- Email: [email protected]
Heritability of syringomyelia in Cavalier King Charles spaniels
The Veterinary Journal 183 (2010) 345–347
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Short Communication
Heritability of syringomyelia in Cavalier King Charles spaniels Tom Lewis a,*, Clare Rusbridge b, Penny Knowler b, Sarah Blott a, John A. Woolliams c a
Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK Stone Lion Veterinary Hospital, Wimbledon, London SW19 5AW, UK c Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9PS, UK b
a r t i c l e
i n f o
Article history: Accepted 20 October 2009
Keywords: Syringomyelia Canine Heritability Breeding value Estimated breeding value Cavalier King Charles spaniel
a b s t r a c t Mixed model analysis of 384 Cavalier King Charles spaniels (CKCS), with a magnetic resonance imaging diagnosis for the presence or absence of a syrinx, in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007, revealed a moderately high estimate of heritability of syringomyelia (h2 = 0.37 ± 0.15 standard error) when analysed as a binary trait. Inspection of cases where the disease segregated within families pointed to genes at more than one locus influencing syringomyelia. The availability of estimated breeding values for Kennel Club registered CKCS is a significant step in being able to select against syringomyelia, particularly given the difficulty of ascertaining the disease phenotype. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Syringomyelia is a neurological condition that is relatively common in the Cavalier King Charles spaniel (CKCS) and has been at the forefront of the current debate about breeding practices and pedigree dogs in the UK (Higgins and Nichols, 2008). The condition is characterised by the development of one or more fluid-containing cavities (syringes) within the parenchyma of the spinal cord due to abnormal flow of cerebrospinal fluid (Rusbridge et al., 2006). This is often attributed to a Chiari-like malformation (CLM) and is believed to be endemic in the CKCS (Cross et al., 2009). Clinical signs in CKCS with syringomyelia are dependent on the width and location of the syrinx and can include scratching, spontaneous vocalisation after sudden postural change, scoliosis, thoracic and/or pelvic limb ataxia and weakness. However, many dogs with a magnetic resonance imaging (MRI) diagnosis of syringomyelia display no clinical signs (Lu et al., 2003; Couturier et al., 2008; Cerda-Gonzalez et al., 2009). Syringomyelia is thought to be genetic in origin and this has contributed to debate as to how to reduce the prevalence of the condition in the CKCS (Rusbridge and Knowler, 2003, 2004). There are no accurate estimates of the prevalence of syringomyelia in CKCS in the UK, primarily due to the difficulty of definitive diagnosis, which requires an MRI scan. The paucity of scanning data on healthy CKCS leads to inaccurate estimation of the number of true * Corresponding author. Tel.: +44 1638 751000; fax: +44 1638 555643. E-mail address: [email protected] (T. Lewis). 1090-0233/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2009.10.022
negative diagnoses and an ascertainment bias in the data. Furthermore, there are few estimates of the proportion of false negative diagnoses in dogs without an MRI scan, although Couturier et al. (2008) reported that 7/16 dogs without clinical signs had a syrinx upon scanning. The aim of this study was to estimate the heritability and calculate the estimated breeding values (EBV) of syringomyelia in CKCS. A single MRI diagnosis of syringomyelia status (affected/clear) of 384 Kennel Club registered CKCS was obtained from scans conducted from 1998 to 2009 by the authors or from MRI results submitted to the Animal Health Trust by CKCS owners. Data were examined for scan records on multiple family members in an attempt to infer more information about modes of inheritance. Statistical analysis fitting a mixed linear model was undertaken using ASREML (Gilmour et al., 2006) to estimate genetic and environmental variance of development of syringomyelia (details supplied in Supplementary Material). Three families were identified with an MRI diagnosis for both parents and at least one progeny. In two families, both sire and dam were diagnosed with syringomyelia, but had progeny that were clear (at 3 years 6 months and 2 years 2 months of age), which appears to rule out syringomyelia being caused by an autosomal recessive allele at a single locus. An extended family where the parents were clear on scanning at >3 years, but with many offspring with a diagnosis of syringomyelia (61 year 3 months) (Fig. 1), appears to rule out syringomyelia being caused by an autosomal dominant allele at a single locus. The lack of clear Mendelian segregation within families suggests that syringomyelia is polygenic or complex in origin. These conclusions are based on the
346
T. Lewis et al. / The Veterinary Journal 183 (2010) 345–347
Fig. 1. Family tree showing syringomyelia segregating within full sib families and offspring affected by syringomyelia from apparently healthy parents. Grey indicates unknown disease status; black indicates syringomyelia diagnosed by MRI; white indicates clear (negative) diagnosis from MRI scan; circle indicates female; square indicates male. The male dog scanned clear at 3 years 7 months, the female on the left scanned clear at 3 years 5 months and the female on the right scanned clear at 4 years 9 months. Such an occurrence would rule out an autosomal dominant mode of inheritance for a single gene.
