J Dev Disord DOI 10.1007/s10803-006-0225-8

ORIGINAL PAPER

Characterization of an Autism-Associated Segmental Maternal Heterodisomy of the 15q11–13 Region

Dorota A. Kwasnicka-Crawford Æ Wendy Roberts Æ Stephen W. Scherer

Springer Science+Business Media, Inc. 2006

Abstract Cytogenetic abnormalities in the Prader- Keywords Autistic disorder Æ Chromosomal Willi/ (PWS/AS) critical region anomalies Æ Prader Willi/Angelman region, small have been described in individuals with autism. supernumerary chromosome Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11–q13. Here, we describe a Introduction 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. Autistic disorder (AD) is a neurodevelopmental condi- The karyotype was designated de novo 47, XX, tion characterized by significant impairment in social, idic(15)(q13). Fluorescence in situ hybridization communicative, and behavioral functioning. Develop- (FISH) and molecular analysis with 15q11–q13 mark- mental abnormalities are apparent in the first 3 years of ers revealed an additional copy of the region being of life and persist into adulthood (Folstein & Rosen- maternal origin. Duplication of the 15q11–q13 segment Sheidley, 2001; Lamb, Moore, Bailey, & Monaco, 2000; represents the most consistent known chromosomal Muhle, Trentacoste, & Rapin, 2004). Studies of the abnormality reported in association with autism. This chromosomal location of cytogenetic abnormalities and present case report reinforces the hypothesis that breakpoints can be extremely useful in the identification additional copies of this chromosome segment are of genes predisposing to disease (Xu, Zwaigenbaum, causally related to autism. Szatmari, & Scherer, 2004). Cytogenetic abnormalities at the 15q11–q13 locus are reported most frequently in individuals with autism (Cook et al., 1998; Gillberg, 1998; Nurmi et al., 2001; Schroer et al., 1998). Chromo- some 15q11–q13 has been identified as a candidate D. A. Kwasnicka-Crawford Æ S. W. Scherer (&) disease region for autism because of both the frequent Program in Genetics and Genomic Biology, The Hospital occurrence of chromosomal abnormalities and sugges- for Sick Children, Toronto, ON, CanadaM5G-1X8 tive linkage and association findings (Cook et al., 1998; e-mail: [email protected] Nurmi et al., 2001;Shaoetal.,2003). D. A. Kwasnicka-Crawford Low copy repeat regions (LCR) located within prox- Department of Kinesiology and Health Science, Faculty of imal 15q seem to facilitate mispairing and unequal Health, York University, Toronto, ON, Canada meiotic exchanges, which results in a relatively high W. Roberts frequency of chromosomal rearrangement of this region Department of Pediatrics, The Child Developmental such as deletions, interstitial duplications, triplications, Center, Toronto, ON, Canada and supernumerary marker (SMCs) (Crolla, Harvey, Sitch, & Dennis, 1995; Wandstrat & S. W. Scherer Department of Molecular and Medical Genetics, University Schwartz, 2000; Wolpert et al., 2000b). Paternally or of Toronto, Toronto, ON, Canada maternally derived deletions of the 15q11–q13 region or

