Original Investigation

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

  • Carl Friedrich ClassenAffiliated withDepartment of Pediatrics, University Hospital
  • , Vera RiehmerAffiliated withDepartment of Human Genetics, Hannover Medical SchoolInstitute of Human Genetics, University of Bonn
  • , Christina LandwehrAffiliated withInstitute of Human Genetics, University of BonnInstitute for Medical Diagnostics
  • , Anne KosfeldAffiliated withDepartment of Human Genetics, Hannover Medical School
  • , Stefanie HeilmannAffiliated withInstitute of Human Genetics, University of BonnDepartment of Genomics, Life and Brain Centre, University of Bonn
  • , Caroline ScholzAffiliated withDepartment of Human Genetics, Hannover Medical School
  • , Sarah KabischAffiliated withDepartment of Pediatrics, University HospitalDivision of Neonatology and Intensive Care, Department of Pediatrics, University Hospital Hamburg-Eppendorf
  • , Hartmut EngelsAffiliated withInstitute of Human Genetics, University of Bonn
  • , Sascha TierlingAffiliated withFR8.3 Biowissenschaften, Genetik/Epigenetik, Universität des Saarlandes
    • , Miroslav ZivicnjakAffiliated withDepartment of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School
    • , Frank SchachererAffiliated withBiobase GmbH
    • , Dieter HaffnerAffiliated withDepartment of Pediatrics, University HospitalDepartment of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School
    • , Ruthild G. WeberAffiliated withDepartment of Human Genetics, Hannover Medical SchoolInstitute of Human Genetics, University of Bonn Email author 

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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.