Chromosomal anomaly with epilepsy as a major feature
-Rare neurologic disease
Multiple congenital anomalies/dysmorphic syndrome-intellectual deficit
-Rare developmental defect during embryogenesis
-Rare genetic disease
Partial deletion of the long arm of chromosome 15
-Rare developmental defect during embryogenesis
-Rare genetic disease
Rare intellectual deficit with developmental anomaly
-Rare neurologic disease
Rare neurologic disease with psychiatric involvement
-Rare neurologic disease
Heterozygous deletion of chromosome 15q13.3 is associated with a highly variable phenotype, even within families segregating the same deletion. Individuals with the deletion may have mild to moderate mental retardation or learning difficulties, or may have no cognitive ... Heterozygous deletion of chromosome 15q13.3 is associated with a highly variable phenotype, even within families segregating the same deletion. Individuals with the deletion may have mild to moderate mental retardation or learning difficulties, or may have no cognitive deficits. Some individuals have epilepsy. Various dysmorphic features have been described, but there is no consistent or recognizable phenotype (review by van Bon et al., 2009). Patients with homozygous deletions in this region have severe neurodevelopmental problems, with epileptic encephalopathy, hypotonia, and poor growth (Endris et al., 2010).
Sharp et al. (2008) reported a recurrent microdeletion syndrome characterized by mental retardation, epilepsy, and variable dysmorphism of the face and digits. They described 9 affected individuals, including 6 probands: 2 with de novo deletions, 2 who inherited ... Sharp et al. (2008) reported a recurrent microdeletion syndrome characterized by mental retardation, epilepsy, and variable dysmorphism of the face and digits. They described 9 affected individuals, including 6 probands: 2 with de novo deletions, 2 who inherited the deletion from an affected parent, and 2 with unknown inheritance. Features shared among 3 or more individuals included hypertelorism, upslanting palpebral fissures, prominent philtrum with full everted lips, short and/or curved fifth finger, and short fourth metacarpals. Skeletal and/or joint defects of the hand were observed in 7 of the 9 individuals. Seizures or abnormal electroencephalograms were reported in 7 of the 9 individuals. Sharp et al. (2008) recommended that testing for the 15q13.3 deletion syndrome should be considered in individuals with unexplained mental retardation, seizures, and mild dysmorphic features. Ben-Shacher et al. (2009) identified 20 individuals, including 14 children and 6 parents from 12 families, with microdeletions of chromosome 15q13.3. Clinical features were variable, but 12 of 14 children had developmental delay, mental retardation, or borderline IQ. At least 6 children had symptoms within the range of autism spectrum disorder (ASD; 209850). Nine children demonstrated abnormal behavior, including aggressiveness, repeated head banging, and/or attention deficit hyperactivity disorder. Only 1 child had seizures. The facial appearance was variable and ranged from near normal to moderately dysmorphic. Common facial features included hypertelorism, short philtrum, and everted and thick upper lip. Mild digital aberrations, including brachydactyly and clinodactyly, were observed in 5 patients. Family studies showed that the deletion was inherited in 7 of 8 families where determinable. Two fathers with the deletion had learning disability and bipolar disorder (see 125480), whereas the 4 other parents with the deletion had no neurologic or psychiatric abnormalities, indicating incomplete penetrance. The last family had no parental samples available, but affected sibs suggested familial inheritance. Of note, 6 of the 14 children had been adopted, suggesting that adoption may have been related to cognitive, psychiatric, or social difficulties in their biologic parents who may have carried the deletion. Ben-Shacher et al. (2009) noted the wide range and heterogeneity of phenotypic expression reported for this deletion. Miller et al. (2009) identified 5 unrelated patients with chromosome 15q13.2-q13.3 deletion involving breakpoints 4 and 5 (BP4-BP5) identified by array comparative genomic hybridization (CGH). All had subtle dysmorphic features, impaired language skills, and developmental delay. One patient had mental retardation, and 4 had below average to average intelligence, including 2 with significant learning disability. The patients often had oromotor dyspraxia with disarticulation. Some had mild motor delay. Most had a diagnosis of an autism spectrum disorder or autistic features, as well as difficulties with attention, hyperactivity, mood regulation, and impulsive behaviors. Two patients inherited the microdeletion from a mother with learning difficulties. The deletion sizes ranged from 1.50 to 1.93 Mb. Shinawi et al. (2009) identified the same 680-kb deletion of chromosome 15q13.3 in 10 