title: Complex X chromosome rearrangement associated with multiorgan autoimmunity.
abstract: BACKGROUND
  Turner syndrome, a congenital condition that affects 1/2,500 births, results from absence or structural alteration of the second sex chromosome. Turner syndrome is usually associated with short stature, gonadal dysgenesis and variable dysmorphic features. The classical 45,X karyotype accounts approximately for half of all patients, the remainder exhibit mosaicism or structural abnormalities of the X chromosome. However, complex intra-X chromosomal rearrangements involving more than three breakpoints are extremely rare.
  
  
  RESULTS
  We present a unique case of a novel complex X chromosome rearrangement in a young female patient presenting successively a wide range of autoimmune diseases including insulin dependent diabetes mellitus, Hashimoto's thyroiditis, celiac disease, anaemia perniciosa, possible inner ear disease and severe hair loss. For the genetic evaluation, conventional cytogenetic analysis and FISH with different X specific probes were initially performed. The complexity of these results and the variety of autoimmune problems of the patient prompted us to identify the exact composition and breakpoints of the rearranged X as well as methylation status of the X chromosomes. The high resolution array-CGH (assembly GRCh37/hg19) detected single copy for the whole chromosome X short arm. Two different sized segments of Xq arm were present in three copies: one large size of 80,3 Mb from Xq11.1 to Xq27.3 region and another smaller (11,1 Mb) from Xq27.3 to Xq28 region. An 1,6 Mb Xq27.3 region of the long arm was present in two copies. Southern blot analysis identified a skewed X inactivation with ≈ 70:30 % ratios of methylated/unmethylated fragments. The G-band and FISH patterns of the rearranged X suggested the aspect of a restructured i(Xq) chromosome which was shattered and fortuitously repaired. The X-STR genotype analysis of the family detected that the patient inherited intact maternal X chromosome and a rearranged paternal X chromosome. The multiple Xq breakages and fusions as well as inverted duplication would have been expected to cause a severe Turner phenotype. However, the patient lacks many of the classic somatic features of Turner syndrome, instead she presented multiorgan autoimmune diseases.
  
  
  CONCLUSIONS
  The clinical data of the presented patient suggest that fragmentation of the i(Xq) chromosome elevates the risk of autoimmune diseases.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, 1094 Budapest, Hungary.
authors.forename: Irén
authors.initials: I
authors.lastname: Haltrich
authors.affiliation: Department of Molecular Genetics and Diagnostics, National Center of Public Health, Budapest, Hungary.
authors.forename: Henriett
authors.initials: H
authors.lastname: Pikó
authors.affiliation: DNA Laboratory, Institute of Forensic Medicine, Network of Forensic Science Institutes, Budapest, Hungary.
authors.forename: Horolma
authors.initials: H
authors.lastname: Pamjav
authors.affiliation: 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Somogyi
authors.affiliation: DNA Laboratory, Institute of Forensic Medicine, Network of Forensic Science Institutes, Budapest, Hungary.
authors.forename: Antónia
authors.initials: A
authors.lastname: Völgyi
authors.affiliation: Department of Human Genetics, Organization National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal.
authors.forename: Dezső
authors.initials: D
authors.lastname: David
authors.affiliation: 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
authors.forename: Artúr
authors.initials: A
authors.lastname: Beke
authors.affiliation: 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Garamvölgyi
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, 1094 Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Kiss
authors.affiliation: Department of Molecular Genetics and Diagnostics, National Center of Public Health, Budapest, Hungary.
authors.forename: Veronika
authors.initials: V
authors.lastname: Karcagi
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, 1094 Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Fekete
keywords: Autoimmune disease; Complex X chromosome rearrangement; Turner syndrome; Type 1 diabetes mellitus; X inactivation disorder