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Microduplications Upstream of MSX2 Are Associated with a Phenocopy Of Downloaded from jmg.bmj.com on April 10, 2013 - Published by group.bmj.com Copy-number variation SHORT REPORT Microduplications upstream of MSX2 are associated with a phenocopy of cleidocranial dysplasia Claus Eric Ott,1 Hendrikje Hein,2,3 Silke Lohan,1,2 Jeannette Hoogeboom,4 Nicola Foulds,5 Johannes Gru¨nhagen,1 Sigmar Stricker,1,2 Pablo Villavicencio-Lorini,1,2 Eva Klopocki,1,2 Stefan Mundlos1,2,3 < Additional materials are ABSTRACT short stature and hand abnormalities, as well as published online only. To view Background Cleidocranial dysplasia (CCD) is an other skeletal changes.1 these files please visit the autosomal dominant skeletal disorder characterised by CCD is mainly caused by loss-of-function journal online (http://jmg.bmj. com/content/49/7.toc). hypoplastic or absent clavicles, increased head mutations in runt-related transcription factor 2 RUNX2 1 circumference, large fontanels, dental anomalies and ( , MIM 600211), also known as core-binding Institute for Medical Genetics 1 2 fi and Human Genetics, short stature. Although CCD is usually caused by factor A1. The osteoblast-speci c transcription Charite´-Universita¨tsmedizin mutations leading to haploinsufficiency of RUNX2, the factor RUNX2 is a member of the runt-domain Berlin, Berlin, Germany underlying genetic cause remains unresolved in about gene family and promotes the differentiation of 2 Research Group Development 25% of cases. mesenchymal cells into osteoblasts.34Point and Disease, Max-Planck Methods Array comparative genomic hybridisation was mutations in RUNX2 can be detected in about Institute for Molecular Genetics, e Berlin, Germany performed to detect copy number variations (CNVs). 60% 70% of all affected individuals with CCD, 3Berlin-Brandenburg Center for Identified CNVs were characterised by quantitative PCR and heterozygous deletions can be identified in Regenerative Therapies (BCRT), and sequencing analyses. The effect of candidate genes about 10%.25 Berlin, Germany on mineralisation was evaluated using viral Some other hereditary skeletal disorders resemble 4Department of Clinical Genetics, Erasmus MC, overexpression in chicken cells. CCD to a certain degree, and at least some of these University Medical Center, Results In 2 out of 16 cases, the authors identified disorders result from mutations in genes that affect Rotterdam, The Netherlands microduplications upstream of MSX2 on chromosome the action of RUNX2 on its target genes. Abnor- 5 Department of Human Genetics 5q35.2. One of the unrelated affected individuals malities in core-binding factor b (CBFB, MIM and Genomic Medicine, presented with a phenocopy of CCD. In addition to University Hospital of 121360), which interacts with RUNX2, cause Southampton NHS Foundation a classical CCD phenotype, the other subject had skeletal anomalies such as large fontanelles, Trust, Faculty of Medicine, a complex synpolydactyly of the hands and postaxial hypoplasia of the distal phalanges and delayed University of Southampton, polydactyly of the feet which have so far never been ossification.6 7 Parietal foramina with cleidocranial Hampshire, UK reported in association with CCD or CNVs on 5q35.2. The dysplasia (PFMCCD, MIM 168550) is caused by w Correspondence to duplications overlap in an 219 kb region that contains loss-of-function mutations of Drosophila muscle Dr rer. nat. Eva Klopocki, several highly conserved non-coding elements which are segment homeobox gene homologue 2 (MSX2, Institute for Medical Genetics likely to be involved in MSX2 gene regulation. Functional MIM 123101) and is therefore another entity and Human Genetics, analyses demonstrated that the inhibitory effect of Msx2 aetiologically and phenotypically distinct from ´ Charite-Universita¨tsmedizin overexpression on mineralisation cannot be ameliorated RUNX2-related CCD. Characteristic clinical Berlin, Augustenburger Platz 1, Runx2 13353 Berlin, Germany; by forced expression. features of PFMCCD are mild clavicular hypoplasia, [email protected] Conclusions These results indicate that CNVs in non- craniofacial abnormalities such as a broad forehead coding regions can cause developmental defects, and and central bossing, and symmetrical oval defects Received 9 March 2012 that the resulting phenotype can be distinct from those of the parietal bones which are termed parietal Revised 17 May 2012 caused by point mutations within the corresponding foramina.8 Parietal foramina can occur in combi- Accepted 29 May 2012 MSX2 Published Online First gene. Taken together, these findings reveal an additional nation with clavicular hypoplasia in case of 20 June 2012 mechanism for the pathogenesis of CCD, particularly mutations or isolated due to mutations in MSX2 or with regard to the regulation of MSX2. aristaless-like 4 (ALX4, MIM 605420).910 Genome-wide screening methods such as micro- array-based comparative genomic hybridisation Cleidocranial dysplasia (CCD, MIM 119600) is an (array CGH) are a valuable tool to detect submi- autosomal dominant skeletal disorder that affects croscopic copy number variations (CNVs). To bones