title: Intra-individual plasticity of the TAZ gene leading to different heritable mutations in siblings with Barth syndrome.
abstract: Infantile-onset skeletal myopathy Barth syndrome (OMIM #302060) is caused by mutations in the X-linked TAZ gene and hence usually manifests itself only in hemizygous males. Confirmatory testing is provided by mutational analysis of the TAZ gene and/or by biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin ratio. Heterozygous females do not usually display a clinical phenotype but may undergo molecular genetic prenatal diagnosis during pregnancy. We characterized two novel and non-identical TAZ gene rearrangements in the offspring of a single female carrier of Barth syndrome. The hg19chrX:g.153634427_153644361delinsKP_123427.1 TAZ gene rearrangement was identified in her affected son, whereas the NM_000116.3(TAZ)c.-72_109+51del TAZ gene deletion was identified in a male foetus during a subsequent pregnancy. The unaffected mother was surprisingly found to harbour both variants in addition to a wild-type TAZ allele. A combination of breakpoint junction sequencing, linkage analysis and assessment of allelic dosage revealed that the two variants had originated independently from an apparently unstable/mutable TAZ maternal allele albeit via different mutational mechanisms. We conclude that molecular prenatal diagnosis in Barth syndrome families with probands carrying TAZ gene rearrangements should include investigation of the entire coding region of the TAZ gene. The identification of the breakpoint junctions of such gross gene rearrangements is important to ensure accurate ascertainment of carriership with a view to providing appropriate genetic counselling.
authors.affiliation: Department of Neurosciences, Pharmacology and Child Health, University of Florence, Florence, Italy.|Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.affiliation: Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Donati
authors.affiliation: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Funghini
authors.affiliation: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Cavicchi
authors.affiliation: Genetics of Neurodegenerative and Metabolic Diseases Unit, IRCCS Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Pensato
authors.affiliation: Genetics of Neurodegenerative and Metabolic Diseases Unit, IRCCS Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gellera
authors.affiliation: Medical Genetics Unit, Ca' Granda IRCCS Foundation, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Natacci
authors.affiliation: Ambulatorio Genetica Medica, Ospedale 'Vittore Buzzi', Milan, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Spaccini
authors.affiliation: Metabolic Unit, San Gerardo Hospital, Monza, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Gasperini
authors.affiliation: Department of Clinical Chemistry and Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Department of Neurosciences, Pharmacology and Child Health, University of Florence, Florence, Italy.|Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Neurosciences, Pharmacology and Child Health, University of Florence, Florence, Italy.|Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
mesh_terms: D000217:Acyltransferases; D000328:Adult; D056889:Barth Syndrome / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D056905:Chromosome Breakpoints; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D035781:Siblings; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human