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.

Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats

“…This result is different from the cases in humans and mice, in which an incomplete penetrance of some HES7 dominant mutations has been reported2328. Additionally, a high rate of infant mortality has been reported for homozygous HES7 mutants in humans, mice and dogs23242728. Theses mutations either produced reading frame shifts (in humans and dogs) or knockout alleles (in mice) resulting in loss-of-function of HES723242728.…”

“…HES7 encodes a basic helix-loop-helix oscillatory transcriptional repressor regulating somite segmentation through the Notch pathway212223. Mutations in HES7 have been shown to be associated with spondylocostal dysostosis (SCD), an axial skeleton development disorder characterized by extensive hemivertebrae and rib anomalies in humans and dogs2425262728, and HES7 -knockout mice exhibit kinked tail in addition to malformation in the spine and ribs2328. The c.5T > C causes a valine-to-alanine missense substitution (p.V2A) at an evolutionarily conserved amino acid residue site in the HES7 protein (Fig.…”

“…To date, at least five HES7 mutations have been identified in human SCD cases, including four missense mutations (p.R25W, p.I58V, p.D142Y, p.D186Y) and one reading frame shift (p.R137QfsX42)24252628. The mutation p.R25W is located within the bHLH domains and impairs the ability of HES7 to bind DNA and form a heterodimer with E47 in vitro 25.…”

Syndromes and Diseases Associated with the Notch Signalling Pathway

“…To date, three reports describe SCD in association with mutations in HES7 (Sparrow et al, 2008(Sparrow et al, , 2010(Sparrow et al, , 2013a. G-SDV occurs in a pattern similar to mild STD ( Figure 10), with ribs appearing to show fusion posteriorly and fanning out in a crab-like fashion.…”

“…An ectopic stenotic anus and talipes were present, and cerebral computerized tomography scan showed Chiari II malformation. An extended kindred with associated but incompletely penetrant dextrocardia has been identified (Sparrow et al, 2013a), so HES7 mutations may give rise to a syndromic form of SCD on occasions.…”