Canine DVL2 variant contributes to brachycephalic phenotype and caudal vertebral anomalies

Julia E Niskanen,Vilma Reunanen,Danika Bannasch,Marjo K Hytönen,Milla Salonen,Anu K Lappalainen,Hannes Lohi

doi:10.1007/s00439-021-02261-8

Julia E Niskanen, Vilma Reunanen + Show 5 more

Open Access

https://doi.org/10.1007/s00439-021-02261-8

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Abstract

A frameshift deletion variant in the Wnt pathway gene dishevelled 2 (DVL2) is associated with a truncated, kinked tail (“screw tail”) in English Bulldogs, French Bulldogs and Boston Terriers. These breeds are also characterized by distinctive morphological traits, including a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans, caused by defects in genes such as DVL1 and DVL3. Based on these phenotypic and genetic similarities, it has previously been hypothesized that the canine DVL2 variant results in a syndromic phenotype called the Robinow-like syndrome. In our study, we investigated the distribution of the DVL2 variant in 1954 dogs from 15 breeds, identifying breeds with allele variation and enabling the dissection of the genotype–phenotype correlation for the first time. With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects. Altogether, our study strengthens the role of DVL2 as one of the contributors to the “bulldog type” morphology and features on the spectrum of human Robinow syndrome.

Highlights

The domestic dog (Canis lupus familiaris) exhibits tremendous morphological variety due to breed propagation
We found the allele in American Staffordshire Terriers, Staffordshire Bull Terriers, Dogues de Bordeaux, American Bulldogs, and Olde English Bulldogges
In American Staffordshire Terrier (AST) and Staffordshire Bull Terrier (SBT), some homozygous individuals were found, which enabled the investigation of the phenotypegenotype correlation to dissect the specific effects of the dishevelled 2 (DVL2) variant

Summary

Introduction

The domestic dog (Canis lupus familiaris) exhibits tremendous morphological variety due to breed propagation. Mansour et al (2018) showed that caudal vertebral malformations, or a shortened and kinked tail ( referred to as a “screw tail”), are a consequence of a frameshift deletion variant in the DVL2 (dishevelled segment polarity protein 2) gene. These breeds are characterized by other vertebral anomalies, brachycephalic skull morphology, widely set eyes, and short stature. Robinow syndrome is characterized by distinctive facial features, e.g., prominent forehead, widely spaced eyes and a flat nasal bridge; mesomelic limb shortening; and variable cardiac, oral and urogenital anomalies (Soman and Lingappa 2015). Based on the genetic and clinical similarities between Robinow patients and these breeds, Mansour et al (2018) suggested that the DVL2 variant could be responsible for the “bulldog type” morphology and contribute to a Robinowlike syndrome in dogs

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