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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.

Original publication

DOI

10.1002/ajmg.a.36073

Type

Journal article

Journal

Am J Med Genet A

Publication Date

09/2013

Volume

161A

Pages

2244 - 2249

Keywords

HES7, dextrocardia, neural tube defects, situs inversus, spondylocostal dysostosis, Abnormalities, Multiple, Amino Acid Substitution, Animals, Basic Helix-Loop-Helix Transcription Factors, Chromosome Mapping, Comparative Genomic Hybridization, Consanguinity, Dextrocardia, Female, Genotype, Heart Defects, Congenital, Hernia, Diaphragmatic, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Pedigree, Phenotype, Situs Inversus