individuals from 4 families. One family of European ancestry contained 6 affected individuals. The proband was an 8-year-old boy with obesity, severe mental retardation, and mild facial dysmorphism, including epicanthal folds, anteverted nares, and a thin upper lip. Although he did not have seizures, EEG was abnormal. The deletion was present in his mother, 2 sibs, maternal aunt, and maternal grandmother. The mother and her sister had a history of mental retardation and epilepsy, and his sibs had global developmental delay. In a second family, the proband was a 21-month-old girl with impaired growth and severe global developmental delay. Her mother, who also carried the deletion, was reported to have normal intelligence, but had a history of epilepsy since age 5. Another unrelated patient with the deletion had mild mental retardation, attention deficit hyperactivity disorder, and aggressive behavior without seizures, and yet another had global developmental delay, hypotonia, and failure to thrive. In all, 4 of 10 individuals with the 680-kb deletion had seizures or EEG abnormalities, and 9 of 10 showed developmental delay and/or mental retardation. Van Bon et al. (2009) reported 18 probands with heterozygous deletion of chromosome 15q13.1-q13.3. Sixteen of the patients who had a BP4-BP5 deletion were detected among a larger cohort of 6,624 persons referred for mental retardation and/or congenital defects, yielding a rate of 0.24%. One of the most severely affected individuals was a girl who had onset of seizures at age 1 month, showed delayed psychomotor development, and was severely mentally retarded with poor speech, apathetic behavior, and sleeping problems. She also had short stature and microcephaly. Dysmorphic features included asymmetric skull with bitemporal narrowing, bristly hair, synophrys, blepharophimosis, squint, bulbous nasal tip, and folded helices. Other features included tapering fingers, deep palmar creases, hypoplastic fourth and fifth toes, an external rotation of the feet, and multiple pigmented nevi. Brain MRI showed showed several abnormalities, such as an arachnoidal cyst, parenchymal hypoplasia, dislocation of cerebellar structures, and mild hypogenesis of the corpus callosum. Microarray analysis showed a deletion between BP4 and BP5, which was also present in the normal mother. At the other end of the phenotypic spectrum was a 9-year-old girl with normal cognitive development who presented at birth with tetralogy of Fallot and triphalangeal thumb. She had mild hypertelorism. Microarray analysis showed a BP4-BP5 deletion with uncertain inheritance. Overall, 16 of 18 probands had some degree of cognitive impairment varying from mild learning problems to all levels of mental retardation. Behavioral problems were frequent (59%), and comprised poor attention span, hyperactivity, and aggressive/impulsive behavior. Less common features were hypotonia (47%), prominent nasal tip (35%), short stature (24%), strabismus (18%), large ears (24%), cardiac defects (17%), fifth finger clinodactyly (24%), and pigmented nevi (18%). However, there were a total of 13 relatives who carried the same deletion as the proband, and all of these frequencies would be significantly lower if those individuals were included. Only 2 patients had a history of seizures. Two individuals had a different deletion of BP3-BP5, and 1 had a deletion of BP3-BP4. In the family of 1 proband with deletion of BP3-BP4, the deletion was also also present in an unaffected brother, father, and uncle, but not present in a mentally retarded brother, suggesting that it is not of clinical significance. Van Bon et al. (2009) concluded that BP4-BP5 deletion does not lead to a clinically recognizable syndrome, but that it likely plays a contributing role in the pathogenesis of conditions affecting the brain, including mental retardation. The variable phenotypic outcome of the deletion is likely to be determined in conjunction with other factors, such as a mechanism for overcoming primary embryologic defects. Pagnamenta et al. (2009) reported 3 male sibs with autism associated with an approximately 2.0-Mb deletion of chromosome 15q13.3 involving BP4-BP5 that was inherited from their unaffected mother. All 3 boys had a history of language delay, and IQ levels ranged from 72 to 96. None had seizures, and none had dysmorphic features, although 2 had an increased head circumference (greater than 97th percentile). Masurel-Paulet et al. (2010) found that 16 (0.35%) of 4,625 patients tested for developmental delay had a microdeletion of chromosome 15q13.3 including the CHRNA7 gene. Twelve patients and 13 relatives had the common deletion between BP4 and BP5 ranging in size from 1.5 to 1.8 Mb. The phenotype was variable, and characterized by mild or no dysmorphic features and mild to moderate mental retardation. Two patients had epilepsy, 6 had anxiety disorder, 3 had phobias, 4 had inhibition, 2 were hyperactive, 1 self-mutilated, and 1 had