Hum Genet (2010) 128:3–26 DOI 10.1007/s00439-010-0827-2 REVIEW ARTICLE Copy number variants at Williams–Beuren syndrome 7q11.23 region Giuseppe Merla · Nicola Brunetti-Pierri · Lucia Micale · Carmela Fusco Received: 23 February 2010 / Accepted: 13 April 2010 / Published online: 1 May 2010 © Springer-Verlag 2010 Abstract Copy number variants (CNVs) of the Williams– CNVs, including the neurocognitive phenotypes, are still Beuren syndrome (WBS) 7q11.23 region are responsible debated. Recent studies suggest that besides the role of the for neurodevelopmental disorders with multi-system genes in the deleted/duplicated interval, multiple factors involvement and variable expressivity. Typical features of such as regulatory sequences, epigenetic mechanisms, WBS microdeletion comprise a recognizable pattern of parental origin of the CNV, and nucleotide variations in the facial dysmorphisms, supravalvular aortic stenosis, connec- non-deleted/duplicated allele may be important in deter- tive tissue abnormalities, hypercalcemia, and a distinctive mining the variable expressivity of 7q11.23 CNV pheno- neurobehavioral phenotype. Conversely, the phenotype of types. Here, we review the clinical and molecular Wndings patients carrying the 7q11.23 reciprocal duplications and the recent insights on genomic disorders associated includes less distinctive facial dysmorphisms and promi- with CNVs involving the 7q11.23 region. nent speech delay. The common deletion/duplication ranges in size from 1.5 to 1.8 Mb and encompasses approxi- mately 28 genes. This region is Xanked by low copy repeats Introduction (LCRs) with greater than »97% identity, which can medi- ate non-allelic homologous recombination resulting from Duplications and deletions, collectively known as copy misalignment of LCRs during meiosis. A clear genotype– number variants (CNVs), are the most prevalent types of phenotype correlation has been established in WBS only structural variations in the human genome (Iafrate et al. for the elastin gene, which is responsible for the vascular 2004; Redon et al. 2006; Sebat et al. 2004). Analysis of the and connective tissue abnormalities. The molecular sub- reference sequence shows that »5% of the human genome strates underlying the other clinical features of 7q11.23 contains CNVs (Bailey et al. 2002; McCarroll et al. 2008). While aVecting functions such as inXammatory response, immunity, and cell proliferation may play a key role in G. Merla (&) · L. Micale · C. Fusco human genome evolution, genomic duplications and dele- Laboratory of Medical Genetics, IRCCS Casa Sollievo Della tions are also an important cause of human diseases (Lupski V So erenza Hospital, San Giovanni Rotondo, Italy 1998) and disease susceptibility (Stankiewicz and Lupski e-mail: [email protected] 2002; Wain et al. 2009). Several studies found that CNVs N. Brunetti-Pierri make a substantial contribution to the genetic mechanisms Telethon Institute of Genetics and Medicine, underlying human diseases and provide greater insight into Via P. Castellino 111, Naples, Italy the etiology of phenotypes that result from complex genetic N. Brunetti-Pierri patterns of inheritance such as neurodevelopmental dis- Department of Pediatrics, eases, autism spectrum disorders, bipolar disorders, and Federico II University of Naples, Naples, Italy schizophrenia (Beckmann et al. 2007). CNVs result in the alteration of a variable number of genes causing changes in N. Brunetti-Pierri Department of Molecular and Human Genetics, gene dosages, which ultimately may lead to disease predis- Baylor College of Medicine, Houston, TX, USA position or speciWc clinical phenotypes. Moreover, as 123 4 Hum Genet (2010) 128:3–26 emerged more recently, the disruption of regulatory regions veriWed with the identiWcation of patients with 7q11.23 within the CNVs can also result into altered dosage and duplications (OMIM 609757). function of genes outside the deleted or duplicated intervals Given the frequency of patients with de novo microdele- (Henrichsen et al. 2009a; Henrichsen et al. 2009b; Merla tions of the WBS critical region, it is surprising that micro- et al. 2006). duplication of WBS region was Wrst reported only recently Chromosomal rearrangements below the limit of detec- (Somerville et al. 2005). This is likely due to a convergence tion of conventional karyotyping contribute signiWcantly to of factors. First, the phenotypes seen in patients with the cause of mental retardation and congenital malforma- 7q11.23 microduplications are quite unlike those seen with tions (Zhang et al. 2009). Interstitial deletions of 7q11.23 the common WBS microdeletion, and Xuorescent in situ cause Williams–Beuren syndrome (WBS; OMIM 194050), hybridization (FISH) analysis of metaphase cells is unlikely one of the best characterized genomic disorders aVecting 1/ to clearly detect the microduplication (ShaVer et al. 1997). 