All the authors declare no conflicts of interest.
Article first published online: 9 JUL 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 159B, Issue 6, pages 710–717, September 2012
How to Cite
Gau, S. S.-F., Liao, H.-M., Hong, C.-C., Chien, W.-H. and Chen, C.-H. (2012), Identification of two inherited copy number variants in a male with autism supports two-hit and compound heterozygosity models of autism. Am. J. Med. Genet., 159B: 710–717. doi: 10.1002/ajmg.b.32074
Hsiao-Mei Liao and Susan Shur-Fen Gau have equal contribution as the first author.
How to cite this article: Gau SS-F, Liao H-M, Hong C-C, Chien W-H, Chen C-H. 2012. Identification of Two Inherited Copy Number Variants in a Male with Autism Supports Two-Hit and Compound Heterozygosity Models of Autism. Am J Med Genet Part B 159B:710–717.
- Issue published online: 9 AUG 2012
- Article first published online: 9 JUL 2012
- Manuscript Accepted: 6 JUN 2012
- Manuscript Received: 9 FEB 2012
- National Science Council. Grant Numbers: NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, NSC 99-3112-B-002-036
- National Taiwan University. Grant Number: 10R81918-03
- National Health Research Institutes, Taiwan
- two-hit model;
- compound heterozygosity
Autism is a childhood-onset neurodevelopmental disorder with complex genetic mechanism underlying its etiology. Recent studies revealed that a few single de novo copy number variants of genomic DNA (copy number variants [CNVs]) are pathogenic and causal in some sporadic cases, adding support to the hypothesis that some sporadic autism might be caused by single rare mutation with large clinical effect. In this study, we report the detection of two novel private CNVs simultaneously in a male patient with autism. These two CNVs include a microduplication of ∼4.5 Mb at chromosome 4q12-13.1 that was transmitted from his mother and a microdeletion of ∼1.8 Mb at 5q32 that was transmitted from his father. Several genes such as LPHN3, POU4F3, SH3RF2, and TCERG1 mapped to these two regions have psychiatric implications. However, the parents had only mild degree of attention deficit symptoms but did not demonstrate any obvious autistic symptoms or psychopathology. Our findings indicate that each of these two CNVs alone may not be pathogenic enough to cause clinical symptoms in their respective carriers, and hence they can be transmitted within each individual family. However, concomitant presence of these two CNVs might result in the clinical phenotypes of the affected patient reported here. Thus, our report of this family may represent an example to show that two hits of CNV and the presence of compound heterozygosity might be important mechanisms underlying the pathogenesis of autism. © 2012 Wiley Periodicals, Inc.
Autism is a childhood-onset neurodevelopmental disorder defined by impaired reciprocal social interaction, deficient language development, and the presence of restricted interest and stereotyped behavior. The estimated prevalence of autism and its related disorders (autism spectrum disorders, ASD) in general population worldwide is approximately 1–2.6%, with male predominance [Kogan et al., 2009; Kim et al., 2011]. Autism has a high heritability of more than 90%; the genetic underpinnings of autism are heterogeneous and complex, and may involve multiple genes, gene–gene interactions, and gene–environment interactions [Eapen, 2011; Holt and Monaco, 2011]. The genetic risk factors of autism identified so far range from common variants conferring a small effect to rare mutations that have a high clinical effect [State and Levitt, 2011].
Recent development of array-based comparative genomic hybridization technology has discovered that submicroscopic deletion and duplication of genomic DNA, known as copy number variants (CNVs), contribute a significant role to the genetic etiology of ASD, and up to 10% of patients with ASD were found to have rare de novo CNVs associated with their clinical phenotypes [Sebat et al., 2007; Marshall et al., 2008]. In a genome-wide rare CNV analysis, ASD patients were found to carry a higher global burden of rare CNVs when compared to controls (1.19-fold, P < 0.012) [Pinto et al., 2010]. De novo CNVs co-segregating with disease in a family are usually considered as pathogenic; however, increasing evidence indicates that the clinical relevance of some CNVs found in patients with neurodevelopmental disorders including ASD is not so obvious and more complicated [Girirajan and Eichler, 2010; Mitchell, 2011; Poot et al., 2011]. For example, in a study of recurrent 16p12.1 microdeletion associated with neurodevelopmental delay, Girirajan and colleagues reported that 16p12.1 microdeletion was not fully penetrant and might predispose to an additional CNV and lead to more severe clinical features.
