title: Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1).
abstract: Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. Here we identify the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. This finding, supported by the similar phenotype in Gdf1 knockout mouse, provides firm evidence that RAI can occur as a recessively inherited condition, with GDF1 as the culprit gene. The results will shed light on the biological basis of human laterality defects and facilitate molecular diagnosis of RAI.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Marianne
authors.initials: M
authors.lastname: Eronen
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D055452:Growth Differentiation Factor 1 / Q000235:genetics* / Q000502:physiology; D006325:Heart Atria / Q000002:abnormalities; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D011247:Pregnancy; D012857:Situs Inversus / Q000235:genetics
chemical_list: C525977:GDF1 protein, human; D055452:Growth Differentiation Factor 1