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 the Enigma

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. Although appears to be the major player in the 1p21.3p21.2 region, deregulation of the 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 that is a complex gene whose expression is epigenetically regulated by long non-coding RNAs (lncRNAs) within the locus. Furthermore, the long interspersed nuclear element-1 () transposon inserted in intronic transcript 1 () lncRNA with its parasites, and pair of repeats appears to be the "weakest link" within the gene liable to break. Identification of the precise mechanism through which is epigenetically regulated, and underlying reasons why exactly the break () 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.