title: Functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 due to X;6 translocation with an atypical X-inactivation pattern.
abstract: Pattern of X chromosome inactivation (XCI) is typically random in females. However, chromosomal rearrangements affecting the X chromosome can result in XCI skewing due to cell growth disadvantage. In case of an X;autosome translocation, this usually leads to an XCI pattern of 100:0 with the derivative X being the active one in the majority of females. A de novo balanced X;6 translocation [46,X,t(X;6)(p22.1;q27)] and a completely skewed XCI pattern (100:0) were detected in a female patient with microcephaly, cerebellar vermis hypoplasia, heart defect, and severe developmental delay. We mapped the breakpoint regions using fluorescence in situ hybridization and found the X-linked gene POLA1 to be disrupted. POLA1 codes for the catalytic subunit of the polymerase α-primase complex which is responsible for initiation of the DNA replication process; absence of POLA1 is probably incompatible with life. Consequently, by RBA banding we determined which of the X chromosomes was the active one in the patient. In all examined lymphocytes the wild-type X chromosome was active. We propose that completely skewed XCI favoring the normal X chromosome resulted from death of cells with an active derivative X that was caused by a non-functional POLA1 gene. In summary, we conclude that functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 are responsible for the clinical phenotype of the patient. This case demonstrates the importance of determining which one of the X chromosomes underwent inactivation to correlate clinical features of a female with an X;autosome translocation with the nature of the genetic alteration.
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Podolska
authors.affiliation: Praxis für Humangenetik, Chemnitz, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kobelt
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.affiliation: Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.affiliation: Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
authors.forename: Nataliya
authors.identifier: http://orcid.org/0000-0001-9439-4677
authors.initials: N
authors.lastname: Di Donato
mesh_terms: D000328:Adult; D065814:Cerebellar Vermis / Q000503:physiopathology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D050172:Genes, X-Linked; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D009006:Monosomy / Q000235:genetics; D010641:Phenotype; D014178:Translocation, Genetic / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: C065639:DNA polymerase A; D004258:DNA Polymerase III
keywords: X-inactivation; X;autosome translocation; cerebellar hypoplasia; microdeletion 6q27