Adult expression of a 3q13.31 microdeletion
© Lowther et al.; licensee BioMed Central Ltd. 2014
Received: 30 December 2013
Accepted: 11 March 2014
Published: 20 March 2014
The emerging 3q13.31 microdeletion syndrome appears to encompass diverse neurodevelopmental conditions. However, the 3q13.31 deletion is rare and few adult cases have yet been reported. We examined a cohort with schizophrenia (n = 459) and adult control subjects (n = 26,826) using high-resolution microarray technology for deletions and duplications at the 3q13.31 locus.
We report on the extended adult phenotype associated with a 3q13.31 microdeletion in a 41-year-old male proband with schizophrenia and a nonverbal learning disability. He was noted to have a speech impairment, delayed motor skills, and other features consistent with the 3q13.31 microdeletion syndrome. The 2.06 Mb deletion overlapped two microRNAs and seven RefSeq genes, including GAP43, LSAMP, DRD3, and ZBTB20. No overlapping 3q13.31 deletions or duplications were identified in control subjects.
Later-onset conditions like schizophrenia are increasingly associated with rare copy number variations and associated genomic disorders like the 3q13.31 microdeletion syndrome. Detailed phenotype information across the lifespan facilitates genotype-phenotype correlations, accurate genetic counselling, and anticipatory care.
Keywords3q13 deletion Schizophrenia Copy number variation Genotype-phenotype correlation Genetic counselling Genomic disorder Nonverbal learning disability
Preliminary evidence suggests that individuals with microdeletions at chromosome 3q13.31 (OMIM #615433) may be predisposed to a broad spectrum of neurodevelopmental/neuropsychiatric conditions including global developmental delay/intellectual disability (DD/ID), speech delay, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) [1–5]. Inconsistent molecular and cytogenetic techniques as well as variable genomic breakpoints have made pinpointing the responsible gene(s) within the 3q13.31 region challenging. In a large case series, Molin et al. defined a 580 kb shortest region of overlap (SRO) that includes five RefSeq genes: DRD3, ZNF80, TIGIT, MIR568, and ZBTB20. Those authors proposed that haploinsufficiency of DRD3 (OMIM #126451), which codes for the D3 subunit of the dopamine receptor, and ZBTB20 (OMIM #606025), a DNA transcription repressor expressed in hippocampal neurons, may contribute to the neurodevelopmental features of the 3q13.31 microdeletion syndrome [1, 6]. Recently, a 1.3 Mb deletion at 3q13.31 downstream of this proposed SRO and encompassing just two genes (LSAMP, GAP43) was identified in a 7-year-old female with ADHD, hypotonia, and postnatal growth above the mean . LSAMP (OMIM #603241) encodes a limbic system-associated membrane protein (LAMP) and has been shown to regulate anxiety-like phenotypes in mice . GAP43 (OMIM #162060) is almost exclusively expressed in neuronal tissue and is a candidate gene for ASD .
Later-onset conditions, including neurodevelopmental diseases like schizophrenia, may also be associated with rare copy number variations (CNVs) . To date, few adult cases with 3q13.31 deletions have been described in the literature, highlighting the paucity of phenotypic data across the lifespan needed to inform genetic counselling and anticipatory care. Here we provide a description of the extended adult phenotype associated with a 3q13.31 microdeletion  that encompasses all four of the previously proposed neurodevelopmental candidate genes at this locus: DRD3, ZBTB20, LSAMP, and GAP43.
He was enrolled in a special education program beginning at age 7 years, with particular difficulties noted in mathematics and writing. At age 33 years, clinical neuropsychological testing revealed a full-scale IQ in the borderline range. Research-based testing at age 39 years using the WASI (Wechsler Abbreviated Scale of Intelligence) demonstrated a full-scale IQ of 75, with a marked difference between verbal (90) and performance (62) scores consistent with a nonverbal learning disability.
The patient developed schizophrenia and was first treated with standard antipsychotic medications at age 24 years. Overall, he has had an unremarkable course of illness (details available upon request); of note, aggressive behaviour at age 28 years prompted a change in his medication regimen. His past medical history also includes type 2 diabetes mellitus treated with insulin and hypercholesterolemia diagnosed in his 20′s, mild hypocalcemia first identified at age 31 years, bilateral L5-S1 disc protrusion requiring surgery at 34 years, and hypertension diagnosed at age 34 years. At time of last contact, he was 41 years old and living in a supported situation in the community.