Hence, they suggested a two-hit model might be more generally applicable to neuropsychiatric disorders [Girirajan et al., 2010; Veltman and Brunner, 2010]. In our series of molecular genetic study of autism, we conducted CNV analysis in patients with ASD who were consecutively recruited into our study. During our study, we identified a young male patient diagnosed as autism who simultaneously carried two CNVs that might contribute to his clinical phenotypes. Notably, these two CNVs were inherited from his parents, respectively, who did not have obvious psychopathology.
SUBJECTS AND METHODS
We recruited 315 patients, aged 3–17 (mean ± standard deviation, 9.08 ± 4.20), who met the diagnostic criteria of autistic disorder defined by the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) from the Children Mental Health Center, Department of Psychiatry, Taiwan University Hospital, Taipei, Taiwan, child psychiatric clinics of private hospitals, and special or resource education programs at nursery schools, kindergartens, primary, and high schools in northern Taiwan into our molecular genetic study of autism project. The clinical diagnosis of autism was confirmed using the Chinese version of the Autism Diagnostic Interview-Revised by qualified child psychiatrists [Chien et al., 2011b; Gau et al., 2010]. The ADI-R interviews of the past behaviors revealed that patients with autism scored 20.31 ± 6.22 in the “qualitative abnormalities in reciprocal social interaction” (cut-off = 10), 14.76 ± 4.28 in the “qualitative abnormalities in communication, verbal” (cut-off = 8), 8.17 ± 3.30 in the “qualitative abnormalities in communication, nonverbal” (cut-off = 7), and 6.93 ± 2.47 in the “restricted, repetitive and stereotyped patterns of behaviors” (cutoff = 3). 93.8% of the patients with autism had abnormal development evident before 30 months of age based on the ADI-R interview and validated by the medical records.
The study protocol was approved by the Research Ethics Committee of National Taiwan University Hospital [ID: 9561709027; ClinicalTrials.gov number, NCT00494754], and written informed consents were obtained from the parents of patients after the procedures were fully explained. All the 315 patients with autism (278 males and 37 females) were recruited for CNV screening. Two CNV databases of Chinese residing in Taiwan were used for comparison [Lin et al., 2008a, 2009]. These two CNV databases contain the CNV information of 300 and 813 anonymous unrelated individuals, respectively. The detailed demographic data are not available.
Affymerix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA) was used for CNV analysis in this study. The SNP 6.0 array contains more than 1.8 million markers including more than 906,600 probes for SNPs and more than 946,000 probes for CNVs. These probes are evenly distributed across the whole genome with median distance between probes of ∼0.7 kb. The microarray experiment was conducted by the National Genotyping Center (Academia Sinica, Taipei, Taiwan) according the protocol provided by the manufacturer. CNVs were called by the computer program Genotyping Console 3.0.2 following the manufacturer's instructions (Affymetrix). Genes involved in the CNVs detected from this study were listed from the annotated gene symbols of the UCSC genome browser (NCBI36/hg 18).
