Senior Corresponding Authors: Matthew E. Hurles, The Wellcome Trust Sanger Institute,

SUMMARYThe Williams-Beuren syndrome (WBS) locus, at 7q11.23, is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS, a multisystem condition with characteristic cardiovascular, cognitive, and behavioral features. It is hypothesized that reciprocal duplications of the WBS interval should also occur, and here we present such a case description. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. Our results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities.The underlying genetic bases for the majority of cases of language impairment have been postulated to be complex, involving several loci that interact with one another and the environment to produce an overall susceptibility to disease onset. 1 Clues to the discovery of which genes potentially influence language ability may be found in mendelian disorders that have distinctive language components to their clinical phenotype. The Williams-Beuren syndrome (WBS) is one such neurodevelopmental disorder, in which persons show considerable strength in expressive language relative to their overall level of intellectual ability. 2 WBS is also associated with a recognizable facies, supravalvular aortic stenosis, hypersensitivity to sound, visual impairment, dental problems, growth deficiency, infantile hypercalcemia, musculoskeletal abnormalities, and a hoarse voice. 3 The syndrome is caused CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptby the recurrent deletion of a specific set of genes, so it provides a unique opportunity to identify genes that are directly involved in language ability. 4 The chromosomal locus that is deleted in WBS (on chromosome 7, band q11.23) is prone to deletion because it is flanked by blocks of DNA that have a very high degree of similarity to one another (called low copy repeats [LCRs]). 4 The deletions, which almost invariably span a common interval, are caused by nonallelic homologous recombination within the LCRs of either the same chromosome 7 (i.e., intrachromosomal) or different chromosome 7s (i.e., interchromosomal). In each case, the chromosomes are envisaged to form loops, thereby allowing the alignment of the two LCRs, the occurrence of recombination, and the excision of the DNA contained within the intervening loop. 4 The syndrome occurs at a frequency of approximately 1 in 7500 live births, with approximately two thirds of the deletion events being interchromosomal. 5 Other microdeletion disorders -including the velocardiofacial syndrome, the Smith-Magenis syndrome, the Prader-Willi and Angelman syndromes, and hereditary neuropathy with liability to pressure palsies -are also mediated by nonallelic homologous recombination. 6 For each of these microdeletions, a reciprocal duplication disorder has also been identified: dup22q11.2, dup17p11.2, dup15q11-q13, a...

22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patient's mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.

Abstract-Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (ACPL1 and Cx50 gene, GJA8) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5-to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.