Chromosomal and DNA anomalies are reported inapproximately 5% of cases, the most common beingfragile X syndrome followed by maternally inheritedtrisomy or tetrasomy of chromosome 15q11.2. There arelimited reports in the literature of an association betweendeletions on chromosome 2 and autism. These reportsseem to be mainly confined to patients with a deletionof 2q37 to the telomere.

Here we report a case of autism associated witha small deletion of chromosome 2 not previously rec-orded in the literature. We believe that this is the firstcase of autism reported as being associated with thesebreakpoints and with such a small deletion. This caseis also interesting because the individual is less se-verely affected than other reported cases of chromo-some 2q deletions.

CLINICAL REPORT

K. is a 14-year-old boy who was ascertained forthe purposes of a molecular genetic study in autism andwas referred for chromosomal analysis to exclude achromosomal origin of his autism.

INTRODUCTION

Autism and Genetics

The clinical syndrome of autism was first describedby Kanner in 1943. It is a neurodevelopmental disorderof childhood presenting with deficits in the three areasof communication, social interaction, and behavior. Thecause(s) of autism are unknown, but there is significantevidence from twin and family studies to suggest thatgenetic factors play a major role in the etiology (Stef-fenburg et al.,1991; Bailey et al.,1995). Linkage stud-ies have found putative evidence for linkage on severalregions and association studies are ongoing (IMGSAC,1998; CLSA, 1999; PARIS, 1999; Risch et al., 1999).

Brief Report: A Case of Autism Associatedwith del(2)(q32.1q32.2) or (q32.2q32.3)

Louise Gallagher,1,2,5 Kristin Becker, 3 Geraldine Kearney,1 Adam Dunlop,3

Ray Stallings,3,4 Andrew Green,3,4 Michael Fitzgerald,1 and Michael Gill,1,2

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occurin the three core areas of communication, social interaction, and behavior. The causes of autismare unknown, but clinical genetic studies show strong evidence in favor of a genetic etiology.Molecular genetic studies report some association with candidate genes, and candidate regionshave emerged from several genome-wide linkage studies. Here we report a clinical case ofautism with a deletion on chromosome 2 in a young male with high-functioning autism. Thedeletion seems to correspond with regions emerging from linkage studies. We propose this asa possible candidate region in the search for autism genes.

KEY WORDS: Autism; genetics; cytogenetics; chromosome 2q.

Journal of Autism and Developmental Disorders, Vol. 33, No. 1, February 2003 (© 2003)

1050162-3257/03/0200-0105/0 © 2003 Plenum Publishing Corporation

1 Department of Psychiatry, Trinity College, Dublin.2 Department of Genetics, Smurfit Institute, Trinity College, Dublin 2.3 National Centre for Medical Genetics, Our Lady’s Hospital,

Crumlin, Dublin 12.4 Department of Medical Genetics, The Conway Institute, University

College, Dublin.5 Autism Research Group, Neuropsychiatric Genetics, Trinity College,

Dublin 2, Republic of Ireland. e-mail: lgallagh@tcd.ie

106 Gallagher et al.

He was born by spontaneous vaginal delivery atterm to healthy parents (mother 20 years old, father27 years old) following a normal pregnancy. Earlymilestones were normal. He did not have any congen-ital malformations, and his physical development andgrowth were normal. Abnormalities in his developmentwere first noted by his parents at 30 months, when hestopped using previously acquired language. This wasassociated with the onset of self-injury, tantrums, anda dislike of crowds. At the time of his third birthday hewas referred to a pediatrician who diagnosed develop-mental delay. Toilet training was not fully achieved until72 months, and there were episodes of nocturnal enure-sis occurring until 96 months. He had difficulties inmainstream school, which he commenced at 51 months,and these continued despite a change of school. Fol-lowing psychological assessment he was diagnosed asbeing on the autism spectrum with a mild learning dis-ability and was referred to a local special needs school.His current academic progress is generally in keepingwith his level of learning disability; however, he dis-plays ability for reading and language comprehensionthat exceeds the level expected in the normal popula-tion for this age-group.

Clinical Assessment

He was assessed using the Autism DiagnosticInterview–Revised (ADI-R) (Le Couteur et al., 1989)and the Autism Diagnostic Interview–Generic (ADOS-G) (Lord et al., 2000), standardized research tools forthe diagnosis of autism.

The findings on the ADI-R indicated that he metthe criteria for classic autism at age 4–5 years. He haddeficits in all three areas of communication, reciprocalsocial interaction, and behavior. His language was lim-ited to simple phrase speech at 4–5 years and primarilyfor the purposes of addressing his needs. He did not makeuse of gaze and gesture at this age. His language wasquite advanced for his age and general level of ability,but he still had limited integration of gesture with lan-guage for the purposes of communication. At 4–5 yearshe was described as living in a world of his own anddid not mix with his peers. Play was limited and lack-ing imagination. He still had difficulties forming nor-mal social relationships and had been the subject ofbullying. He had a restricted range of interests in booksand locomotive engines, which tended to dominate hisconversation. He showed evidence of repetitive use ofobjects in the past. He is somewhat routine and ritual-istic. He had stereotyped complex mannerisms in whichhe engaged when bored or frustrated. He engaged in

self-injury in the past but this was no longer in evidence.His scores on the ADI-R algorithm for impairments insocial interaction, communication, repetitive behaviorsand abnormality of development were 20, 12, 6, and 5,respectively.