Real-Time Quantitative PCR (RT-qPCR)
RT-qPCR was performed using SYBR Green method and implemented in StepOnePlus Real-Time PCR System according to the manufacturer's protocol (Applied Biosystmes, Forster City, CA). A comparative ΔΔCt method was used to validate the CNV in this study. For quantification of the 4q13.1 duplication, fragments of latrophilin 3 gene (LPHN3, GeneID: 23284) at 4q13.1 and FERM, RhoGEF, and pleckstrin domain protein two gene (FARP2, GeneID: 9855) at 2q37.3, were PCR amplified from the genomic DNA of each individual, respectively. The ΔΔCt of each subject was first obtained by subtracting the Ct of LPHN3 by the Ct of FARP2 of his own DNA, then by ΔCt of a normal control subject. The relative fold change to the normal subject was determined as . Similarly, for quantification of the 5q32 deletion, fragments of leucyl-tRNA synthetase gene (LARS, GeneID: 51520) at 5q32 and metaxin 2 gene (MTX2, GeneID: 10651) at 2q31.1, were PCR amplified from genomic DNA of each individual, respectively. The ΔΔCt of each subject was first obtained by subtracting the Ct of DLGAP2 by the Ct of MTX2 of his own DNA, then by ΔCt of a normal control subject. The relative fold change to the normal subject was determined as . The PCR was carried out in triplicates. The primer sequences, optimal annealing temperature and the size of amplicon are listed in Table I.
|Gene symbol||Forward primer||Reverse primer||Ta (°C)||Size (bp)|
Proband and Family
The patient, an 18-year-old Taiwanese boy, is the only child of unrelated parents. Regular blood tests, ultrasonic examinations, and one amniocentesis during maternal pregnancy did not reveal any abnormal findings. Despite no maternal infection or exposures to substances such as coffee, alcohol, or tobacco during the pregnancy, his mother suffered from high blood sugar in the third trimester. She took multi-vitamins designed for pregnant woman during gestational age of 25–38 weeks. He was born through cesarean section smoothly due to maternal premature rupture of membrane, at his mother's age as 36 years old and father, 39. He was a full-term baby with body weight of 2,700 g without any remarkable complications during infancy. His parents denied that he had any systemic disease or neuropsychiatric disorders such as epilepsy later in life. He did not have any dysmorphic features, either.
He walked alone at age of 18 months old, and spoke his first word other than papa/mama at age of 5 years old and first sentence after 10 years of age. The patient's language is mainly used to express his basic needs and not for communication. At 2.5 years of age, he was clinically diagnosed with autistic disorder and childhood autism based on the DSM-IV and ICD-10 diagnostic criteria, respectively, by board-certificated child psychiatrists specialized in autism assessments and treatments at an autism early intervention center in Taipei. His major manifestations were: non-meaningful verbal outputs, some echolalia, a lack of social reciprocity, no direct gaze, no response to any verbal stimuli, or gestures meant to catch his attention, and restricted and stereotyped behaviors and activities.
Since the first psychiatric contact, he has received irregular but wide-ranging early intervention programs including speech therapy and occupational therapy at 3–5 years old, followed by special education programs at kindergarten for 1 year. He continued receiving special education programs at a primary school (Grade 1–6) and a junior high (Grade 7–9) in Taipei. He is now 11th grader of a senior high school specialized for mental retardation or autism in Taipei. In addition to typical autistic symptoms, he was found to have high level of hyperactivity, impulsivity, and inattention since the age of 3 and lasting till junior high. These symptoms had apparently impeded the progress of his early intervention, which was recognized by his parents as not effective. However, he has never taken any medication to treat attention deficit and/or hyperactivity disorder (ADHD) symptoms.
At the age of 16.5 years old, his mother was interviewed by using the Chinese version of the ADI-R [Gau et al., 2011] in December 2009. The clinical assessment and ADI-R clearly showed that the past and current symptoms of the patient reached the criteria for autistic disorder (autism) as defined by the DSM-IV and ICD-10. The ADI-R revealed that in the past (current), the patient scored 28 (17) in the “qualitative abnormalities in reciprocal social interaction” area (cut-off = 10), 18 (12) in the “qualitative abnormalities in communication” (cut-off = 8), and 10 (8) in the “restricted, repetitive, stereotyped patterns of behaviors” (cutoff = 3).
