J Autism Dev Disord DOI 10.1007/s10803-006-0225-8 ORIGINAL PAPER Characterization of an Autism-Associated Segmental Maternal Heterodisomy of the Chromosome 15q11–13 Region Dorota A. Kwasnicka-Crawford Æ Wendy Roberts Æ Stephen W. Scherer Ó Springer Science+Business Media, Inc. 2006 Abstract Cytogenetic abnormalities in the Prader- Keywords Autistic disorder Æ Chromosomal Willi/Angelman syndrome (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 chromosomes (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 chromosome 15, 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 centromeres 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, seizure 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