title: Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis.
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.
authors.affiliation: Department of Pediatrics, University Hospital, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany.
authors.forename: Carl Friedrich
authors.initials: CF
authors.lastname: Classen
authors.forename: Vera
authors.initials: V
authors.lastname: Riehmer
authors.forename: Christina
authors.initials: C
authors.lastname: Landwehr
authors.forename: Anne
authors.initials: A
authors.lastname: Kosfeld
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.forename: Caroline
authors.initials: C
authors.lastname: Scholz
authors.forename: Sarah
authors.initials: S
authors.lastname: Kabisch
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Sascha
authors.initials: S
authors.lastname: Tierling
authors.forename: Miroslav
authors.initials: M
authors.lastname: Zivicnjak
authors.forename: Frank
authors.initials: F
authors.lastname: Schacherer
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D018628:Gene Dosage; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C111952:OPHN1 protein, human
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