His current ADHD symptoms based on the mother reports on the Chinese version of the Swanson, Nolan, and Pelham, version IV scale revealed six items of overt inattention and 1item of overt hyperactivity–impulsivity symptoms according to the DSM-IV ADHD symptom criteria [Gau et al., 2008]. However, based on psychiatric interview using the Chinese version of the Kiddie Epidemiologic Version of the Schedule for Affective Disorders and Schizophrenia [Gau et al., 2005] and clinical assessment by the corresponding author, he had sub-threshold inattention symptoms and severe functional impairment, which did not meet the full DSM-IV ADHD diagnostic criteria. Due to his limited communication ability (only immediate echolalia with a maximum of four to five words in length) and lack of response to gesture or verbal commands, he cannot perform the intelligence like Weschler Intelligence Scale for Children-3rd edition or other neuropsychological tests like the Conner's Continuous Performance Test and Wisconsin Card Sorting Test at the age of 16 years and 3 months old and 18 years old.
His mother and father also received clinical assessments and reported on the Adult Autism Spectrum Quotient (cut-off = 32) as 18 and 22, respectively. Based on clinical assessment, his mother did not have social difficulties, but his father, despite no past and current typical autistic symptoms elicited during interview, was not socially active and spoke slowly providing only simple answers with his mother's assistance. In addition, his father had a history of speech delay that he started his first word at age 5 and progressive hearing loss for the past decade. Using the Chinese version of the Adult Self-Report Inventory-4 [Chien et al., 2011a] to assess a wide range of the DSM-IV psychopathology of the parents, they did not report overt symptoms to meet the DSM-IV diagnostic criteria. However, the mother currently showed sub-threshold inattention and hyperactivity/impulsivity symptoms based on her report on the Adult ADHD Self-Report Scale [Yeh et al., 2008] that were confirmed by the clinical interview. In summary, the patient had typical symptoms of autism and some ADHD symptoms; his parents did not demonstrate any obvious autistic symptoms or DSM-IV psychopathology but the mother had sub-threshold ADHD symptoms and his father had a history of speech delay, gradual hearing impairment in the past decade, and may have some autistic trait in social reciprocity dimension.
Array CGH Analysis
As shown in Figure 1, the proband was found to have an interstitial duplication at chromosome 4q12-13. The 4q12-13 duplication started from the nucleotide position 57884499 and ended at the nucleotide position 62417220, with the size of ∼4.5 Mb. The duplication was inherited from his mother who had the same duplication as shown in Figure 1. The proband was also detected to have an interstitial deletion at chromosome 5q32. The deletion started from the nucleotide position 144752343 and ended at the nucleotide position 146539262, with the size of ∼1.8 Mb (Fig. 2). The deletion was transmitted from his father who was found to have the same deletion as shown in Figure 2.
Using the RT-qPCR of genomic DNA as a supplementary confirmation method for CNVs detected in this family, we found that the fold changes of LPHN3 at the 4q13.1 duplication as normalized by the FARP2 at 2q37.3 in the proband and his mother relative to the control subject were approximately 1.5, while his father had the fold change of approximately 1.0 (Fig. 3a). Regarding the 5q32 deletion, we found that the fold changes of LARS at the 5q32 as normalized by the MTX2 at 2q31.1 in the proband and his father relative to the control subject were approximately 0.5, while his mother has the fold change of approximately 1.0 (Fig. 3b).
The study reported two concurrent submicroscopic CNVs, an interstitial duplication of ∼4.5 Mb at chromosome 4q12-13 and an interstitial deletion of ∼1.8 Mb at chromosome 5q32 in a young male patient with clinical diagnosis of autism since early childhood. Family study showed that the 4q12-13 duplication was transmitted from his mother, while the 5q32 deletion was inherited from his father. To our knowledge, these two CNVs were not found in the databases of genome variations, including UCSC Genome Browser (http://genome.ucsc.edu/cgi-bin/hgGateway), ENSEMBLE (http://www.ensembl.org/index.html), and Toronto DGV (Database of Genomic variants, http://projetcs.tcag.ca/variants) till the submission of this article. They were also not detected in the public genomic variation databases in Taiwanese population [Lin et al., 2008b, 2009]. We have tried to map the breakpoint sequences of these CNVs, but in vain. Hence, it is difficult to infer the mechanism of the occurrence of these two CNVs at the present time.