autistic features. None had schizophrenia. In 6 families, the deletion was inherited from an apparently normal parent, indicating incomplete penetrance; in 4 families, the carrier parent reported learning disabilities. One patient with a severe phenotype including epileptic encephalopathy with retinopathy, autistic features, and choreoathetosis was homozygous for a 1.5-Mb BP4-BP5 deletion. Both of his parents, who carried the deletion, had mild mental retardation. In addition, 3 patients and 2 relatives had a smaller 500-kb deletion. A review of reported cases in the literature indicated that male carriers of a 15q13 deletion are more likely to be symptomatic. Of 1,035 individuals carrying copy number variants associated with schizophrenia, Sahoo et al. (2011) identified 69 individuals with microdeletion at 15q13.3. Indications for study in these 69 individuals included developmental delay, autism, dysmorphic features, seizures, hypotonia, obsessive compulsive disorder, and congenital heart defect. The average age at diagnosis was 6.6 years with an age range of 0.1 to 19.7 years. Sahoo et al. (2011) concluded that these and other results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions. Hoppman-Chaney et al. (2013) identified 19 individuals, including 10 probands and 9 family members, with a heterozygous deletion of chromosome 15q13.3 including only the CHRNA7 gene and no neighboring genes, and 1 patient with a homozygous deletion of CHRNA7. The patients were ascertained from a database of over 15,000 individuals who underwent cytogenetic testing. Ten individuals were from 2 independent extended families, and the deletion segregated with the phenotype. Among 15 children with the deletion, 5 were under the age of 2 years and did not have obvious neurocognitive problems. The other children had variable developmental delay, cognitive disability, autistic features, and/or attention-deficit hyperactivity disorder. Five of 6 patients with available clinical information had dysmorphic features, such as upslanting palpebral fissures, dental malocclusion, hypertelorism, and macro- or microcephaly. Only 1 patient had seizures. One patient had a de novo deletion, and another with a more severe phenotype had a homozygous deletion. All 5 parents with the deletion had neurocognitive features of the disorder.
Hoppman-Chaney et al. (2013) identified 9 probands with heterozygous deletions of chromosome 15q13.3 including only the CHRNA7 gene (118511) and no neighboring genes, who had a variety of neurocognitive defects consistent with the larger chromosome 15q13.3 deletion syndrome. ... Hoppman-Chaney et al. (2013) identified 9 probands with heterozygous deletions of chromosome 15q13.3 including only the CHRNA7 gene (118511) and no neighboring genes, who had a variety of neurocognitive defects consistent with the larger chromosome 15q13.3 deletion syndrome. One of the patients with a more severe phenotype was homozygous for the deletion, and 1 additional patient carried a de novo deletion. The findings provided further evidence that deletion of the CHRNA7 gene is responsible for the clinical features of this syndrome.
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....
DiagnosisClinical 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).TestingCytogenetic 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 testingDuplication/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 View in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityChromosomal microarray (CMA)Copy number variants100% with appropriate BACs, oligonucleotides, or SNPsClinicalTargeted deletion analysis Deletion of 2.0-Mb common region 2100% with appropriate probesClinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Deletions identified by CMA can be confirmed by targeted deletion analysis using a variety of methods including FISH, MLPA, and quantitative PCR. Testing StrategyTo 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.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.
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]. ...
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.
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.)...
Differential DiagnosisThe 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.)
To establish the extent of disease in an individual diagnosed with a 15q13.3 microdeletion, the following evaluations are recommended:...
ManagementEvaluations 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 evaluationCognitive assessmentNeuropsychological and developmental evaluation by a clinical psychologist to help determine needs for subsequent treatmentEEG if epilepsy is suspectedTreatment of ManifestationsIdeally 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameNot applicable15q13.3Not applicableData 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) View in own window 612001CHROMOSOME 15q13.3 DELETION SYNDROMEMolecular 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.