A likely HOXC4 predisposition variant for Chiari malformations

Abstract

Objective: Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique high-risk pedigree population resource and approach to identify rare candidate variants that likely predispose individuals to CM and protein structure prediction tools to identify pathogenicity mechanisms.

Methods: By using the Utah Population Database, the authors identified pedigrees with significantly increased numbers of members with CM diagnosis. From a separate DNA biorepository of 451 samples from CM patients and families, 32 CM patients belonging to 1 or more of 24 high-risk Chiari pedigrees were identified. Two high-risk pedigrees had 3 CM-affected relatives, and 22 pedigrees had 2 CM-affected relatives. To identify rare candidate predisposition gene variants, whole-exome sequence data from these 32 CM patients belonging to 24 CM-affected related pairs from high-risk pedigrees were analyzed. The I-TASSER package for protein structure prediction was used to predict the structures of both the wild-type and mutant proteins found here.

Results: Sequence analysis of the 24 affected relative pairs identified 38 rare candidate Chiari predisposition gene variants that were shared by at least 1 CM-affected pair from a high-risk pedigree. The authors found a candidate variant in HOXC4 that was shared by 2 CM-affected patients in 2 independent pedigrees. All 4 of these CM cases, 2 in each pedigree, exhibited a specific craniocervical bony phenotype defined by a clivoaxial angle less than 125°. The protein structure prediction results suggested that the mutation considered here may reduce the binding affinity of HOXC4 to DNA.

Conclusions: Analysis of unique and powerful Utah genetic resources allowed identification of 38 strong candidate CM predisposition gene variants. These variants should be pursued in independent populations. One of the candidates, a rare HOXC4 variant, was identified in 2 high-risk CM pedigrees, with this variant possibly predisposing patients to a Chiari phenotype with craniocervical kyphosis.

Keywords: Chiari malformation; Utah Population Database; craniocervical kyphosis; high-risk pedigree; predisposition; protein prediction modeling.

FIG. 1.

Flowchart showing patient identification.

FIG. 2.

High-risk CM pedigree. A: HOXC4 variant–carrying, high-risk CM pedigree, including a pair of distantly related, affected cases who both have the HOXC4 variant. CM cases are fully shaded. Sequenced HOXC4 carriers (+) are noted. Slashes indicate deceased individuals. B: Midline sagittal cervical T2-weighted MR images showing CM and craniocervical kyphosis in the 2 affected individuals included in panel A. The CXA values are shown for each patient. C: Radiological measurements of the 2 affected individuals. CXA is shown in degrees, and pBC2, tonsillar ectopia, and C-C2SVA are shown in millimeters. pBC2 = maximum perpendicular distance to the basion-inferoposterior point of the C2 body. Figure is available in color online only.

FIG. 3.

High-risk CM pedigree. A: HOXC4 variant–carrying, high-risk CM pedigree in which 1 girl (arrow) who carried the HOXC4 variant was identified with UPDB pedigree analysis. The carrier status of her mother, father, and CM-affected sister identified in a previous WGS CM analysis of this nuclear family are also shown. Both sisters and the nonpedigree-member mother carry the variant. CM cases are fully shaded. Sequenced HOXC4 carriers (+) and noncarriers (–) are noted. Slashes indicate deceased individuals. B: Radiological measurements of the sequenced patient and her CM-affected sister are shown. CXA is shown in degrees, and pBC2, tonsillar ectopia, and C-C2SVA are shown in millimeters. C: Midline sagittal cervical T2-weighted MR images showing CM and craniocervical kyphosis in the case identified with UPDB pedigree analysis. D: Midline sagittal cervical T2-weighted MR images of the CM-affected sister. OCF = occipitocervical fusion; SODD = suboccipital decompression; TOR = transoral odontoid resection; TPX = tonsillopexy. Figure is available in color online only.

FIG. 4.

Wild-type homeobox sequence of HOXC4. The site of the mutation reported here is shown in red and underlined. Figure is available in color online only.

FIG. 5.

Superpositions of the wild-type (yellow/cyan) and mutant (red/green) predicted structures (model 1) of the homeobox domain with their relationships to the predicted DNA binding.