The 4q12-13 duplication encompasses three genes (based on Build 36.3), including SRIL, LPHN3, and LOC727997. Both SRIL and LOC727997 are inferred pseudogenes, while the LPHN3 is a validated gene coding for latrophilin 3, a member of the latrophilin subfamily of G-protein coupled receptors. LPHN3 is specifically expressed in brain tissue [Martinez et al., 2011]. Recently, a linkage analysis on multigenerational families in an isolated population followed by association study in five samples revealed that LPHN3 was associated with ADHD and predicted the effectiveness to stimulant medication [Arcos-Burgos et al., 2010]. The association of LPHN3 and ADHD was replicated in samples of adult ADHD [Ribases et al., 2011], further supporting the involvement of LPHN3 in the neurobiology of ADHD across lifespan [Franke et al., 2011]. Moreover, a recent study demonstrated that a cooperative interaction of LPHN3 and 11q doubles the risk of ADHD [Jain et al., 2011]. In our study, the patient had overt ADHD symptoms, while his mother who also carried the 4q12-13 duplication currently still had sub-threshold ADHD symptoms at her age of 53 according to her report on the Adult ADHD Self-Report Scale [Yeh et al., 2008] and the clinical assessment by the corresponding author. It is likely that the ADHD symptoms of the mother can be attributed to the duplication of LPHN3 gene, while the more prominent ADHD symptoms found in the patient can be attributed to the interaction between LPHN3 and other genes, especially those in the 5q32 deletion region.
A total of 13 genes were mapped to the 5q32 deletion region (based on Build 36.3), including LOC650866, PRELID2, LOC643226, SH3RF2, PLAC8L1, LARS, RBM27, POU4F3, TCERG1, GPR151, and PPP2R2B. LOC650866 is a pseudogene and LOC650866 is a provisional protein-coding gene, while the rest are validated protein-coding genes. PPP2R2B encodes a brain-enriched regulatory subunit B of protein phosphatase 2A (PP2A) that is involved in various cellular functions, signaling pathways, and apoptosis [Janssens and Goris, 2001; Lechward et al., 2001; Van Hoof and Goris, 2003]. Expansion of CAG repeat at the promoter region of the PPP2R2B is associated with autosomal dominant spinocerebellar ataxia type 12 (SCA12) [Holmes et al., 1999], a late-onset, slowly progressive neurodegenerative disease characterized by action tremor, hyperreflexia, ataxia, and cortical dysfunction [O'Hearn et al., 2012]. The CAG repeat functions as a cis element to up-regulate the expression of PPP2R2B. Increased number of CAG repeat is associated with elevated PPP2R2B expression, while deletion of CAG repeat down-regulates the expression PPP2R2B [Lin et al., 2010]. Hence, the pathogenesis of SCA12 can be attributed to the increased PPP2R2B expression in the brain. In contrast, shorter CAG repeats (n = 5–7) of the PPP2R2B has lower reporter gene activities than the longer CAG repeat (n = 10, 13, and 16), and associate with Alzheimer's disease and essential tremor [Chen et al., 2009; Kimura et al., 2011]. Together, these studies indicate that strict regulation of the PPP2R2B expression is essential for the healthy brain. Hence, it is likely that haploinsufficiency of the PPP2R2B in our patient may lead to decreased expression of PPP2R2B in his brain and contribute to his clinical phenotypes.
POU4F3 encodes the POU domain, class 4, transcription factor 3 that is a member of POU family of transcription factors, and is expressed mainly in inner ear hair cells. It plays an essential role for the normal development and proper function of inner ear hair cells. Mutations of the POU4F3 are associated with an adult-onset, non-syndromic, autosomal dominant progressive hearing impairment in humans [Vahava et al., 1998; Collin et al., 2008; de Heer et al., 2009; Lee et al., 2010]. So far, the patient was not found to have hearing problem, but his father was found to have progressive hearing loss, which can be attributed to the haploinsufficiency of the POU4F3.
