title: Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving theDPYDenigma.
abstract: We describe an as yet unreported neocentric small supernumerary marker chromosome (sSMC) derived from chromosome 1p21.3p21.2. It was present in 80% of the lymphocytes in a male patient with intellectual disability, severe speech deficit, mild dysmorphic features, and hyperactivity with elements of autism spectrum disorder (ASD). Several important neurodevelopmental genes are affected by the 3.56 Mb copy number gain of 1p21.3p21.2, which may be considered reciprocal in gene content to the recently recognized 1p21.3 microdeletion syndrome. Both 1p21.3 deletions and the presented duplication display overlapping symptoms, fitting the same disorder category. Contribution of coding and non-coding genes to the phenotype is discussed in the light of cellular and intercellular homeostasis disequilibrium. In line with this the presented 1p21.3p21.2 copy number gain correlated to 1p21.3 microdeletion syndrome verifies the hypothesis of a cumulative effect of the number of deregulated genes - homeostasis disequilibrium leading to overlapping phenotypes between microdeletion and microduplication syndromes. AlthoughmiR-137appears to be the major player in the 1p21.3p21.2 region, deregulation of theDPYD (dihydropyrimidine dehydrogenase) gene may potentially affect neighboring genes underlying the overlapping symptoms present in both the copy number loss and copy number gain of 1p21. Namely, the all-in approach revealed thatDPYDis a complex gene whose expression is epigenetically regulated by long non-coding RNAs (lncRNAs) within the locus. Furthermore, the long interspersed nuclear element-1 (LINE-1)L1MC1transposon inserted inDPYDintronic transcript 1 (DPYD-IT1) lncRNA with its parasites,TcMAR-Tigger5band pair ofAlurepeats appears to be the "weakest link" within theDPYDgene liable to break. Identification of the precise mechanism through whichDPYDis epigenetically regulated, and underlying reasons why exactly the break (FRA1E) happens, will consequently pave the way toward preventing severe toxicity to the antineoplastic drug 5-fluorouracil (5-FU) and development of the causative therapy for the dihydropyrimidine dehydrogenase deficiency.
authors.affiliation: Croatian Institute for Brain Research, University of Zagreb Medical School, Šalata 12, 10000 Zagreb, Croatia; Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb Medical School, University Hospital Center Zagreb, Šalata 2, 10000 Zagreb, Croatia.
authors.forename: Lukrecija
authors.initials: L
authors.lastname: Brečević
authors.affiliation: Croatian Institute for Brain Research, University of Zagreb Medical School, Šalata 12, 10000 Zagreb, Croatia; Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb Medical School, University Hospital Center Zagreb, Šalata 2, 10000 Zagreb, Croatia; Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rinčić
authors.affiliation: Croatian Institute for Brain Research, University of Zagreb Medical School, Šalata 12, 10000 Zagreb, Croatia.
authors.forename: Željka
authors.initials: Ž
authors.lastname: Krsnik
authors.affiliation: Croatian Institute for Brain Research, University of Zagreb Medical School, Šalata 12, 10000 Zagreb, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Sedmak
authors.affiliation: Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Ahmed B
authors.initials: AB
authors.lastname: Hamid
authors.affiliation: Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Kosyakova
authors.affiliation: Center for Rehabilitation Stančić, Stančić bb, 10370 Stančić, Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Galić
authors.affiliation: Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.affiliation: Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb Medical School, University Hospital Center Zagreb, Šalata 2, 10000 Zagreb, Croatia.
authors.forename: Fran
authors.initials: F
authors.lastname: Borovečki
keywords: Bones and dental anomalies; Common fragile site FRA1E; Epigenetics; Human brain transcriptome; Neurodevelopmental genes; Neuronal homeostasis; Non-coding RNAs; Overlapping phenotypes; Tc1/mariner family of transposable elements; Transposons