assumption of complete penetrance at age of scanning, which cannot be guaranteed. The heritability of syringomyelia was 0.37 (±0.15 standard error), indicating a moderate genetic effect on susceptibility to development of syringomyelia. There was a significant effect of both year of birth (P < 0.001) and age (P < 0.01) on development of syringomyelia (Fig. 2). A trend of decreasing age at scanning is illustrated by the broadly diagonal pattern of cells (showing data distribution) and the pattern of shading indicates that earlier scanning years tended to yield more syringomyelia cases. There was no significant association of syringomyelia with coat colour. EBVs for transmissible genetic susceptibility to syringomyelia were calculated for all animals in the Kennel Club CKCS pedigree database (n = 333,287; mean 0.0019 units ± 0.0331 standard deviation; co-efficient of skew 1.0123). Fig. 3 shows the mean EBVs for all Kennel Club registered dogs from 1990 to 2006 (where date of birth was recorded) in relation to year of birth and number born per year and indicates a possible improving trend, but which is subject to the ascertainment bias. Although this study presents strong evidence to suggest that syringomyelia in the CKCS is a disease with a genetic basis, it does not appear to be a single deleterious mutation that may have originated by chance and drifted to a significant frequency, aided by the low effective population size of the breed. It therefore remains possible that syringomyelia is related to an aspect of the breeding
objectives for the CKCS, such as skull morphology, but this cannot be resolved without further quantitative studies. Limitations of the present study include the small size of the database and, as one collected for presence of disease, the likelihood of biased estimates arising from a lack of random sampling. Such biases are particularly problematic when the database is compiled over the period during which the disease emerges. The transition to routine screening could explain the effects of year of birth and age of scanning shown in Fig. 2. The analysis used in the present study was designed to minimise bias by including the interaction between year of birth and age at MRI scanning; however correction of bias requires collection of a random sample to establish the true prevalence and the true degree of bias. Nevertheless, the data used in the present study is based on the reference standard (MRI) for diagnosis of the disease and clearly demonstrates the presence of genetic variation. The prevalence of syringomyelia in CKCS is likely to be reduced by selection using EBVs if these are given sufficient priority to over-ride any positive selection on the basis of conformation. In conclusion, syringomyelia has a moderately high heritability (h2 = 0.37 ± 0.15 standard error) and thus selection against syringomyelia should be feasible. The use of EBVs will assist in this aim, particularly since there is not an easily ascertained phenotype or definitive clinical signs. However, care must be taken in any proposed breeding programme to ensure that breeding away from
Age in years Year of birth 1991 1992
0
1
2
3
4
5
6
7
###
###
8
9
10
### ###
###
###
1993 1994 1995
###
1996 1997 1998 1999 2000 2001
###
###
###
### ###
### ### ###
### ### ### ###
### ###
###
### ###
### ### ###
### ### ###
### ### ###
### ### ###
### ### ###
### ###
###
###
### ### ###
2002 2003 2004
### ### ###
### ### ###
### ### ###
### ### ###
2005 2006 2007
### ### ###
### ### ###
### ###
###
### ### ### ### ###
11 ### ###
### ###
### ###
Fig. 2. Heat map showing predicted probabilities of syringomyelia for year of birth related to age at scanning: Light grey < 0.2; dark grey 0.2–0.6; black > 0.6.
347
T. Lewis et al. / The Veterinary Journal 183 (2010) 345–347
18000
0.008
16000
Number Born
Mean EBV
0.006
14000 0.004
0.002
10000 8000
0
Mean EBV
Number Born
12000
6000 -0.002 4000 -0.004
2000
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
-0.006 1990
0
Fig. 3. Mean and standard error of EBVs related to number of dogs born and registered with the Kennel Club per year from 1990 to 2006.
syringomyelia does not result in a concomitant increase in other diseases, such as myxomatous mitral valve disease, or a substantial loss of genetic diversity.
Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of this paper.
Acknowledgements This work was funded by the Kennel Club Charitable Trust. JAW is grateful to BBSRC for funding.
Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tvjl.2009.10.022.
References Cerda-Gonzalez, S., Olby, N.J., Pease, T.P., 2009. Morphology of the caudal fossa in Cavalier King Charles spaniels. Veterinary Radiology and Ultrasound 50, 37–46. Couturier, J., Rault, D., Cauzinille, L., 2008. Chiari-like malformation and syringomyelia in normal Cavalier King Charles spaniels: a multiple diagnostic imaging approach. Journal of Small Animal Practice 49, 438–443. Cross, H.R., Capello, R., Rusbridge, C.R., 2009. Comparison of cerebral cranium volumes between cavalier King Charles spaniels with Chiari-like malformation, small breed dogs and Labradors. Journal of Small Animal Practice 50, 399–405. Gilmour, A.R., Gogel, B.J., Cullis, B.R., Thompson, R., 2006. ASReml User Guide Release 2.0. VSN International Ltd., Hemel Hempstead, HP1 1ES, UK. Higgins, A., Nichols, F.W., 2008. The breeding of pedigree dogs: time for strong leadership. The Veterinary Journal 178, 157–158. Lu, D., Lamb, C.R., Pfeiffer, D.U., Targett, M.P., 2003. Neurological signs and results of magnetic resonance imaging in 40 Cavalier King Charles spaniels with Chiari type 1-like malformations. Veterinary Record 153, 260–263. Rusbridge, C., Knowler, S.P., 2003. Hereditary aspects of occipital bone hypoplasia and syringomyelia (Chiari type I malformation) in Cavalier King Charles spaniels. Veterinary Record 153, 107–112. Rusbridge, C., Knowler, S.P., 2004. Inheritance of occipital bone hypoplasia (Chiari type I malformation) in Cavalier King Charles spaniels. Journal of Veterinary Internal Medicine 18, 673–678. Rusbridge, C., Greitz, D., Iskander, B.J., 2006. Syringomyelia: current concepts in pathogenesis, diagnosis, and treatment. Journal of Veterinary Internal Medicine 20, 469–479.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Short Communication
Heritability of syringomyelia in Cavalier King Charles spaniels Tom Lewis a,*, Clare Rusbridge b, Penny Knowler b, Sarah Blott a, John A. Woolliams c a
Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK Stone Lion Veterinary Hospital, Wimbledon, London SW19 5AW, UK c Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9PS, UK b
a r t i c l e
i n f o
Article history: Accepted 20 October 2009
Keywords: Syringomyelia Canine Heritability Breeding value Estimated breeding value Cavalier King Charles spaniel
a b s t r a c t Mixed model analysis of 384 Cavalier King Charles spaniels (CKCS), with a magnetic resonance imaging diagnosis for the presence or absence of a syrinx, in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007, revealed a moderately high estimate of heritability of syringomyelia (h2 = 0.37 ± 0.15 standard error) when analysed as a binary trait. Inspection of cases where the disease segregated within families pointed to genes at more than one locus influencing syringomyelia. The availability of estimated breeding values for Kennel Club registered CKCS is a significant step in being able to select against syringomyelia, particularly given the difficulty of ascertaining the disease phenotype. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Syringomyelia is a neurological condition that is relatively common in the Cavalier King Charles spaniel (CKCS) and has been at the forefront of the current debate about breeding practices and pedigree dogs in the UK (Higgins and Nichols, 2008). The condition is characterised by the development of one or more fluid-containing cavities (syringes) within the parenchyma of the spinal cord due to abnormal flow of cerebrospinal fluid (Rusbridge et al., 2006). This is often attributed to a Chiari-like malformation (CLM) and is believed to be endemic in the CKCS (Cross et al., 2009). Clinical signs in CKCS with syringomyelia are dependent on the width and location of the syrinx and can include scratching, spontaneous vocalisation after sudden postural change, scoliosis, thoracic and/or pelvic limb ataxia and weakness. However, many dogs with a magnetic resonance imaging (MRI) diagnosis of syringomyelia display no clinical signs (Lu et al., 2003; Couturier et al., 2008; Cerda-Gonzalez et al., 2009). Syringomyelia is thought to be genetic in origin and this has contributed to debate as to how to reduce the prevalence of the condition in the CKCS (Rusbridge and Knowler, 2003, 2004). There are no accurate estimates of the prevalence of syringomyelia in CKCS in the UK, primarily due to the difficulty of definitive diagnosis, which requires an MRI scan. The paucity of scanning data on healthy CKCS leads to inaccurate estimation of the number of true * Corresponding author. Tel.: +44 1638 751000; fax: +44 1638 555643. E-mail address: [email protected] (T. Lewis). 1090-0233/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2009.10.022