7,500–1/10,000 live births (Stromme et al. 2002). As with Clinicians were unlikely to order interphase FISH for WBS many other genomic disorders, the common recurrent 1.55- in patients who were not clinically suspected to have WBS. Mb microdeletion occurs by non-allelic homologous In fact, the Wrst patient reported to harbor a microduplica- recombination (NAHR) (Stankiewicz and Lupski 2002) tion of chromosome 7q11.23 was initially evaluated for between LCRs (Urban et al. 1996) Xanking the deleted velocardiofacial syndrome (VCFS) by real-time quantita- region (Bayes et al. 2003; Hillier et al. 2003) (Fig. 1). tive PCR (qPCR) that instead fortuitously revealed duplica- Because NAHR can generate both microdeletions and tion of markers within the WBS region (Somerville et al. microduplications, it was suspected that reciprocal micro- 2005). Second, although the recombination reciprocal of duplication of microdeletion syndromes should also occur the WBS microdeletion was postulated to occur (Lupski (Lupski 1998). With the advent of diagnostic array compar- 1998), it would have been diYcult to predict the phenotype ative genomic hybridization (aCGH), this prediction was associated with the microduplication based on what was Fig. 1 Schematic representation of 7q11.23 genomic rearrangements medial copy of LCR block B and within the centromeric and the medial (not drawn to scale). The centromeric (c), middle (m), and telomeric (t) copy of LCR block A are shown. Schematic representation of the LCRs are shown as colored arrows with their relative orientation to 7q11.23 deletion, duplication, triplication, and inversion are shown. In each other. Please note that multicopy genes within the blocks are the triplication case, the location of the breakpoints is shown with represented only once. In the middle, the common deletions of 1.5 and black dots representing the blocks Am, Bt and the region between 1.8 Mb are depicted; breakpoints within the centromeric and the FZD9 and BAZ1B genes, respectively 123 Hum Genet (2010) 128:3–26 5 known about the contributions of genes in this region to the speciWc growth charts is recommended (Giannotti et al. WBS phenotype. 2001; Hill et al. 2005; Pittschieler et al. 1993; Partsch et al. 1999; Santer et al. 1996). Although it was recognized early as a feature of WBS 7q11.23 deletion syndrome: clinical Wndings (Black and Carter 1963), transient hypercalcemia is docu- mented only in a minority (6–15%) of patients (American The Wrst pictures of patients with WBS were likely reported Academy of Pediatrics Committee on Genetics 2001; in 1956 by Dr. Schlesinger in a paper describing the associ- Amenta et al. 2005; Ferrero et al. 2007). ation of unusual facies and infantile hypercalcemia (Schle- A prevalence of 2–40% of hypothyroidism, which is singer et al. 1956). Dr. Williams was the Wrst to recognize more frequently subclinical, has been described (American WBS as a distinct clinical entity in 1961 (Williams et al. Academy of Pediatrics Committee on Genetics 2001; 1961) and shortly thereafter, Dr. Beuren reported four more Amenta et al. 2005; Cambiaso et al. 2007; Cherniske et al. WBS patients (Beuren et al. 1962). Since then the WBS 2004; Ferrero et al. 2007; Stagi et al. 2005). Reduced vol- phenotype has been extensively studied and aVected indi- ume and morphological abnormalities of the thyroid gland viduals typically have a distinctive facies, cardiovascular such as hypoplasia, hemiagenesis, and ectopia have been abnormalities, connective tissue anomalies, infantile hyper- reported (Cambiaso et al. 2007; Stagi et al. 2005). Another calcemia, and a characteristic neurocognitive and behav- common endocrine abnormality, especially in WBS adults, is ioral phenotype (Pober 2010). diabetes mellitus or impaired glucose tolerance (Cherniske et al. 2004). Facial characteristics Cardiovascular abnormalities and connective tissue The distinctive WBS facial Wndings include broad fore- involvement head, periorbital fullness, epicanthal folds, Xat nasal bridge, a short upturned nose, long philtrum, and wide mouth with The connective tissue abnormalities include a hoarse/deep full lips, full cheeks, and small jaw. In blue- and green-eyed voice, hernias, bladder/bowel diverticulae, soft/lax skin, individuals, a stellate or lacy pattern of the irides is usually joint laxity or limitation, and cardiovascular anomalies. The present (Greenberg and Lewis 1988). Patients with WBS spectrum, natural history, and pathological Wndings of car- also exhibit malocclusion, hypoplastic enamel, a high preva- diovascular and connective tissue lesions in WBS patients lence of dental caries, small and slender