OMIA:000218-9615 : Choroidal hypoplasia, NHEJ1-related in Canis lupus familiaris (dog)

Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611290 (gene)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2007

Cross-species summary: Phene was previously called 'Collie eye anomaly' [16/06/2023]

Species-specific name: Collie eye anomaly; Collie eye defect, choroidal hypoplasia, Collie ectasia syndrome, scleral ectasia syndrome

Species-specific symbol: cea

Species-specific description: Collie eye anomaly (CEA) is a complex developmental defect of the posterior segment of the eye characterized by choroid hypoplasia. Malformations are present at birth and may include inadequate development of the choroid (choroidal hypoplasia), defects of the choroid, sclera, and/or optic nerve (coloboma/staphyloma), and complete retinal detachment (with or without hemorrhage). Mildly affected animals will have no detectable vision deficit. (Genetics Committee of the American College of Veterinary Opthalmologists, 2021).

Inheritance: Colobomas only occur in dogs of four breeds (Collie, Border Collie, Australian Shepherd, and Shetland Sheepdog) that are homozygous for the likely causal mutation (Parker et al., 2007). Some affected dogs in these breeds have been observed to “go normal” later, most of which were homozygous for the likely causal mutation, but a small minority were heterozygous. This suggests other loci may have an effect on CEA expression, i.e. that the disorder is multifactorial.

Mapping: CFA37

Markers: Kucharczyk et al. (2019) reported "the occurrence of choroidal hypoplasia in the Australian Kelpie breed in Poland, the affected dogs testing positive for the Collie Eye Anomaly NHEJ1 gene mutation" (i.e. g.28697542-28705340del7799)

Molecular basis: By a neat bit of detective work that makes use of between-breed variation in linkage disequilibrium in tracking down mutations that are common to several breeds, Parker et al. (2007) discovered that a likely causal variant for Collie Eye Anomaly in four breeds (Collie, Border Collie, Australian Shepherd, and Shetland Sheepdog) is a deletion of 7.8kb in the NHEJ1 gene: 37:g.28,697,542–28,705,340del. A warning that the causality of this mutant may not be as straightforward as initially thought, was provided by Fredholm et al. (2016) who reported that " the deletion in NHEJ1 is not predictive for CH [choroidal hypoplasia] in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population." Further doubt on the causality of the deletion was raised by the results of Brown et al. (2018) in Nova Scotia Duck Tolling Retrievers. Grosås et al. (2018) reported "A good compliance between the clinical diagnosis and the genetic test results was found" in 103 puppies from a random sample of 16 unrelated Norwegian Border Collie litters. The authors reported that one puppy was clinically affected and one puppy was homozygous for the deletion variant, but intriguingly, readers were not told whether this was the same puppy. Also, even though the parents were genotyped, readers were not told whether the parents of the affected puppy were both heterozygotes.

Clinical features: CEA presents as varying levels of visual impairment, from no visual impairment to complete blindness. As summarised by Fredholm et al. (2016), "Collie eye anomaly (CEA) is a congenital, inherited ocular disorder which is widespread in herding breeds. Clinically, the two major lesions associated with CEA are choroidal hypoplasia (CH) and coloboma, and both lesions are diagnosed based on ophthalmological examination". Choroidal hypoplasia is noted as a defect in the ocular fundus temporal to the optic nerve, which can be detected during ophthalmoscopic exam. Some affected dogs have tortuous retinal vessels and multiple retinal folds. More severely affected dogs can develop retinal detachments leading to blindness. These dogs can also develop subretinal and preretinal neovascularization and intraocular hemorrhage (Lowe et al., 2003).

Pathology: The choroid is the vascular supply to the retina. The primary defect in this disorder is choroidal hypoplasia. Secondary lesions include colobomas around and in the optic nerve head or the adjacent fundus. Retinal detachment is also a secondary lesion.

Prevalence: Prevalence is estimated to be 70-97% in rough and smooth collies in the USA and Great Britain, and 68% in rough collies in Sweden. In Border collies, prevalence is estimated at 2-3% in the USA and Great Britain (Lowe et al., 2003). Mizukami et al. (2016) reported the frequency of the NHEJ1 deletion allele as 0.143 in 500 Border collies in Japan. Grosås et al. (2018) reported the frequency of the deletion variant as 6.3% in Norwegian Border Collies. In a sample of 465 Italian dogs from five breeds, Marelli et al. (2022) reported that the frequency of carriers (healthy heterozygotes) for the deletion variant (OMIA variant 632) was 50% in Shetland Sheepdog, 45% in Nova Scotia Duck Tolling Retriever, 30% in Border Collie, 17% in Australian Shepherd, and 13% in Rough Collies. Donner et al. (2018) reported that the variant (OMIA variant 632) was identified in additional breeds and reported carrier frequencies: Australian Kelpie: 7.5% (6/80), Chinook: 0.7% (1/151), Jack Russell Terrier: 3.8% (4/105), Parson Russell Terrier: 1.2% (3/243), Koolie: 41% (16/39), Lapponian Herder: 5% (1/20), Tamaskan Dog: 3.5% (3/86) Clark et al. (2023) "utilized a large set of genotypes from dogs tested for the progressive rod-cone degeneration–progressive retinal atrophy (prcd-PRA) G>A missense PRCD variant (n = 86,667) and the collie eye anomaly (CEA)-associated NHEJ1 deletion (n = 33,834) ... . ... the NHEJ1 deletion may actually be linked to the true causal mutation, as the deletion does not segregate with coloboma or CH in some cases ... . Regression modeling showed time progression to significantly affect the odds of a dog being homozygous or heterozygous for either [variant], as do variables including breed and breed popularity. This study shows that genetic testing informed breeding decisions to produce fewer affected dogs. However, the presence of dogs homozygous for the disease variant, especially for prcd-PRA, was still observed fourteen years after test availability, potentially due to crosses of unknown carriers."