negative diagnoses and an ascertainment bias in the data. Furthermore, there are few estimates of the proportion of false negative diagnoses in dogs without an MRI scan, although Couturier et al. (2008) reported that 7/16 dogs without clinical signs had a syrinx upon scanning. The aim of this study was to estimate the heritability and calculate the estimated breeding values (EBV) of syringomyelia in CKCS. A single MRI diagnosis of syringomyelia status (affected/clear) of 384 Kennel Club registered CKCS was obtained from scans conducted from 1998 to 2009 by the authors or from MRI results submitted to the Animal Health Trust by CKCS owners. Data were examined for scan records on multiple family members in an attempt to infer more information about modes of inheritance. Statistical analysis fitting a mixed linear model was undertaken using ASREML (Gilmour et al., 2006) to estimate genetic and environmental variance of development of syringomyelia (details supplied in Supplementary Material). Three families were identified with an MRI diagnosis for both parents and at least one progeny. In two families, both sire and dam were diagnosed with syringomyelia, but had progeny that were clear (at 3 years 6 months and 2 years 2 months of age), which appears to rule out syringomyelia being caused by an autosomal recessive allele at a single locus. An extended family where the parents were clear on scanning at >3 years, but with many offspring with a diagnosis of syringomyelia (61 year 3 months) (Fig. 1), appears to rule out syringomyelia being caused by an autosomal dominant allele at a single locus. The lack of clear Mendelian segregation within families suggests that syringomyelia is polygenic or complex in origin. These conclusions are based on the
346
T. Lewis et al. / The Veterinary Journal 183 (2010) 345–347
Fig. 1. Family tree showing syringomyelia segregating within full sib families and offspring affected by syringomyelia from apparently healthy parents. Grey indicates unknown disease status; black indicates syringomyelia diagnosed by MRI; white indicates clear (negative) diagnosis from MRI scan; circle indicates female; square indicates male. The male dog scanned clear at 3 years 7 months, the female on the left scanned clear at 3 years 5 months and the female on the right scanned clear at 4 years 9 months. Such an occurrence would rule out an autosomal dominant mode of inheritance for a single gene.
assumption of complete penetrance at age of scanning, which cannot be guaranteed. The heritability of syringomyelia was 0.37 (±0.15 standard error), indicating a moderate genetic effect on susceptibility to development of syringomyelia. There was a significant effect of both year of birth (P < 0.001) and age (P < 0.01) on development of syringomyelia (Fig. 2). A trend of decreasing age at scanning is illustrated by the broadly diagonal pattern of cells (showing data distribution) and the pattern of shading indicates that earlier scanning years tended to yield more syringomyelia cases. There was no significant association of syringomyelia with coat colour. EBVs for transmissible genetic susceptibility to syringomyelia were calculated for all animals in the Kennel Club CKCS pedigree database (n = 333,287; mean 0.0019 units ± 0.0331 standard deviation; co-efficient of skew 1.0123). Fig. 3 shows the mean EBVs for all Kennel Club registered dogs from 1990 to 2006 (where date of birth was recorded) in relation to year of birth and number born per year and indicates a possible improving trend, but which is subject to the ascertainment bias. Although this study presents strong evidence to suggest that syringomyelia in the CKCS is a disease with a genetic basis, it does not appear to be a single deleterious mutation that may have originated by chance and drifted to a significant frequency, aided by the low effective population size of the breed. It therefore remains possible that syringomyelia is related to an aspect of the breeding