123 J Autism Dev Disord uniparental disomy (UPD) result in Prader-Willi or severity of developmental outcomes in these individu- Angelman syndrome (PWS/AS) phenotype, respec- als (Borgatti et al., 2001; Flejter et al., 1996; Mignon tively. Duplications of the 15q11–q13 region with an et al., 1996; Robinson et al., 1993b), it is more difficult estimated frequency of 1:600 individuals (Thomas, to find a correlation between gene dosage and autism Roberts, & Browne, 2003) show a distinct phenotype and phenotype. The severity of autistic symptoms varied a parent-of-of origin effect. Paternally derived duplica- widely in individuals with idic(15). This could be due to tions are generally associated with normal phenotype lack of sufficient description of autism behavior in (Bolton et al., 2001;Cooketal.,1997). In contrast, many reports or the fact that many reports did not use additional maternal copies of 15q11–13 produce pheno- a standardized measure of autism. However, clinical type usually associated with autistic behavior and varying and molecular reports of the association of idic(15) degrees of learning disability (Bolton et al., 2001;Simic with autism in addition to linkage and gene-mapping &Turk,2004). Most of the duplications occur through a analysis implicate that the chromosome 15q11–13 supernumerary marker , SMC (15)s. The region harbors a genetic risk for autism. Our goal is to estimated frequency of chromosome 15-derived marker distinguish genes within this region whose aberrant is ~1 in 5,000 live births and represent about 50% of all expression contributes to the autism phenotype. SMCs. (Crolla et al., 1995;Webb,1994). Here, we describe a patient carrying a supernumer- SMC(15)s can contain two copies of the satellite ary idic(15) chromosome. Conventional and molecular short arm and two and are also called i- cytogenetic studies confirmed the chromosomal origin sodicentric 15 [idic(15)], or inverted duplication 15 [inv of the supernumerary chromosome and showed that the dup (15)] (Roberts, Maggouta, Thomas, Jacobs, & duplicated region extended to band 15q13. An analysis Crolla, 2003; Simic & Turk, 2004; Wandstrat & Sch- of chromosome 15 microsatellite polymorphisms sug- wartz, 2000; Wolpert et al., 2000b). SMC (15)s range in gested a maternal origin of the idic(15) chromosomes size from small, largely heterochromatic chromosomes to and biparental inheritance of the two intact chromo- large euchromatic SMC (15) (Eggermann et al., 2002; some 15 homologs. Interestingly, the patient carries a Huang et al., 1997). The small dicentric chromosomes rare segmental heterodisomic maternal UPD(15) of the without the PWS/AS region are often familial or de proximal part of chromosome 15 and her phenotype novo and not associated with any clinical abnormality met the standardized criteria for autism. (Cheng, Spinner, Zackai, & Knoll, 1994). Large supernumerary idic(15) chromosomes containing the PWACR are usually maternal in origin and have a Materials and methods wide range of developmental problems that can include severe mental retardation, disorders, Diagnostic Ascertainment various degrees of developmental delay, and some autism phenotype (Bolton et al., 2001; Cook et al., The present study was approved by the Research 1997; Eggermann et al., 2002; Flejter et al., 1996; Ethics Board of the Hospital for Sick Children and Gillberg et al., 1991; Roberts et al., 2002b; Robinson informed consent was obtained from the participants. et al., 1993b; Schinzel et al., 1994). Paternal inheri- The proband, a 6-year-old girl, is the only child of tance also has been reported in some cases (Egger- nonconsanguineous parents. Behavioral assessments mann et al., 2002; Werner et al., 2004) Individuals with were carried out blind to genetic status. An experi- supernumerary isodicentric(15) chromosomes often enced developmental pediatrician made a diagnosis of have three copies of maternal genes from the chro- autism based on a comprehensive history and on the mosome 15q11–q13 region have adverse developmen- Autism Diagnostic Observation Schedule (ADOS)- tal outcomes and also meet criteria for autism (Cheng Module 1 (Lord et al., 2000) and the Autism Diag- et al., 1994; Gillberg et al., 1991; Leana-Cox et al., nostic Interview (ADI) (Lord et al., 1997, 2000; Lord, 1994). There are also reports of individuals with severe Rutter, & Le Couteur, 1994). Module 1 is often con- developmental impairments having partial hexasomy ducted while moving around a room, reflecting the for chromosome 15 arising because of the presence of interests and activity levels of young children or chil- either two idic(15) chromosomes or a large idic(15) dren with very limited language. The ADI contains chromosome with six copies of the PWCR (Huang & items in three content areas: communication, social Bartley, 2003; Maggouta, Roberts, Dennis, Veltman, & interaction, and restricted, repetitive behavior. Gen- Crolla, 2003; Mann et al., 2004; Qumsiyeh et al., 2003). erally, items are coded ‘‘0’’ (no evidence of abnor- Although it might be easier to draw a correlation mality), ‘‘1’’ (some evidence of abnormality), and ‘‘2’’ between the degree of PWACR gene dosage and the (evidence of marked abnormality). The Vineland

