Abstract for presentation at 11th International Congress of Human Genetics

Disruption of conserved non-coding elements in a t(10;13)(q26;q31)de novo

  • Ms Elizabeth Engenheiro, Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Genetics, IMBG, University of Copenhagen, Denmark
  • Ms Debbie Goode, School of Biological and Chemical Sciences, Queen Mary University of London, United Kingdom
  • Ms Heather Callaway, School of Biological and Chemical Sciences, Queen Mary University of London, United Kingdom
  • Dr Maximina Pinto, Instituto de Genética Médica Jacinto Magalhães, Porto, Portugal
  • Dr Gabriela Soares, Instituto de Genética Médica Jacinto Magalhães, Portugal
  • Dr Zeynep Tümer, 1Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Genetics, IMBG, University of Copenhagen, Denmark
  • Dr Greg Elgar, School of Biological and Chemical Sciences, Queen Mary University of London, United Kingdom
  • Prof Niels Tommerup, Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Genetics, IMBG, University of Copenhagen, Denmark

    • It was recently discovered that not only disruption of important developmental genes can cause disease, but so can disruption of the regulatory landscapes surrounding these genes, e.g. by translocations that remove regulatory elements from the gene they regulate. Here we present a balanced t(10,13)(q26;q31)de novo, in a patient with mental retardation, deafness, epilepsy and ataxia. Both breakpoints were mapped by FISH using BAC and fosmid clones, to gene deserts downstream of the homeobox genes HMX2 and HMX3, on chromosome 10q26, and downstream of SLITKR5 on chromosome 13q31. The breakpoint on chromosome 10q26 disrupts a cluster of conserved non-coding elements (CNEs) associated with HMX2 and HMX3. It has recently been shown that similar conserved elements probably function as tissue-specific enhancers and that they are important for the diverse spatio-temporal functions of the associated key developmental genes. The disrupted elements downstream of the breakpoint on chromosome 10q26 have been studied in vivo by a functional assay using zebrafish. Four of these elements revealed GFP expression in the zebrafish central nervous system. Mouse studies have shown that HMX2 and HMX3 are involved in inner ear morphogenesis and specification of vestibular inner ear and therefore are potentially involved in deafness. Furthermore, these 2 genes are also thought to retain a primary function in central nervous system development, which might be potentially related to the mental retardation, epilepsy and ataxia. The objectives of this study are to identify regulatory sequences related to the candidate genes associated with the 10q26 breakpoint in this translocation and contribute to the understanding of the etiology of mental retardation associated with deafness, ataxia and epilepsy.

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