Abstract
When a known microimbalance affecting multiple genes is detected in a patient with syndromic intellectual disability, it is usually presumed causative for all observed features. Whole exome sequencing (WES) allows questioning this assumption. In this study of three families with children affected by unexplained syndromic intellectual disability, genome-wide copy number and subsequent analyses revealed a de novo maternal 1.1 Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. In patient 1 carrying the 14q32 microdeletion, tall stature and renal malformation were unexplained by paternal UPD(14), and there was no altered DLK1 expression or unexpected methylation status. By WES and filtering with a mining tool, a novel FBN1 missense variant was found in patient 1 and his mother, who both showed clinical features of Marfan syndrome by thorough anthropometric assessment, and a novel EYA1 missense variant as a probable cause of the renal malformation in the patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- and hyperpigmentation and two malignancies were only partially explained. By WES, compound heterozygous BLM stop founder mutations were detected causing Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited from his unaffected father, WES identified a novel missense variant in the OPHN1 X-linked intellectual disability gene inherited from the unaffected mother as a possible additional cause for developmental delay. Thus, WES seems warranted in patients carrying microdeletions or microduplications, who have unexplained clinical features or microimbalances inherited from an unaffected parent.
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Acknowledgments
We express our gratitude to the children and their families for kindly participating in this study. We thank Gabriele Krüger and Monika Mix, Rostock, Germany, for excellent patient care; Bernhard Radlwimmer, Heidelberg, Germany, for providing large insert clone arrays; Saskia Biskup, CeGaT GmbH, Tübingen, Germany, and Daniel Swan, OGT, Begbroke, UK, for providing technical details of WES; Christian Kubisch, Ulm, Manfred Stuhrmann-Spangenberg and Mine Arslan-Kirchner, Hannover, Germany, for helpful scientific discussions. Support for this study was obtained from the Else Kröner-Fresenius-Stiftung (2010_A97). The funding organization had no role in the design or conduct of this research. The contents of this publication reflect only the authors’ views and not the views of the funding organization.
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C. F. Classen and V. Riehmer contributed equally as first authors. D. Haffner and R. G. Weber contributed equally as senior authors.
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Classen, C.F., Riehmer, V., Landwehr, C. et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet 132, 825–841 (2013). https://doi.org/10.1007/s00439-013-1296-1
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DOI: https://doi.org/10.1007/s00439-013-1296-1