3q13.31 deletion expression in adults
Clinical features of four adults with 3q13.31 deletions
Molin et al. Case 1
Molin et al. Case 8
Shuvarikov et al. Case 6
Borderline intellectual disability (VIQ 90, PIQ 62)
[Severe intellectual disability] (FSIQ < 50)
[Borderline intellectual disability] (VIQ 94, PIQ 61)
[Schizophrenia], aggressive behaviour
ADHD, some repetitive behaviours
Social and emotional immaturity
Delayed motor development, focal hypoplasia of the superior cerebellar vermis (15 y), enuresis
Cerebellar agenesis, EEG abnormalities, hypotonia, enuresis
Bilateral L5-S1 disc protrusion, slight kyphosis
Small testes (8 ml)
Broad neck, facial asymmetry, strabismus, narrow palpebral fissures, long philtrum, narrow high arched palate, flat occiput, frontal and occipital hair whorls (Figure 1)
Dolichocephaly, prominent broad forehead, strabismus, myopia, ptosis, antimongoloid slant, short philtrum, high arched palate, large ears, crowded teeth, soft enamel
Prominent/broad forehead, high arched palate, large fleshy ears, pointed chin
Absent eyebrows, epicanthal folds, down slanting palpebral fissures, ptosis, high palate, nystagmus, microstomia, small teeth, large palatine tori
Hands and feet
Cubitus valgus, bilateral short 4th and 5th metacarpals, narrow feet with mild bilateral clinodactyly and camptodactyly of toes
Small hands, long fingers
Pes cavus, middle finger clinodactyly bilaterally
Pregnancy and birth
Uneventful pregnancy, birth weight 3941 g (75th-90th percentile)
Birth weight 3430 g (50-85th percentile)
Placental calcifications, marginally small for dates
Insulin dependent Type 2 diabetes mellitus, hypercholesterolemia, hypocalcemia, hypertension
Large angioma in right shoulder, dorsocervical fat pad
Neuropsychiatric phenotypes (i.e., ADHD and ASD) have been previously associated with the 3q13.31 microdeletion; however, this is the first report of schizophrenia in an individual with a 3q13.31 microdeletion. Moreover, the patient described in this report had a >25 point discrepancy between his performance and verbal IQ scores, consistent with a nonverbal learning disability . Interestingly, the 42 year old female (Case 6) reported in Shuvarikov et al.  demonstrated a similar trend in IQ scores (Table 1). Raw IQ scores were not given for many of the paediatric cases, however Vuillaume et al.  described an affected 16 year old female (Case 1) as “being able to read and write but educational learning was difficult,” potentially describing a nonverbal learning disability. Detailed neuropsychological phenotyping of additional cases will help determine if nonverbal learning disabilities are part of the emerging 3q13.31 microdeletion syndrome.
Candidate genes for neuropsychiatric expression
The four genes (GAP43, DRD3, LSAMP, and ZBTB20) that have been posited as contributing to the brain phenotype of the 3q13.31 microdeletion syndrome are all overlapped by this patient's deletion (Figure 2) [1, 2]. Regarding these genes and their potential role in schizophrenia and related neuropsychiatric conditions, non-synonymous point mutations in GAP43 were recently identified in two unrelated schizophrenia cases in a next-generation sequencing study . DRD3 has been a longstanding candidate gene for schizophrenia, largely based on its affinity to bind antipsychotic drugs and its localization in limbic brain structures . Further, LSAMP and ZBTB20 have each been implicated in various brain regions associated with schizophrenia. In a post-mortem study of schizophrenia, LSAMP expression was noted to be increased by ~20% in the dorsolateral prefrontal cortex of individuals with schizophrenia compared to controls . In mice, ZBTB20 knockdowns were noted to have faulty hippocampal cytoarchitecture and selective ablation of ZBTB20 in mature hippocampal CA1 neurons led to disruptions in learning and memory [20, 21].
