title: Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations.
abstract: Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Suzuki
authors.forename: Hirohito
authors.initials: H
authors.lastname: Shima
authors.forename: Machiko
authors.initials: M
authors.lastname: Toki
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hanew
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsubara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kamimaki
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D000293:Adolescent; D000328:Adult; D041321:Chromosomes, Human, X / Q000235:genetics*; D000072837:Chromothripsis; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D005260:Female; D015321:Gene Rearrangement; D018095:Germ-Line Mutation; D006801:Humans; D008957:Models, Genetic; D010049:Ovarian Diseases / Q000235:genetics*; D012729:Sex Chromosome Aberrations; D014424:Turner Syndrome / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics