title: Complex intrachromosomal rearrangement in 1q leading to 1q32.2 microdeletion: a potential role of SRGAP2 in the gyrification of cerebral cortex.
abstract: BACKGROUND
  Van der Woude syndrome (MIM: 119300, VWS) is a dominantly inherited and the most common orofacial clefting syndrome; it accounts for ~2 % of all cleft lip and palate cases. Intellectual disability (ID) is characterized by significant limitations, both in intellectual functioning (cognitive deficit) and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. Karyotyping has been the first standard test for the detection of genetic imbalance in patients with ID for more than 35 years. Advances in genetic diagnosis have laid chromosomal microarrays (CMA) as a new standard and first first-line test for diagnosis of patients with ID, as well as other conditions, such as autism spectrum disorders or multiple congenital anomalies.
  
  
  METHODS
  The present case was initially studied due to unexplained cognitive deficit. Physical examination at the age of 18 years revealed cleft palate, lower lip pits and hypodontia, accompanied with other dysmorphic features and absence of speech. Brain MRI uncovered significantly reduced overall volume of gray matter and cortical gyrification. Banding cytogenetics revealed an indistinct intrachromosomal rearrangement in the long arm of one chromosome 1, and subsequent microarray analyses identified a 5.56 Mb deletion in 1q32.1-1q32.3, encompassing 52 genes; included were the entire IRF6 gene (whose mutations/deletions underlay VWS) and SRGAP2, a gene with an important role in neuronal migration during development of cerebral cortex. Besides, a duplication in 3q26.32 (1.9 Mb in size) comprising TBL1XR1 gene was identified. Multicolor banding for chromosome 1 and molecular cytogenetics applying a battery of locus-specific probes covering 1q32.1 to 1q44 characterized a four breakpoint-insertional-rearrangement-event, resulting in 1q32.1-1q32.3 deletion.
  
  
  CONCLUSIONS
  Considering that the human-specific three-fold segmental duplication of SRGAP2 gene evolutionary corresponds to the beginning of neocortical expansion, we hypothesize that aberrations in SRGAP2 are strong candidates underlying specific brain abnormalities, namely reduced volume of grey matter and reduced gyrification.
authors.affiliation: Croatian Institute for Brain Research, School of Medicine University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Rincic
authors.affiliation: Croatian Institute for Brain Research, School of Medicine University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
authors.forename: Milan
authors.initials: M
authors.lastname: Rados
authors.affiliation: Croatian Institute for Brain Research, School of Medicine University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Krsnik
authors.affiliation: Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, and University Hospital Center Zagreb, Šalata 2, 10 000 Zagreb, Croatia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gotovac
authors.affiliation: Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, and University Hospital Center Zagreb, Šalata 2, 10 000 Zagreb, Croatia ; Department of Neurology, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia.
authors.forename: Fran
authors.initials: F
authors.lastname: Borovecki
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, D-07743 Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.affiliation: Croatian Institute for Brain Research, School of Medicine University of Zagreb, Salata 12, 10000 Zagreb, Croatia.
authors.forename: Lukrecija
authors.initials: L
authors.lastname: Brecevic