123 J Autism Dev Disord

Adaptive Behavior Scale (VABS) (Fenton et al. 2003) Results was also performed in addition to ADOS and ADI to examine adaptive behavior profile and developmental Clinical Report delay in the patient. VABS measures personal and social skills from birth to adulthood and is organized The proband was first seen for developmental assess- around four Behavior Domains: Communication, ment at age 4 years and 3 months. She was the first Daily Living Skills, Socialization, and Motor Skills. child of healthy, unrelated parents and was born at 34 weeks gestation because of abruptio placentae Chromosome Analyses causing bleeding, which started at 32 weeks. The birth weight was 4 lbs. 13 oz. She cried immediately after Chromosome analysis from peripheral blood lympho- birth and was observed in an isolate for 1 week before cytes using G-banding showed abnormal karyotype: 47, going home. She was described as a very passive and XX, idic (15) q13. Routine cytogenetic analyses were quiet infant who had difficulty feeding. When seen for performed on Epstein-Barr (EBV)-immortalized lym- a pediatric evaluation at 2 years, her height was on the phocytes from the affected patient and her parents. 45th percentile, weight on the 35th percentile and head Karotypes were determined by analysis of G-banded circumference on the 40th percentile. She had low metaphase chromosomes. muscle tone with extra flexibility at her major joints and she had been noted to have delayed fine and gross motor skills. She was able to sit unsupported since the Fluorescent In Situ Hybridization (FISH) age of 12 months, crawl at between 12 and 15 months and did not walk independently until 24 months of age. FISH experiments were performed according to stan- She spoke her first words at about 2 years. When seen dard procedures (Lichter, Cremer, Borden, Manueli- for a developmental assessment at 4 years, her parents dis, & Ward, 1988; Pinkel et al., 1988). Metaphase reported phrase speech starting at 2½ years and tem- chromosome spreads were prepared from lympho- per tantrums developing around 3 years of age and blastoid cell lines established from the proband and her persisting in quite a severe pattern. She was noted to be parents. The probes used were derived from BACs hyperactive and displayed aggression particularly to- spanning the 15q11–13 region. BAC DNA was isolated ward her mother. according to standard protocols (Qiagen) and 1 lgof A developmental assessment included a Vineland DNA was labeled with the Biotin-Nick translation Interview (carried out at 4 years and 3 months), Aut- TM TM mix or the DIG-Nick translation mix (Boehringer ism Diagnostic Observation Schedule (ADOS) Module Mannheim) as described by the supplier. Spreads were 1, and Autism Diagnostic Interview (ADI) (both car- then observed on an epifluorescent microscope (Zeiss). ried out at 4 years and 7 months). At that time, her language consisted mainly of phrases: ‘‘no music’’, Molecular Analysis ‘‘show me duck’’. These phrases were used to request and label but not to share interest. She had some Genotyping was performed using microsatelite immediate echoing of others’ phrases, she pointed both markers across chromosome 15. Markers were chosen by touching and to refer to objects at a distance, but from established maps spanning the 15q11–q13 she did not use coordinated eye contact and did not use (http://www.marshmed.org/genetics/). Copy number any other communicative gestures. She was able to was carried out using quantitative PCR. PCR follow simple one-step commands but not more com- amplifications were performed using primers from plex or abstract ones. She had very limited eye contact chromosome 15 (microsatelite markers listed in Fig. 3 and social smiling and showed no response to an adult and exon 2 of GABAA-b3). An additional fragment, calling her name or when any other verbal attempts corresponding to exon 4 of CFTR located on chro- were made to get her attention. She showed no unusual mosome 7, was co-amplified, as a control, in each sensory interests but did have some body and hand PCR reaction. Reactions for each marker were tensing throughout the assessment. She also seemed completed in triplicate and the entire experiment was afraid of certain sounds including those made by a performed twice. The forward primer of each pair mechanical bunny. On the ADOS scale her scores were was 5¢-labeled with the 6-FAM fluorochrome. The above cut-off (scores greater than cut-off represent height of each peak was compared with the control classical autism phenotype). On communication peak in each sample and the ratio was calculated and domain she scored 6 with cut-off being at 4, and on plotted as shown in Fig. 4. social domain she scored at 8 with cut-off at 7. Her

123 J Autism Dev Disord total score (communication and social domain) was at reciprocal interaction and very limited social play 14 with cut-off at 12. ADI assessment documented along with many repetitive patterns of behaviour. little imaginative play, limited interest in other children and no approaches to her peers in play situations. Her Chromosome Analysis and FISH repetitive interests consisted of opening and closing doors, tearing paper and throwing objects back and Cytogenetic analysis using G-banding identified the forth. She sometimes had minor difficulties with tran- presence of a unique SMC (15) in 100% of metaphase sitions in her routine and had resisted toilet training. cells examined (Fig. 1). The parental chromosomes She would jump and flap and shake her head when were normal, indicating that the marker arisen de anxious or excited. On the ADI scale she received novo. The C-banding showed the SMC to be isodi- score of 24 on social domain (cut-off at 10), and 8 on centric (not shown). To confirm that the SMC (15) had communication domain (cut-off at 7). Her restrictive, two copies of the PWS/AS critical region, FISH was repetitive and stereotyped pattern of behavior was performed using multiple probes (Fig. 2) to charac- scored at 7 (cut-off at 3). On the Vineland Interview at terize the extent of the . For the age of 4 years and 3 months she was rated below example, metaphase and interphase spreads were the 1st percentile across all domains: communication at hybridized with RP11-303I17 and RP11-81N9. The equivalence of 1 year 6 months, daily living skills at normal chromosome 15 contained one copy of RP11- 1 year 8 months, socialization at 1 year 4 month, mo- 303I17 and one copy of RP11-81N9 (Fig. 3A, B). The tor skills at 1 year 5 month and adaptive behavior SMC (15) was found to be dicentric and contained two composite at 1 year 5 month. Overall, she was in the copies of RP11-303I17 but not RP11-81N9 (Fig. 3A, range of a moderate deficit and was rated as being B). Probes that were located proximal to the break- below the level expected for same-aged peers. In point showed signals on normal chromosomes and two summary, the results of the developmental assessment signals on idic(15) (Fig. 3C). indicated overall developmental delay at a moderately severe level with severely delayed expressive and Genotyping Analysis receptive language skills and behaviour which met DSM-IV criteria for an autistic disorder. Autistic fea- Molecular analysis of the proband and parents using tures included poor eye contact, relative difficulty with polymorphic markers from across chromosome 15q

Fig. 1 G-banded chromosome 15 from the proband. Two centromeres of the isodicentric chromosome 15 are indicated by the arrow