On direct assessment with the ADOS-G he scoredmildly under the cut-off for classic autism on recip-rocal social interaction. Notably, his eye contact wasconsidered quite good. His scores on the ADOS-Galgorithm for communication, impairments in socialinteraction, imagination, and stereotyped behaviors/restricted interests were 4, 4, 1, and 1, respectively.Communication and social scores were 8 combined,which is below the autism cut-off but places him on theautism spectrum.

Physical Findings

On physical examination he was noted to be talland slim with long fingers and toes. He displayedhyperextensibility around his wrist and had flat feet,a high-arched palate and pectus carinatum. The pos-sibility of Marfan syndrome had been raised by acommunity pediatrician. There was no family historyof Marfan. An echocardiogram was normal. An eyeexamination for lens dislocation was normal. His ap-pearance was therefore of a Marfanoid habitus, ratherthan actual Marfan syndrome.

Cytogenetic Studies

Chromosomal analysis of G-banded metaphasesshowed a male karyotype with a small interstitialdeletion on part of the long arm of chromosome 2.[del(2)(q32.1q32.2) or (q32.2q32.3)] (Fig. 1). Exactbreakpoints were difficult to define, but the deletion

Fig. 1. G-banded metaphase chromosome 2 homologues displayingthe normal banding pattern for bands q32.1 and q32.2 (left) and adeletion of either band q32.1 or q32.2 (right).

appears to involve either band 2q32.1 or 2q32.3.Because there are reports in the literature of an associ-ation between autism and a deletion of 2q37, FISHanalysis using the 2qtel probe was performed for thisregion. This showed the presence of the distal portionsof both chromosomes 2.

Chromosomal analyses of the parents revealednormal karyotypes in both cases. Thus the identifieddeletion seems to have arisen de novo.

DISCUSSION

This is the first case that we are aware of show-ing an association between autism and an interstitialdeletion of chromosome 2q. There have been reportsof an association between the disorder and deletionsinvolving 2q37 (Ghaziuddin & Burmeister, 1999;Stein, Del Signore, Bellinger, & Bryke, 1992), but wehave confirmed the presence of this region in thisindividual. There have been a number of other reportsof deletions of 2q31q33 (Al-Awadi et al.,1983; Bensenet al.,1986; Buchanan et al.,1983; Franceschim et al.,1983; Taysi et al., 1981; Young et al., 1983) and atleast one report of a duplication of this region (Rameret al.,1990). None of these cases report an associationwith autism, although, as Ghaziuddin and Burmeisternote, some of these reported cases were too young atthe time for a diagnosis of autism to have been made.The most consistent clinical manifestations of thesereports include low birth weight, cleft palate, devel-opmental delay/learning disability generally in themoderate range, microcephaly, and abnormalities ofthe digits, including syndactyly and camptodactyly.Pai, Rogers, & Sommer (1983) reported siblings witha deletion of 2q37. Both cases had developmentaldelay, microcephaly, micrognathia, and abnormal ears.

This case differs from all of the above in that thedeletion reported is much smaller and the clinicalmanifestations are mild. Apart from above-averageheight, which appears to be familial, and high-archedpalate, no dysmorphic features were noted. The levelof learning disability was in the mild range, with anabove-average ability for reading and language com-prehension out of keeping with the degree of disabil-ity. His clinical presentation is significant mainly forthe presence of an autistic spectrum disorder.

The relationship between autism and genetic fac-tors has been established through clinical genetic stud-ies, and there have been several published genome-widelinkage studies showing putative evidence for linkageon chromosomes 1p, 2q, 6p, 7q, 15q, 16p, and 19p

A Case of Autism Associated with del(2)(q32.1q32.2) or (q32.2q32.3) 107

(IMGSAC, 1998; CLSA 1999; Buxbaum et al., 2001;Phillipe et al.,1999; Risch et al.,1999). Strong evidencefor linkage on chromosome 2 was recently published(IMGSAC, 2001), reporting a multipoint MaximumLod Score (MLS) of 3.74 at marker D2S2188, whichincreases to 4.80 when the analysis was confined to asubset of families using strict diagnostic criteria.Buxbaum et al.,(2001), reported a maximal multipointnonparametric linkage (NPL) score of 2.39 betweenmarkers D2S364 and D2S335. Analysis of familiesmeeting stricter diagnostic criteria increased the evi-dence for linkage in this region to an NPL score of 3.32.The deletion identified in this boy lies within the re-gions showing evidence for linkage in the publishedstudies. There are a considerable number of potentialcandidate genes within the putative deleted region,including several neurally expressed transcriptionfactors and signal transduction genes. We propose thatthis region may also be significant in the search for sus-ceptibility genes in autism. We are in the process ofmapping the deletion on the molecular level and willreport our findings shortly.

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