Stefansson et al, 2014). Therefore, having this deletion creates a susceptibility to some neurodevelopmental disorders, but it is not necessarily causal. Lack of any direct associated phenotype in some carriers of this deletion makes it difficult to predict outcomes. Therefore, it can leave clinicians, such as genetic counselors, challenged to interpret and communicate the meaning of these results to the patients and families (Burnside et al, 2011; Chaste et al, 2014; De wolf et al, 2013). There has been some speculation regarding the possible presence of intermediate phenotypes in 15q11.2 deletion carriers who are not affected (De Wolf et al, 2013, Stefansson et al, 2014). This hypothesis was examined in a paper published in 2014 by Stefansson et al. Stefansson looked for relationships between individuals harboring CNVs known to increase risk for neurodevelopmental disease and altered cognition. The selection of CNVs was based on a literature review to identify those known to be associated with schizophrenia or autism, including 15q11.2 deletions. Subjects were recruited from four groups: carriers of a CNV associated with a neuropsychiatric disorder, including 15q11.2 deletion carriers, carriers of other CNVs not associated with neuropsychiatric disorders, controls with no CNVs, and patients with schizophrenia. Subjects were all between 18 to 65 years old (Stefansson e al, 2014). Participants were tested for cognitive functions including attention, spatial working memory, logical memory, executive functioning, cognitive flexibility, language and speed processing, using standardized tests such as Mini International Neuropsychiatric Interview (M.I.N.I.)(Stefansson et al, 2014). According to Stefansson these cognitive functions are known to be affected in individuals with schizophrenia. In addition, subjects were tested for dyslexia and dyscalculia (Stefansson et al, 2014). In this study, Stefansson found that 15q11.2 deletion carriers’ performance on tests of cognitive function fell between those of general population and patients with schizophrenia. The discrepancy with the general population was greatest for dyslexia and dyscalculia (Stefansson et al, 2014). Stefansson deduced that the cognitive activity of carriers fell somewhere between the non-carriers and patients with schizophrenia, providing support for this hypothesis (Stefansson et al, 2014). In order to further study the effect of CNVs on a carrier’s brain, Stefansson, utilized magnetic resonance imaging (MRI). Carriers of a 15q11.2 deletion were found to have reduced grey matter volume in anterior cingulate cortex and left insula, reduced white matter volume in temporal lobe, and increased corpus callosum volume. Interestingly, the reduced grey matter observed in these carriers is similar to that found in individuals with dyslexia and dyscalculia. Stefansson concluded that perhaps 15q11.2 events are associated with specific aspects of cognition and brain structure (Stefansson et al, 2014). Prior to Stefansson’s work, Murthy et al, in 2007, published the first case report on a three and a half year old boy with a 253 Kb deletion in 15q11.2, between bp1 and bp2. Prior to this report, other reported cases of 15q11.2 deletions were larger and not limited to the region between bp1 and bp2 (Butler 2004, and Milner 2005). Those cases had deletions that included the region between BP2 and BP3, and hence usually a diagnosis of Prader-Willi syndrome or Angelman syndrome. Murthy reported on a patient with mental retardation, developmental delay and speech problems. The deletion was found to be paternally inherited. The child’s father had similar but milder symptoms (Murthy et al, 2007). However, Murthy did not speculate any reason for the milder presentation in the father. Doornbos et al, published the second case report, reporting on 9 cases in 2009. Probands all harbored 15q11.2 deletions and manifested developmental delay, mental retardation, dysmorphic facial features and behavioral problems. Behavioral problems encompassed autism, attention deficit hyperactivity disorder (ADHD), and obsessivecompulsive disorder (OCD). A control population of 350 was screened, and no deletion carriers were found. This group concluded that there might be a correlation between 15q11.2 deletions and developmental delay and mental retardation. In this study, 7 of the 9 reported patients were noted to have inherited the deletion from an unaffected or a mildly affected parent (Doornbos et al, 2009). Again, no rationale for the milder presentation of these individuals was offered. In 2010, Von der Lippe et al, reported on 7 patients with the same symptoms as those described by Doornbos patients, except facial dysmorphism. This study provided additional support for the association of developmental delay, mental retardation and behavioral problems with 15q11.2 deletions (Von der Lippe et al, 2010). The first large study of 15q11.2 deletions was done in 2008, a year after the first case report. Investigators were interested to know whether there was an association between schizophrenia and three recently discovered common deletions, including 15q11.2. They screened a population of 4,718 patients with schizophrenia for the three deletions, and compared it to the prevalence of the deletion in a control population of 41,194. With regards to 15q11.2 deletions, 26 of 4,718 (0.55%) patients with schizophrenia and psychosis were carriers while only 79 of 41,194 (0.19%) controls had the deletion (Stefansson et al, 2008). This group concluded that indeed there was an association between schizophrenia and 15q11.2 deletions. In 2012, Van Den Bossche et al, confirmed this association by screening a different population of patients with schizophrenia as well as patients with bipolar disorder, major depressive disorder, and intellectual disability, for deletions in 15q11.2. 15q11.2 deletions were found to be associated with increased susceptibility to both schizophrenia and intellectual disability. This group speculated that CNVs in this region could cause disturbances in brain development, which consequently can increase predisposition to different neuropsychiatric conditions (Van Den Bossche et al, 2012). In 2010, De Kovel et al looked at the association of five commonly reported deletions, including 15q11.2 deletions, with epilepsy. This study looked at the prevalence of these deletions in a patient population with common idiopathic generalized epilepsy syndrome, and 12 of 1234 (1%) patients and 6 of 3022 (0.2%) controls were found to have 15q112 microdeletions (Kovel et al, 2010). Therefore, this group concluded a susceptibility to epilepsy did exist for carriers of this deletion. All these cases were inherited from a non-affected parent, and again no explanation for this finding was offered. In 2011, Cooper et al, screened a large sample of 15,767 children with intellectual disability and developmental delay for the presence of 15q11.2 deletion, and compared it to 8329 unaffected adults patients. This group found the 15q11.2 deletion in one out of every 167 affected patients with intellectual disability and developmental delay, providing support for the association of 15q11.2 deletion with intellectual disability and developmental delay (Cooper et al, 2011). Additionally, Burnside et al, in the same year, screened a total of 3,992 patients. Patients were affected with autism, developmental delay, motor and language delays, and behavioral problems. A total of 0.86% of the 3,992 were found to carry either duplication or a deletion (0.41% deletion) in the 15q11.2 region. However, only 0.38% of 6,329 controls were found to carry a mutation in 15q11.2 (Burnside et al, 2011). Most of the mutations in Burnside study were inherited from unaffected parents. Possible explanations for these results included “reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances” (Burnside, 2011). The current study assessed the cognitive phenotypes of 15q11.2 deletion carriers. As demonstrated above, unaffected parents harboring a 15q11.2 deletion were observed in most of the studies. Finding a possible intermediate or associated phenotype in the 15q11.2 deletion carriers would not only provide important insight into this deletion’s neurobiology, but also aid clinicians to interpret the outcome of such deletions for patients with increased certainty.