123 J Autism Dev Disord

Fig. 2 Schematic diagram showing the location of the PWS/AS critical region at the D15S1035 chromosome 15q11–13. Miscrosatelite markers used MAGEL2 RP11-373J1 for molecular analysis are 11.2 NDN

PWS D15S646 indicated. FISH probes used for cytogenetic analysis are SNRPN RP11-87I21 BP RP11-171C8 shown as bars. Probes are UBE3A listed in order AS (top) to telomere (bottom) ATP10C GABRB3 D15S97 D15S511 RP11-142M24 GABARB3 D15S1192 12 GABARA5 GABRA5 GABARG3 D15S822 D15S975

OCA2 D15S217 PWS/AS/AD Interstitial Del/Dup

Autism Candidate Region HERC2 RP11-957L5

RP11-94G7

RP11-143J24 13 RP11-1109N12 D15S165 Breakpoint RP11-303I17 TRPM1

RYR3 D15S144 RP11-81N9 D15S995 D15S1007

(Fig. 2) confirmed that the patient had additional de novo. The proband’s isodicentric (15) contained copies of the PWACR. The proband has biparental three copies of D15S165 but not the D15S144 located inheritance of two normal chromosome 15 and approximately 6 cM distal to D15S165 indicating that maternal inheritance of the isodicentric chromosome. the breakpoint is located between these two markers Figure 4 shows the allele peaks for marker D15S822. (Table 1, Fig. 2). The results from the microsatelite One allele is of paternal origin and the remaining two marker analysis demonstrated that the extra chromo- distinct alleles are of maternal origin. Haplotype some 15 material was maternal in origin. analysis demonstrated that there are two maternal Using quantitative PCR (Q-PCR) amplification of alleles for each proximal 15q marker analyzed, which microsatelite markers we also confirmed that the pro- proved the heterodisomy of the maternal 15q region band had two additional copies of the PWACR (Table 1, Fig. 4). No additional alleles were found in (Fig. 5). These results show that the dicentric (15) the mother, confirming that this SMC (15) had arisen contained two copies of this region and confirmed the

Fig. 3 FISH analysis of interphase (A) and metaphase (B, C) contains one copy of RP11-303I17 and one copy of RP11-81N9. chromosomes from EBV-transformed lymphocytes of the pro- The SMC (15) (arrow) is dicentric and contains two copies of band showing normal and isodicentric chromosome. Hybridiza- RP11-303I17 but not RP11-81N9. Hybridization with RP11- tion with RP11-303I17 (green) and RP11-81N9 (red) probes is 87I21 (red) shows one signal on both normal chromosome 15 and shown in (A and B). The normal chromosome 15 (arrow) isodicendric (C)

123 J Autism Dev Disord

Fig. 4 Genescan peak data for molecular marker D15S822 in the proband and the parents

location of the breakpoint (Fig. 5). The results of the abnormalities, idic(15) chromosome of maternal origin

Q-PCR using GABAA-b3 exon 2 as a marker also show is most frequently associated with autism (Crolla et al., that the patient has 4 copies of the gene. 1995; Huang et al., 1997). The mechanism of formation In summary, chromosome analysis showed isodi- of this SMC has been described as a pericentromeric centric chromosome 15. Based on FISH and G-banding break, followed by a U-type connection between the results, the SMC (15) marker was identified as an sister chromatids (Caine, Mason, Daly, & Ricketts, isodicentric chromosome 15, commonly referred to as 1993). Individuals with idic(15) have been described as an inverted chromosome 15 and the karyotype was having a range of developmental delays with various designated 47, XX, +idic(15)(q13). Molecular analysis autistic-like behaviors. The severity of autistic symp- also determined two additional copies of the PWS/AS toms vary widely in these individuals (Rineer, Finu- critical region. It is possible that one or more genes are cane, & Simon, 1998; Simic & Turk, 2004; Wolpert responsible for the disease pathology due to the in- et al., 2000b) and the actual association between creased dosage of the region.

Discussion

Number of case reports described an association of de Mother Father Control novo, maternally derived proximal 15q chromosome 2.50 abnormalities with autism (Cook et al., 1997, 1998; Flejter et al., 1996; Schroer et al., 1998; Weidmer- 2.00 Mikhail, Sheldon, & Ghaziuddin, 1998; Wolpert, 1.50 Pericak-Vance, Abramson, Wright, & Cuccaro, 2000a; 1.00 Wolpert et al., 2000b). Of these 15q chromosome