derived from endochondral as well as intra- further investigate the underlying genetic cause of membranous ossification such as the cranium, the CCD, we performed array CGH (244 K or 1M clavicles and, to a lesser degree, long bones. Char- oligonucleotide array, Agilent Technologies, Santa acteristic features of the skull are enlarged fonta- Clara, California, USA) in 16 individuals in whom nelles with delayed closure, Wormian bones, frontal mutations and CNVs in RUNX2, CBFB and MSX2 bossing and mid-face hypoplasia. The most prom- had been excluded. Data analysis was carried out as inent clinical feature is narrow, sloping shoulders described previously.11 Using this approach, we that can be apposed at the midline due to aplastic detected microduplications of different sizes on or hypoplastic clavicles. Further features include chromosome 5q35.2 in two unrelated affected indi- various dental anomalies, including supernumerary viduals (Supplementary figure S1, Supplementary teeth and delayed eruption of permanent teeth, figure S2). J Med Genet 2012;49:437e441. doi:10.1136/jmedgenet-2012-100825 437 Downloaded from jmg.bmj.com on April 10, 2013 - Published by group.bmj.com Copy-number variation Affected individual 1 (P1) presented with typical signs of CCD. (chr5:172,411,905-172,412,552) flanked by qPCR amplicons A3 As shown in figure 1A, he was able to appose his shoulders at the and A4, and the telomeric breakpoint within an w2.1 kb midline due to a complete absence of both clavicles (figure 1B). At interval (chr5:174,066,198-174,068,279) flanked by amplicons A9 the age of 4 years, he showed a persistent anterior fontanelle and A10 (figure 2A; genomic positions are given according to (figure 1C) but no signs of parietal foramina or other abnor- hg19). Analysis by PCR with primers A9-forward and A4-reverse malities of the skull (figure 1D). X-rays of the hands (figure 1E) (Supplementary table S1) on genomic DNA level allowed and the pelvis (figure 1F) revealed signs of delayed bone age. The amplification and sequencing analysis of a junction fragment anlagen of some deciduous teeth were missing (figure 1G). which contained a homology of 37 bp beginning at the telomeric Cardiac arrhythmia had been repeatedly found during cardio- site on position 174,067,202 and at the centromeric site on logical examination including Holter ECG monitoring, but no position 172,412,091 (Supplementary figure S4A). Both break- structural heart malformation was detectable by ultrasound. points were localised within AluY elements. These data are Array CGH identified an w1.7 Mb duplication upstream of consistent with unequal homologous recombination as MSX2 in this individual (Supplementary figure S1; Decipher a conceivable mechanism leading to the w1655 kb micro- BER264221). Quantitative PCR (qPCR) was used to refine the duplication oriented in direct tandem and localised w69 kb breakpoint intervals and to confirm de novo occurrence of the upstream of MSX2 (figure 2B). duplication (Supplementary figure S3A). The centromeric Affected individual 2 (P2) presented with typical features of breakpoint was localised within an w0.7 kb interval CCD. Both clavicles were absent (figure 1H), and at the age of Figure 1 Clinical phenotypes associated with microduplications at the MSX2 locus on 5q35.2. (AeG) Clinical phenotype of P1. (A) Hypermobility of the shoulders. (B) X-rays of the thorax showing absent clavicles on both sides (arrows). (C) The skull defect at the age of 4 years and 3 months is marked by an arrow (lateral view). (D) AP picture. There are no signs of parietal foramina or craniosynostosis. (E) X-rays of the hands at the age of 4 years and 6 months. The middle phalanges of digit II and V appear slightly shortened (asterisks). Os triquetrum and os lunatum are not visible in both wrists (arrows) which correspond to a carpal age of 2 years. (F) X-rays of the pelvis. On both sides, the synchondrosis ischiopubica is still open (asterisks) and the ossification centres of trochanter major are relatively small (arrows). (G) Orthopantogram at the age of 7 years and 11 months. The anlagen of the deciduous teeth 22 and 27 (circles) as well as 35 and 45 (arrows) are missing. HeJ Clinical phenotype of P2. (H) X-rays of the thorax showing absent clavicles on both sides (arrows). (I) Limb phenotype with synpolydactyly of both hands and (J) corresponding x-rays. 438 J Med Genet 2012;49:437e441. doi:10.1136/jmedgenet-2012-100825 Downloaded from jmg.bmj.com on April 10, 2013 - Published by group.bmj.com Copy-number variation Figure 2 Schematic overview of microduplications at the MSX2 locus on 5q35.2. The duplicated sequences observed in the affected individuals with CCD are shown as coloured rectangles (green, duplication P1; orange, proximal duplicon P2; yellow, distal duplicon P2). Coloured boxes in B and C correspond to the junction fragments shown in Supplementary figure S4. (A) The approximate positions of quantitative PCR amplicons used to refine the breakpoint intervals are indicated (A1eA10). On top, the proximal overlapping duplicated sequence (region 1) is enlarged showing the genes within this interval.
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