title: Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus.
abstract: Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing.
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: Eissa Ali
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Bahauddin
authors.initials: B
authors.lastname: Sallout
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alswaid
authors.forename: Faroug
authors.initials: F
authors.lastname: Ababneh
authors.forename: Moeenaldeen
authors.initials: M
authors.lastname: Al-Sayed
authors.forename: Hadeel
authors.initials: H
authors.lastname: Rukban
authors.forename: Wafaa M
authors.initials: WM
authors.lastname: Eyaid
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D003914:Dextrocardia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006548:Hernia, Diaphragmatic / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012857:Situs Inversus / Q000175:diagnosis / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C486601:HES7 protein, human
keywords: HES7; dextrocardia; neural tube defects; situs inversus; spondylocostal dysostosis