Copy number 0.50

Table 1 Microsatelite marker analysis 0.00 Microsatellite Mother’s Patient’s Father’s marker allele allele allele D15S511 D15S217 D15S165 D15S995 D15S1192 D15S1007 D15S1035 5/7 5/4/7 4/5 GABRB3-EX2 GABRB3 1/4 1/2/4 2/7 Fig. 5 Quantitative PCR analysis showing copy number of the D15S511 1/2 1/5/2 5/6 PWACR. Results are an average of six replicated. ‘‘1.00’’ D15S822 1/3 1/5/3 5/8 represents two copies from two normal chromosome 15 and D15S165 1/2 1/3/2 3/8 ‘‘2.00’’ represents 4 copies, two from normal chromosome 15 and D15S144 2/3 2/3 3/2 two from SMC(15). Markers are shown in order from centro- D15S995 3/4 3/3 3/2 mere to telomere. Q-PCR of the GABA -b3 exon 2 (GABRB3- D15S1007 2/5 2/3 3/2 A EX2) is also included. The breakpoint is indicated by the arrow

123 J Autism Dev Disord autistic behavior and chromosome 15 still remains (Nazarenko et al., 2004). This case study adds further unclear. This could be due to lack of detailed behav- evidence for the presence of genetic factor(s) for aut- ioral description of autism phenotype and standardized ism in the proximal region of chromosome 15q and evaluation protocols in the reported findings. However, implicates even narrower region between marker the available clinical data, cytogenetic analysis, linkage GABRB3 and D15S165 as a potential susceptibility and association findings and gene-mapping implicate locus for autism. chromosome 15q11–q13 as a susceptibility locus for There are several potential candidate genes in this autism. segment already implicated in the aetiology of AD In this study we have described a patient carrying a (Nurmi et al., 2001; Schroer et al., 1998; Wang, Liu, supernumerary marker chromosome. Using cytogenetic Parokonny, & Schanen, 2004), for instance the and molecular analyses, we determined that the SMC c-aminobutyric acid type A (GABAA) receptor sub- derived from chromosome 15 and is of maternal origin, unit genes (a5, b3, and c3) (Buxbaum et al., 2002; which seems to be consistent with almost all reported Cook et al., 1998; Menold et al., 2001). Several SMC (15)s. This proband was described to have four studies reported linkage disequilibrium between copies of the proximal 15q11–13 region with two copies individuals with AD and polymorphism in the located on a single SMC and one copy on each chro- GABAA-b3 locus. GABAA is an inhibitory neuro- mosome 15 homologue. Our FISH and molecular data transmitter expressed in the central and peripheral suggest that the SMC (15) is composed of two mater- nervous systems (Olsen & Tobin, 1990). An imbal- nally derived PWS/AS regions. Comprehensive micro- ance in the availability of the GABAA receptor satellite markers analysis of the proband showed subunit may alter receptor activity and consequently maternal heterodisomy 15 at the 15q11–13 region (also alter the activity of the brain’s major inhibitory referred to as a segmental heterodisomic maternal neurotransmitter (Olsen & Tobin, 1990). UPD15). Analysis of markers mapping to more distal The results presented in this study reinforce the segments of the long arm of chromosome 15 demon- hypothesis that additional copies of the critical 15q11– strated biparental inheritance. Although maternal q13 region are causally related to the autism phenotype UPD(15) and paternal UPD(15) has been described and that the segment beyond 15q11–q13 has no addi- previously in individuals with PWS and AS, respec- tional influence on the phenotype. Consequently, if the tively (Nicholls, Saitoh, & Horsthemke, 1998;Roberts, dosage is important at a given time in development the Maggouta, Thompson, Price, & Thomas, 2002a; Rob- excess of gene expression could potentially result in inson et al., 1993a; Vogels, Matthijs, Legius, Devriendt, specific abnormal brain development and contribute to & Fryns, 2003), as far as we know only one case of this phenotype. segmental maternal UPD(15) has been reported in a patient with PWS (Nazarenko, Sazhenova, Baumer, & Acknowledgments This study was supported by Genome Schinzel, 2004). Interestingly, our patient has a Canada and the Hospital for Sick Children Foundation. We would like to thank Martin Li, Simone Russell, Mary Ann maternal heterodisomy 15 at the 15q11–13 region and George, and Lili Senman for their help. SWS in an Investigator met the standardized DSM-IV criteria for autism. She of the Canadian Institute of Health Research and an Interna- showed indistinguishable characteristics from individu- tional Scholar of the Howard Hughes Medical Institute. als with autism in the areas of social interactions, communication, developmental delay, stereotypical References and repetitive behavior, and an overall measure of autism. She differed from individuals with autism in Bolton, P. F., Dennis, N. R., Browne, C. E., Thomas, N. S., the area of mild fine motor milestones, a characteristic Veltman, M. W., Thompson, R. J., & Jacobs, P. (2001). The phenotypic manifestations of interstitial duplications of usually found in individuals with isodicentric 15 proximal 15q with special reference to the autistic spectrum anomalies (Eggermann et al., 2002; Rineer et al., 1998; disorders. American Journal of Medical Genetics, 105, 675– Wolpert et al., 2000b). Our patient was described as 685. maternal heterodisomy 15 at the 15q11–13 region Borgatti, R., Piccinelli, P., Passoni, D., Dalpra, L., Miozzo, M., Micheli, R., Gagliardi, C., & Balottin, U. (2001). Relation- (breakpoint at D15S165 marker). Her phenotype was ship between clinical and genetic features in ‘‘inverted established according to standardized evaluation of duplicated chromosome 15’’ patients. Pediatric Neurology, autism and was much different from that of patients 24, 111–116. with typical maternal UPD of the entire chromosome Buxbaum, J. D., Silverman, J. M., Smith, C. J., Greenberg, D. A., Kilifarski, M., Reichert, J., Cook, E. H. Jr., Fang, Y., 15 and that of a patient with another segmental hete- Song, C. Y., & Vitale, R. (2002). Association between a rodisomic maternal UPD15 located at 15q11.1–12.2 GABRB3 polymorphism and autism. Molecular Psychia- (with a breakpoint next to GABRB3 marker) try, 7, 311–316.