PRELID2 encodes protein of relevant evolutionary and lymphoid interest domain containing protein 2. The function of this protein is still unclear, but it is believed to be a mitochondrial protein and required for mitochondrial respiratory ability. A study reported that this gene was conserved, and widely and persistently expressed in mouse embryonic development, suggesting that the Prelid2 gene is involved in mouse embryonic development [Gao et al., 2009]. SH3RF2 encodes SH3 domain containing ring finger 2 protein that was found as a region-specific molecular marker of nucleus accumbens of human brain [Wilhelm et al., 2012]. Sh3rg2 was demonstrated to promote cell survival by ring-mediated proteasomal degradation of the c-Jun N-terminal kinase scaffold POSH (Plenty of SH3s) protein in many cell types [Wilhelm et al., 2012]. PLAC8L1 encodes placenta-specific gene 8 protein (PLAC8)-like 1 protein; however, its function is unclear. GPR151 encodes G protein-coupled receptor 151 with unclear function. LARS encodes cytoplasmic leucyl-tRNA synthetase that forms a macromoleuclar protein complex with other aminoacyl-tRNA synthetases and interacting proteins to catalyze the attachment of their cognate amino acid to the 3′-end of the specific tRNA [Park et al., 2010]. It is also involved in editing non-cognate amino acid transfer [Chen et al., 2011]. However, the clinical relevance of haploinsufficiency of these genes remains to be studied.
TCERG1 encodes transcription elongation regulator 1 that regulates transcriptional elongation and pre-mRNA splicing. It also plays a prevalent role in mRNA processing [Pearson et al., 2008]. TECRG1 also interacts with huntingtin protein and involves the pathogenesis of Huntington's disease. It was found to modify the age-of-onset of Huntington's disease [Holbert et al., 2001]. Expression of TECRG1 can delay striatal cell death induced by mutant huntingtin neurotoxicity in transgenic mice [Arango et al., 2006]. Together, these studies suggest that TECRG1 might play an important role in neurons, and haploinsufficiency of this gene might have relevance to the clinical phenotypes of this patient.
Autism is a complex disease with highly heterogeneous genetic underpinnings. Although recent studies have revealed that some de novo CNVs were pathogenic and causal in some sporadic cases, increasing evidence suggests that some CNVs are inherited and their clinical relevance may not be straightforward [Girirajan and Eichler, 2010; Mitchell, 2011; Poot et al., 2011]. In the present study, the parents who carried the respective 5q13 duplication and 4q32 deletion did not have obvious psychopathology, suggesting that each of these two CNVs alone may not be pathogenic enough to cause clinical phenotypes, while the concurrence of these two CNVs in the affected patient suggest that interactions among genes involved in these two CNVs may lead to clinical phenotypes. Our findings are in line with the hypothesis that two-hit model might be more generally applicable to neuropsychiatric disorders as proposed by Girirajan and colleagues [Girirajan et al., 2010; Veltman and Brunner, 2010].
In addition to the two-hit model, our findings are also in line with the compound heterozygosity model of autism. In a genetic study of high-functioning, idiopathic ASD, Schaaf et al.  reported that in addition of de novo rare mutations, patients with ASD had a significantly higher proportion of multiple events of compound heterozygosity than control subjects, suggesting compound heterozygosity is a new potential mechanism in the pathogenesis of ASD.
Together, our findings support that both the two-hit CNV model and the compound heterozygosity model as complex genetic mechanisms underlying autism. Nevertheless, it is also possible that the clinical presentations of the affected patient were precipitated by other genetic factors or environmental factors in addition to these two CNVs.
This work was supported by grants from National Science Council (NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, and NSC 99-3112-B-002-036), National Taiwan University (10R81918-03), and intramural grant from National Health Research Institutes, Taiwan.
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