Estimate of the prevalence of chromosome 15q11‐q13 duplications

We refer to the recent letter in which Moeschler et al. [2002] estimated a frequency of 1 in 200 for chromosome 15q11-q13 duplications. The figure was derived from a molecular screen of 400patients referredwith suspected fragile X. As part of a 5 year study to characterize structural abnormalities of chromosome 15, we recently published our findings on 16 interstitial duplications [Roberts et al., 2002]. Collecting these patients took considerable effort and in our experience a frequency of 1 in 200 seems an overestimate We first reported that cytogenetically visible duplications of proximal 15q could be divided into those which included the critical region for Prader–Willi and Angelman syndromes (PWACR) in 15q11-q13 [Browne et al., 1997] and those caused by more proximal pseudogene expansions [Barber et al., 1998]. Routine cytogenetic analysis during the previous 3 years identified a PWACR positive duplication in approximately 1 in 600 individuals referred with developmental delay. In support of this estimate we re-assessed samples referred to the Wessex Regional Genetics Laboratory (Salisbury, UK) for cytogenetic analysis over the period January 1997 to September 2002 (Table I). Karyotypes were determined for all patients by analysis of G banded metaphase chromosomes, harvested from peripheral blood, at an ISCN band level of 550. During this time we received 2,982 samples referred with developmental delay or suspected fragile X and 327 samples with behavioral problems suspected to fall within an Autistic Spectrum Disorder (ASD). The majority of the ASD referrals had developmental delay and were tested to exclude fragile X. From this total of 3,309 individuals we identified four who carried a cytogenetically visible 15q11-q13 duplication (Table II). Not all PWACR duplications are visible cytogenetically [Roberts et al., 2002] and so a cytogenetic screen alone may underestimate the frequency. In order to detect cryptic duplications we screened a subset of the cytogenetic referrals using a combination of two PCR methods: microsatellite analysis at 4–6 loci within the PWACR and quantitative fluorescent PCR at a further 2 loci [Roberts et al., 2002]. Almost all duplications are of a uniform size and include the entire 4 Mb PWACR cassette. Approximately two thirds of interstitial duplications arise from an interchromosomal event and would be recognized by the presence of three different alleles. The remaining one third of duplications are intrachromosomal in origin and would require assessment of thepeakheights ofmicrosatellite products.Both categories would be detected by quantitative PCR. Thus we are unlikely to miss any standard duplications. Using both PCRmethods we tested a total of 457 cytogenetic referrals and an additional 83 autistic individuals, who underwent an Autism Diagnostic Interview, forwhomwereceived onlyaDNAsample.Themolecular screen identified one additional interstitial duplication carrier and one individual with a cryptic maternal deletion of 15q11-q13 resulting in a diagnosis of AS (Table I). Both abnormalities were confirmed by FISH. Although we found no abnormalities in 83 patients with confirmed autism (molecularly) and 327with a suspectedASD (cytogenetically), imbalances of thePWACR represent one of the most frequent chromosome disorders found in autistic samples. From patients attending an autism clinic Cook et al. [1997] estimated that collectively chromosome 15 rearrangements could account for up to 3% of cases. Full details of the five duplication carriers are reported in Roberts et al. [2002] but a summary is given in Table II. The twopatients in familyfivewerehalf-sisters but considered as independent referrals because one sister carried two separate duplications, one inherited from each parent. The study of Moeschler et al. [2002] screened patients with developmental delay and reported one patient with an interstitial duplication, one patient with a supernumerarymarker chromosome, SMC(15), and one patient with an apparent duplication who also carried an unidentified marker chromosome. (Approximately 50% of SMC(15) are derived from chromosome 15 [Buckton et al., 1985; Blenow et al., 1995] and it was not indicated whether FISH analysis was performed to demonstrate that the additional PWACR copies were interstitial rather than carried on the SMC. ) *Correspondence to: Dr. N. Simon Thomas, Ph.D., Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, United Kingdom. E-mail: dr.s. thomas@salisbury.nhs. uk