123 J Autism Dev Disord

Caine, A., Mason, G., Daly, H. A., & Ricketts, S. M. (1993). An Lord, C., Pickles, A., McLennan, J., Rutter, M., Bregman, J., unusual tricentric X chromosome detected prenatally. Pre- Folstein, S., Fombonne, E., Leboyer, M., & Minshew, N. natal Diagnosis, 13, 1061–1065. (1997). Diagnosing autism: Analyses of data from the Aut- Cheng, S. D., Spinner, N. B., Zackai, E. H., & Knoll, J. H. (1994). ism Diagnostic Interview. Journal of Autism and Develop- Cytogenetic and molecular characterization of inverted mental Disorders, 27, 501–517. duplicated chromosomes 15 from 11 patients. American Lord, C., Risi, S., Lambrecht, L., Cook, E. H. Jr., Leventhal, Journal of Human Genetics, 55, 753–759. B. L., DiLavore, P. C., Pickles, A., & Rutter, M. (2000). The Cook, E. H. Jr., Courchesne, R. Y., Cox, N. J., Lord, C., Gonen, autism diagnostic observation schedule-generic: A standard D., Guter, S. J., Lincoln, A., Nix, K., Haas, R., Leventhal, measure of social and communication deficits associated B. L., & Courchesne, E. (1998). Linkage-disequilibrium with the spectrum of autism. Journal of Autism and Devel- mapping of autistic disorder, with 15q11–13 markers. opmental Disorders, 30, 205–223. American Journal of Human Genetics, 62, 1077–1083. Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism Diag- Cook, E. H. Jr., Lindgren, V., Leventhal, B. L., Courchesne, R., nostic Interview-Revised: A revised version of a diagnostic Lincoln, A., Shulman, C., Lord, C., & Courchesne, E. interview for caregivers of individuals with possible perva- (1997). Autism or atypical autism in maternally but not sive developmental disorders. Journal of Autism and paternally derived proximal 15q duplication. American Developmental Disorders, 24, 659–685. Journal of Human Genetics, 60, 928–934. Maggouta, F., Roberts, S. E., Dennis, N. R., Veltman, M. W., & Crolla, J. A., Harvey, J. F., Sitch, F. L., & Dennis, N. R. (1995). Crolla, J. A. (2003). A supernumerary marker chromosome Supernumerary marker 15 chromosomes: a clinical, molec- 15 tetrasomic for the Prader-Willi/Angelman syndrome ular and FISH approach to diagnosis and prognosis. Human critical region in a patient with a severe phenotype. Journal Genetics, 95, 161–70. of Medical Genetics, 40, e84. Eggermann, K., Mau, U. A., Bujdoso, G., Koltai, E., Engels, H., Mann, S. M., Wang, N. J., Liu, D. H., Wang, L., Schultz, R. A., Schubert, R., Eggermann, T., Raff, R., & Schwanitz, G. Dorrani, N., Sigman, M., & Schanen, N. C. (2004). Super- (2002). Supernumerary marker chromosomes derived from numerary tricentric derivative chromosome 15 in two boys chromosome 15: analysis of 32 new cases. Clinical Genetics, with intractable epilepsy: Another mechanism for partial 62, 89–93. hexasomy. Human Genetics, 115, 104–111. Fenton, G., D’Ardia, C., Valente, D., Del Vecchio, I., Fabrizi, Menold, M. M., Shao, Y., Wolpert, C. M., Donnelly, S. L., A., & Bernabei, P. (2003). Vineland adaptive behavior Raiford, K. L., Martin, E. R., Ravan, S. A., Abramson, R. profiles in children with autism and moderate to severe K., Wright, H. H., Delong, G. R., Cuccaro, M. L., Pericak- developmental delay. Autism, 7, 269–287. Vance, M. A., & Gilbert, J. R. (2001). Association analysis Flejter, W. L., Bennett-Baker, P. E., Ghaziuddin, M., McDonald, of chromosome 15 gabaa receptor subunit genes in autistic M., Sheldon, S., & Gorski, J. L. (1996). Cytogenetic and disorder. Journa of Neurogenetics, 15, 245–259. molecular analysis of inv dup(15) chromosomes observed in