objectives for the CKCS, such as skull morphology, but this cannot be resolved without further quantitative studies. Limitations of the present study include the small size of the database and, as one collected for presence of disease, the likelihood of biased estimates arising from a lack of random sampling. Such biases are particularly problematic when the database is compiled over the period during which the disease emerges. The transition to routine screening could explain the effects of year of birth and age of scanning shown in Fig. 2. The analysis used in the present study was designed to minimise bias by including the interaction between year of birth and age at MRI scanning; however correction of bias requires collection of a random sample to establish the true prevalence and the true degree of bias. Nevertheless, the data used in the present study is based on the reference standard (MRI) for diagnosis of the disease and clearly demonstrates the presence of genetic variation. The prevalence of syringomyelia in CKCS is likely to be reduced by selection using EBVs if these are given sufficient priority to over-ride any positive selection on the basis of conformation. In conclusion, syringomyelia has a moderately high heritability (h2 = 0.37 ± 0.15 standard error) and thus selection against syringomyelia should be feasible. The use of EBVs will assist in this aim, particularly since there is not an easily ascertained phenotype or definitive clinical signs. However, care must be taken in any proposed breeding programme to ensure that breeding away from
Age in years Year of birth 1991 1992
0
1
2
3
4
5
6
7
###
###
8
9
10
### ###
###
###
1993 1994 1995
###
1996 1997 1998 1999 2000 2001
###
###
###
### ###
### ### ###
### ### ### ###
### ###
###
### ###
### ### ###
### ### ###
### ### ###
### ### ###
### ### ###
### ###
###
###
### ### ###
2002 2003 2004
### ### ###
### ### ###
### ### ###
### ### ###
2005 2006 2007
### ### ###
### ### ###
### ###
###
### ### ### ### ###
11 ### ###
### ###
### ###
Fig. 2. Heat map showing predicted probabilities of syringomyelia for year of birth related to age at scanning: Light grey < 0.2; dark grey 0.2–0.6; black > 0.6.
347
T. Lewis et al. / The Veterinary Journal 183 (2010) 345–347
18000
0.008
16000
Number Born
Mean EBV
0.006
14000 0.004
0.002
10000 8000
0
Mean EBV
Number Born
12000
6000 -0.002 4000 -0.004
2000
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
-0.006 1990
0
Fig. 3. Mean and standard error of EBVs related to number of dogs born and registered with the Kennel Club per year from 1990 to 2006.
syringomyelia does not result in a concomitant increase in other diseases, such as myxomatous mitral valve disease, or a substantial loss of genetic diversity.
Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of this paper.
Acknowledgements This work was funded by the Kennel Club Charitable Trust. JAW is grateful to BBSRC for funding.
Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tvjl.2009.10.022.
References Cerda-Gonzalez, S., Olby, N.J., Pease, T.P., 2009. Morphology of the caudal fossa in Cavalier King Charles spaniels. Veterinary Radiology and Ultrasound 50, 37–46. Couturier, J., Rault, D., Cauzinille, L., 2008. Chiari-like malformation and syringomyelia in normal Cavalier King Charles spaniels: a multiple diagnostic imaging approach. Journal of Small Animal Practice 49, 438–443. Cross, H.R., Capello, R., Rusbridge, C.R., 2009. Comparison of cerebral cranium volumes between cavalier King Charles spaniels with Chiari-like malformation, small breed dogs and Labradors. Journal of Small Animal Practice 50, 399–405. Gilmour, A.R., Gogel, B.J., Cullis, B.R., Thompson, R., 2006. ASReml User Guide Release 2.0. VSN International Ltd., Hemel Hempstead, HP1 1ES, UK. Higgins, A., Nichols, F.W., 2008. The breeding of pedigree dogs: time for strong leadership. The Veterinary Journal 178, 157–158. Lu, D., Lamb, C.R., Pfeiffer, D.U., Targett, M.P., 2003. Neurological signs and results of magnetic resonance imaging in 40 Cavalier King Charles spaniels with Chiari type 1-like malformations. Veterinary Record 153, 260–263. Rusbridge, C., Knowler, S.P., 2003. Hereditary aspects of occipital bone hypoplasia and syringomyelia (Chiari type I malformation) in Cavalier King Charles spaniels. Veterinary Record 153, 107–112. Rusbridge, C., Knowler, S.P., 2004. Inheritance of occipital bone hypoplasia (Chiari type I malformation) in Cavalier King Charles spaniels. Journal of Veterinary Internal Medicine 18, 673–678. Rusbridge, C., Greitz, D., Iskander, B.J., 2006. Syringomyelia: current concepts in pathogenesis, diagnosis, and treatment. Journal of Veterinary Internal Medicine 20, 469–479.