Quantitative Trait Loci (QTL) Study Identifies Novel Genomic Regions Associated to Chiari-Like Malformation in Griffon Bruxellois Dogs

Abstract

Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.

Inheritance of Chiari-Like Malformation: Can a Mixed Breeding Reduce the Risk of Syringomyelia?

“…T1-weighted sagittal DICOM images were compared with a purebred outcross family with varying affectedness for CM and SM. It builds on data from four previous studies in the GB that investigates the phenotype, the risk of CM and SM and its inheritance and the successful identification of two Qualitative Trait Loci and candidate genes [ 1 , 19 , 21 , 29 ]. Furthermore, analysis of familial morphometric differences in the eight litters and 19 progeny, we were able to identify potential traits that might be useful for grading the severity of CM and SM.…”

“…These results, together with the fact CM is known to skip a generation in an earlier familial study of 33 GB [ 19 ], suggests the involvement of recessive traits that are protective against CM and/or gene penetrance is variable involving individual traits that are additive in severity. Line bc is associated with CFA9 and CFA24 and line ae with CFA14 [ 29 ], i.e. these segregated traits may or may not be expressed in any one individual as illustrated by the variations in F1and F2 generations.…”

“…The family (n = 27) comprised three foundation bitches C,D, H and two foundation dogs E and K that were part of the previously mentioned larger 155 GB cohort [ 1 ] used in genetic studies [ 29 ]. Furthermore, foundation Dog E was the offspring of a CM/SM affected GB that formed part of separate family (n = 32) where CM was investigated using radiographs [ 19 ].…”

“…Quantitative analysis of both CM and SM has been undertaken in the GB (n = 155) [ 1 ]. Six highly significant traits for CM and SM, confirmed by subsequent quantitative trait loci (QTL) analysis [ 29 ], were associated with five Canis Familiaris Autosomes (CFAs). One trait, angle FAC, was unique in that it was highly significant for CM but not for SM.…”

Using machine learning to understand neuromorphological change and image‐based biomarker identification in Cavalier King Charles Spaniels with Chiari‐like malformation‐associated pain and syringomyelia

“…Whereas identification of SM is straightforward, assessment of CM is more difficult. Originally described in 2000 as a small‐volume caudal fossa with cerebellar herniation, numerous studies have now shown that the condition is more complex . In addition to hypoplasia of the supra‐ and basioccipital bones, resulting in short cranial base, decreased caudal fossa volume, and tendency for cerebellar herniation, the condition is associated with a compensatory increase in the height of the cranial fossa with decreased occipital crest, rostral displacement of the atlas and axis (atlanto‐occipital overlapping), medulla oblongata elevation with or without kinking, more acute angulation of the axis bone to the cranial base (cervical flexure), more acute angle at the spheno‐occipital synchondrosis (sphenoid flexure), a relatively large cerebellum, decreased volume of jugular foramen and venous sinus, and dorsal compression of the spinal cord by atlantoaxial bands .…”