Mignon, C., Malzac, P., Moncla, A., Depetris, D., Roeckel, N., two patients with autistic disorder and mental retardation. Croquette, M. F., & Mattei, M. G. (1996). Clinical hetero- Am J Med Genet, 61, 182–187. geneity in 16 patients with inv dup 15 chromosome: Cyto- Folstein, S. E., & Rosen-Sheidley, B. (2001). Genetics of autism: genetic and molecular studies, search for an imprinting Complex aetiology for a heterogeneous disorder. Nature effect. European Journal of Human Genetics, 4, 88–100. Review Genetics, 2, 943–955. Muhle, R., Trentacoste, S. V., & Rapin, I. (2004). The genetics of Gillberg, C. (1998). Chromosomal disorders and autism. Journal autism. Pediatrics, 113, e472–e486. of Autism and Developmental Disorders, 28, 415–425. Nazarenko, S., Sazhenova, E., Baumer, A., & Schinzel, A. Gillberg, C., Steffenburg, S., Wahlstrom, J., Gillberg, I. C., (2004). Segmental maternal heterodisomy of the proximal Sjostedt, A., Martinsson, T., Liedgren, S., & Eeg-Olofsson, part of chromosome 15 in an infant with Prader-Willi syn- O. (1991). Autism associated with marker chromosome. drome. European Journal Human Genetics, 12, 411–414. Journal of the American Academy of Child and Adolescent Nicholls, R. D., Saitoh, S., & Horsthemke, B. (1998). Imprinting Psychiatry, 30, 489–494. in Prader-Willi and Angelman syndromes. Trends in Huang, B., & Bartley, J. (2003). Partial hexasomy of chromo- Genetics, 14, 194–200. some 15. American Journal of Medical Genetics Part A, 121, Nurmi, E. L., Bradford, Y., Chen, Y., Hall, J., Arnone, B., 277–280. Gardiner, M. B., Hutcheson, H. B., Gilbert, J. R., Pericak- Huang, B., Crolla, J. A., Christian, S. L., Wolf-Ledbetter, M. E., Vance, M. A., Copeland-Yates, S. A., Michaelis, R. C., Macha, M. E., Papenhausen, P. N., & Ledbetter, D. H. (1997). Wassink, T. H., Santangelo, S. L., Sheffield, V. C., Piven, J., Refined molecular characterization of the breakpoints in Folstein, S. E., Haines, J. L., & Sutcliffe, J. S. (2001). small inv dup(15) chromosomes. Human Genetics, 99, 11–17. Linkage disequilibrium at the Angelman syndrome gene Lamb, J. A., Moore, J., Bailey, A., & Monaco, A. P. (2000). UBE3A in autism families. Genomics, 77, 105–113. Autism: Recent molecular genetic advances. Human Olsen, R. W., & Tobin, A. J. (1990). Molecular biology of Molecular Genetics, 9, 861–868. GABAA receptors. Faseb Journal, 4, 1469–1480. Leana-Cox, J., Jenkins, L., Palmer, C. G., Plattner, R., Sheppard, Pinkel, D., Landegent, J., Collins, C., Fuscoe, J., Segraves, R., L., Flejter, W. L., Zackowski, J., Tsien, F., & Schwartz, S. Lucas, J., & Gray, J. (1988). Fluorescence in situ hybrid- (1994). Molecular cytogenetic analysis of inv dup(15) chro- ization with human chromosome-specific libraries: Detec- mosomes, using probes specific for the Prader-Willi/Angel- tion of trisomy 21 and translocations of chromosome 4. man syndrome region: clinical implications. American Proceedings of the National Academy of Sciences, 85, 9138– Journal of Human Genetics, 54, 748–756. 9142. Lichter, P., Cremer, T., Borden, J., Manuelidis, L., & Ward, D. Qumsiyeh, M. B., Rafi, S. K., Sarri, C., Grigoriadou, M., Gyf- C. (1988). Delineation of individual human chromosomes in todimou, J., Pandelia, E., Laskari, H., & Petersen, M. B. metaphase and interphase cells by in situ suppression (2003). Double supernumerary isodicentric chromosomes hybridization using recombinant DNA libraries. Human derived from 15 resulting in partial hexasomy. Americal Genetics, 80, 224–234. Journal of Medical Genetics Part A, 116, 356–359.

