Human Genetics

, Volume 132, Issue 7, pp 825–841

Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis

Authors

  • Carl Friedrich Classen
    • Department of PediatricsUniversity Hospital
  • Vera Riehmer
    • Department of Human GeneticsHannover Medical School
    • Institute of Human GeneticsUniversity of Bonn
  • Christina Landwehr
    • Institute of Human GeneticsUniversity of Bonn
    • Institute for Medical Diagnostics
  • Anne Kosfeld
    • Department of Human GeneticsHannover Medical School
  • Stefanie Heilmann
    • Institute of Human GeneticsUniversity of Bonn
    • Department of Genomics, Life and Brain CentreUniversity of Bonn
  • Caroline Scholz
    • Department of Human GeneticsHannover Medical School
  • Sarah Kabisch
    • Department of PediatricsUniversity Hospital
    • Division of Neonatology and Intensive Care, Department of PediatricsUniversity Hospital Hamburg-Eppendorf
  • Hartmut Engels
    • Institute of Human GeneticsUniversity of Bonn
  • Sascha Tierling
    • FR8.3 Biowissenschaften, Genetik/EpigenetikUniversität des Saarlandes
  • Miroslav Zivicnjak
    • Department of Pediatric Kidney, Liver and Metabolic DiseasesHannover Medical School
  • Frank Schacherer
    • Biobase GmbH
  • Dieter Haffner
    • Department of PediatricsUniversity Hospital
    • Department of Pediatric Kidney, Liver and Metabolic DiseasesHannover Medical School
    • Department of Human GeneticsHannover Medical School
    • Institute of Human GeneticsUniversity of Bonn
Original Investigation

DOI: 10.1007/s00439-013-1296-1

Cite this article as:
Classen, C.F., Riehmer, V., Landwehr, C. et al. Hum Genet (2013) 132: 825. doi:10.1007/s00439-013-1296-1

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.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013