Severe language delay associated with duplication of the Williams-Beuren critical region. J.S. Berg¹, N. Brunetti-Pierri¹, B. Nowakowska^1,2, E. Obersztyn², C-T. Fong³, A. Summers⁴, A. Patel¹, A.L. Beaudet¹, S.W. Cheung¹. 1) Dept of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX; 2) Dept of Medical Genetics, Institute of Mother and Child, Warsaw, Poland; 3) Pediatric Genetics, University of Rochester, New York, NY; 4) North Bay Health Unit - Genetics, Ontario, Canada.
   The Williams-Beuren Syndrome (WBS) is among the most well-characterized microdeletion syndromes, caused in most cases by recurrent de novo deletions at 7q11.23 mediated by non-allelic homologous recombination between low copy repeats (LCR) flanking this region. Given the presence of numerous LCRs and the frequency with which deletions in the WBS region are observed, one would expect that duplications of the same segment might also occur. This hypothesis was recently demonstrated to be correct with the identification of an eight-year-old male with severe language delay and duplication of the WBS critical region (Somerville, NEJM 2005). However, the degree to which duplications of this region contribute to the overall burden of language delay or other developmental disorders is unclear.
   We now report five additional patients with severe language delay associated with 7q11.23 duplications. Two patients with prominent language delay were found to have reciprocal duplications of the classical WBS critical region. One 47,XXY patient with uncharacteristically severe language delay was found to have ~33% mosaicism for a ring chromosome containing material from 7q11.23. Two siblings with dysmorphic features and significant language delay were shown to have ~20% mosaicism for a >10 Mb 7q11-q11.23 duplication. These duplications were all first identified by array-comparative genomic hybridization and confirmed by FISH, thus confirming the initial report of severe language delay seen in duplication of the WBS region and further delineating the phenotypic spectrum of this condition. We propose that duplications of the WBS region may be more frequent than previously suspected and that screening for this duplication is warranted in children with language delay.