123 J Autism Dev Disord

Rineer, S., Finucane, B., & Simon, E. W. (1998). Autistic Simic, M., & Turk, J. (2004). Autistic spectrum disorder asso- symptoms among children and young adults with isodicen- ciated with partial duplication of chromosome 15; three tric chromosome 15. American Journal of Medical Genetics, case reports. European Child and Adolescent Psychiatry, 81, 428–433. 13, 389–393. Roberts, S., Maggouta, F., Thompson, R., Price, S., & Thomas, S. Thomas, N. S., Roberts, S. E., & Browne, C. E. (2003). Estimate (2002a). A patient with a supernumerary marker chromo- of the prevalence of chromosome 15q11–q13 duplications. some (15), Angelman syndrome, and uniparental disomy Americal Journal of Medical Genetics Part A, 120, 596–598. resulting from paternal meiosis II non-disjunction. Journal Vogels, A., Matthijs, G., Legius, E., Devriendt, K., & Fryns, J. P. of Medical Genetics, 39, E9. (2003). Chromosome 15 maternal uniparental disomy and Roberts, S. E., Dennis, N. R., Browne, C. E., Willatt, L., Woods, psychosis in Prader-Willi syndrome. Journal of Medical G., Cross, I., Jacobs, P. A., & Thomas, S. (2002b). Charac- Genetics, 40, 72–73. terisation of interstitial duplications and triplications of Wandstrat, A. E., & Schwartz, S. (2000). Isolation and molecular chromosome 15q11-q13. Human Genetics, 110, 227–234. analysis of inv dup(15) and construction of a physical map of Roberts, S. E., Maggouta, F., Thomas, N. S., Jacobs, P. A., & a common breakpoint in order to elucidate their mechanism Crolla, J. A. (2003). Molecular and fluorescence in situ of formation. Chromosoma, 109, 498–505. hybridization characterization of the breakpoints in 46 large Wang, N. J., Liu, D., Parokonny, A. S., & Schanen, N. C. (2004). supernumerary marker 15 chromosomes reveals an unex- High-resolution molecular characterization of 15q11–q13 pected level of complexity. American Journal of Human rearrangements by array comparative genomic hybridiza- Genetics, 73, 1061–1072. tion (array CGH) with detection of gene dosage. American Robinson, W. P., Binkert, F., Gine, R., Vazquez, C., Muller, W., Journal of Human Genetics, 75, 267–281. Rosenkranz, W., & Schinzel, A. (1993a). Clinical and Webb, T. (1994). Inv dup(15) supernumerary marker chromo- molecular analysis of five inv dup(15) patients. European somes. Journal of Medical Genetics, 31, 585–594. Journal of Human Genetics, 1, 37–50. Weidmer-Mikhail, E., Sheldon, S., & Ghaziuddin, M. (1998). Robinson, W. P., Wagstaff, J., Bernasconi, F., Baccichetti, C., Chromosomes in autism and related pervasive develop- Artifoni, L., Franzoni, E., Suslak, L., Shih, L. Y., Aviv, H., & mental disorders: a cytogenetic study. Journal of Intellectual Schinzel, A. A. (1993b). Uniparental disomy explains the Disability Research, 42(Pt 1), 8–12. occurrence of the Angelman or Prader-Willi syndrome in Werner, M., Ben-Neriah, Z., Silverstein, S., Lerer, I., Dagan, Y., patients with an additional small inv dup(15) chromosome. & Abeliovich, D. (2004). A patient with Prader-Willi syn- Journal of Medical Genetics, 30, 756–760. drome and a supernumerary marker chromosome Schinzel, A. A., Brecevic, L., Bernasconi, F., Binkert, F., Berthet, r(15)(q11.1–13p11.1)pat and maternal heterodisomy. F., Wuilloud, A., & Robinson, W. P. (1994). Intrachromos- American Journal of Medical Genetics Part A, 129, 176–179. omal triplication of 15q11–q13. Journal of Medical Genetics, Wolpert, C., Pericak-Vance, M. A., Abramson, R. K., Wright, H. 31, 798–803. H., & Cuccaro, M. L. (2000a). Autistic symptoms among Schroer, R. J., Phelan, M. C., Michaelis, R. C., Crawford, E. C., children and young adults with isodicentric chromosome 15. Skinner, S. A., Cuccaro, M., Simensen, R. J., Bishop, J., American Journal of Medical Genetics, 96, 128–129. Skinner, C., Fender, D., & Stevenson, R. E. (1998). Autism Wolpert, C. M., Menold, M. M., Bass, M. P., Qumsiyeh, M. B., and maternally derived aberrations of chromosome 15q. Donnelly, S. L., Ravan, S. A., Vance, J. M., Gilbert, J. R., American Journal of Medical Genetics, 76, 327–336. Abramson, R. K., Wright, H. H., Cuccaro, M. L., & Pericak- Shao, Y., Cuccaro, M. L., Hauser, E. R., Raiford, K. L., Menold, Vance, M. A. (2000b). Three probands with autistic disorder M. M., Wolpert, C. M., Ravan, S. A., Elston, L., Decena, K., and isodicentric chromosome 15. American Journal of Donnelly, S. L., Abramson, R. K., Wright, H. H., DeLong, Medical Genetics, 96, 365–372. G. R., Gilbert, J. R., & Pericak-Vance, M. A. (2003). Fine Xu, J., Zwaigenbaum, L., Szatmari, P., & Scherer, S. W. (2004). mapping of autistic disorder to chromosome 15q11–q13 by Molecular of autism. Current Genomics, 5, use of phenotypic subtypes. American Journal of Human 347–364. Genetics, 72, 539–548.

123