In addition to genic haploinsufficiency, other molecular mechanisms may contribute to the phenotype of the 3q13.31 microdeletion syndrome. In particular, recent reports suggest miRNAs may play a role in mediating the risk for neurodevelopmental disorders [22, 23]. Both miRNAs overlapped by the 3q13.31 deletion in this patient (miR-4796, miR-568) have predicted targets that are additional candidate genes for schizophrenia and related disorders, including SHANK2 and FMR1[24, 25]. The individual and collective influence of the above mentioned genes and miRNAs on the neuropsychiatric expression of the 3q13.31 microdeletion is deserving of further study. Of interest with respect to genotype-phenotype correlations are the few reports to date of the reciprocal 3q13.31 duplication, in which individuals appear to share some (i.e., DD/ID, hypotonia) but not all of the same clinical features as the 3q13.31 microdeletion [4, 26]. The fact that neither deletions nor duplications at 3q13.31 were identified in 26,826 controls suggest that copy number aberrations in this region, rather than haploinsufficiency alone, may be associated with the deleterious phenotypic consequences.
Implications for clinical practice
Cytogenetic anomalies may be found in up to 5-8% of cases with schizophrenia, suggesting a potential future role for clinical microarray testing in this population . The occurrence of schizophrenia in the patient reported here could be unrelated to the 3q13.31 microdeletion. However, multiple lines of evidence, including the variable expression of many other recurrent large, rare CNVs, suggest a genetically-related neuropsychiatric spectrum of disease that includes both DD/ID and schizophrenia [9, 27, 28]. This is, to our knowledge, the first report of a 3q13.31 deletion discovered in a schizophrenia cohort. This attests to the overall rarity of these variants, and to the relative paucity of available data (almost all of which are research-based) compared with diseases like DD/ID where clinical microarray testing is now the first-tier diagnostic test [9, 29]. More data are needed to delineate the role of pathogenic CNVs in the dual-diagnosis (schizophrenia and premorbid ID) population to which this patient would belong, where the yield may be significantly higher and where clinical testing is already indicated .
In conclusion, we have identified an adult male with schizophrenia and a 3q13.31 deletion overlapping four promising neurodevelopmental candidate genes: DRD3, ZBTB20, GAP43, and LSAMP. Later-onset conditions like schizophrenia are increasingly associated with rare CNVs. Detailed phenotypic information across the lifespan facilitates genotype-phenotype correlations, accurate genetic counselling, and anticipatory care.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review through the Editor-in-Chief of this journal.
Developmental delay/intellectual disability
Autism spectrum disorder
Attention deficit hyperactivity disorder
Shortest region of overlap
Copy number variation
Wechsler Abbreviated Scale of Intelligence
Clinical Laboratory Improvement Ammendments
The Centre for Applied Genomics.
The authors thank the patient for his participation, research assistants and staff at Saint John Community Mental Health Services and the Saint John Regional Hospital, and staff at The Centre for Applied Genomics (TCAG). The authors would also like to thank the anonymous reviewers for their valuable feedback. This study was supported by Canadian Institutes of Health Research (CIHR) grants (MOP-111238 and MOP-89066 to A.S.B.). A.S.B. holds the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, and the Dalglish Chair in 22q11.2 Deletion Syndrome.
Control datasets were obtained, along with permission for use, from the database of Genotypes and Phenotypes (dbGaP) found at http://ncbi.nlm.nih.gov/gap through accession numbers phs000143.v1.p1 (Starr County Health Studies’ Genetics of Diabetes Study), phs000091.v2.p1 (GENEVA NHS/HPFS Diabetes study), phs000169.v1.p1 (Whole Genome Association Study of Visceral Adiposity in the HABC Study), phs000303.v1.p1 (Genetic Epidemiology of Refractive Error in the KORA Study) and phs000404.v1.p1 (COGEND; The Genetic Architecture of Smoking and Smoking Cessation). The Starr County Health Studies Genetics of Diabetes Study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIDDK Central Repositories. Support for the GWAS of Gene and Environment Initiatives in Type 2 Diabetes was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01HG004399). The human subjects participating in the GWAS derive from The Nurses’ Health Study and Health Professionals’ Follow-up Study and these studies are supported by National Institutes of Health (NIH) grants CA87969, CA55075 and DK58845. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446) and the National Center for Biotechnology Information. Support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH GEI (U01HG004424). Support for the ‘CIDR Visceral Adiposity Study’ was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Health ABC Study (HABC) Investigators. The KORA dataset was obtained from the NEI Refractive Error Collaboration (NEIREC) Database, support for which was provided by the National Eye Institute. Support for genotyping of the COGEND samples, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1X01 HG005274-01. Assistance with genotype cleaning of the COGEND samples, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01HG004446). Support for the collection of COGEND datasets and samples were provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724).
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