Genetic testing: For limitations on the utility of testing for the published likely causal variant, see the results of Fredholm et al. (2016) and Brown et al. (2018).

Breeds: Alaskan Husky (Dog) (VBO_0200015), Australian Kelpie (Dog) (VBO_0200090), Australian Shepherd (Dog) (VBO_0200095), Border Collie (Dog) (VBO_0200193), Boykin Spaniel (Dog) (VBO_0200214), Chinook (Dog) (VBO_0200353), Collie Rough (Dog) (VBO_0200376), Collie Smooth (Dog) (VBO_0200377), Hokkaido (Dog) (VBO_0200671), Jack Russell Terrier (Dog) (VBO_0200724), Koolie (Dog) (VBO_0200782), Lancashire Heeler (Dog) (VBO_0200808), Lapponian Herder (Dog) (VBO_0200814), Long-Haired Whippet (Dog) (VBO_0200833), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964), Old English Sheepdog (Dog) (VBO_0200969), Parson Russell Terrier (Dog) (VBO_0200987), Shetland Sheepdog (Dog) (VBO_0201217), Siberian Husky (Dog) (VBO_0201233), Silken Windhound (Dog) (VBO_0201235), Smithfield (Dog) (VBO_0201256), Tamaskan Dog (Dog) (VBO_0201334).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
NHEJ1 nonhomologous end-joining factor 1 Canis lupus familiaris 37 NC_051841.1 (25735139..25652649) NHEJ1 Homologene, Ensembl , NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
632 Collie eye anomaly NHEJ1 deletion, gross (>20) Naturally occurring variant CanFam3.1 37 g.25698028_25705826del c.588+462_588+8260del XM_005640671.1; a deletion of 7799bp in the NHEJ1 gene; for limitations on the utility of testing for the published likely causal variant, see the results of Fredholm et al. (2016) and Brown et al. (2018) 2007 17916641

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:000218-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

References

Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2023 Clark, J.A., Anderson, H., Donner, J., Pearce-Kelling, S., Ekenstedt, K.J. :
Global frequency analyses of canine progressive rod-cone degeneration-progressive retinal atrophy and Collie eye anomaly using commercial genetic testing data. Genes (Basel) 14:2093, 2023. Pubmed reference: 38003037. DOI: 10.3390/genes14112093.
Majchrakova, Z., Hrckova Turnova, E., Bielikova, M., Turna, J., Dudas, A. :
The incidence of genetic disease alleles in Australian Shepherd dog breed in European countries. PLoS One 18:e0281215, 2023. Pubmed reference: 36848350. DOI: 10.1371/journal.pone.0281215.
2022 Gray, A.P., Sato, Y., Miyadera, K., Aguirre, G.D. :
Novel insights into chorioretinal and juxtapapillary colobomas by optical coherence tomography. Vet Ophthalmol 25 Suppl 1:136-143, 2022. Pubmed reference: 35092136. DOI: 10.1111/vop.12970.
Lerdkrai, C., Phungphosop, N. :
A novel multiplex polymerase chain reaction assay for the genotypic survey of the non-homologous end-joining factor 1 gene associated with Collie eye anomaly in Thailand. Vet World 15:132-139, 2022. Pubmed reference: 35369581. DOI: 10.14202/vetworld.2022.132-139.
Marelli, S.P., Rizzi, R., Paganelli, A., Bagardi, M., Minozzi, G., Brambilla, P.G., Polli, M. :
Genotypic and allelic frequency of a mutation in the NHEJ1 gene associated with collie eye anomaly in dogs in Italy. Vet Rec Open 9:e26, 2022. Pubmed reference: 35127102. DOI: 10.1002/vro2.26.
2021 Genetics Committee of the American College of Veterinary Opthalmologists :
The Blue Book: Ocular disorders presumed to be inherited in purebred dogs. 13th Edition https://ofa.org/wp-content/uploads/2022/10/ACVO-Blue-Book-2021.pdf , 2021.
Thorsrud, J.A., Huson, H.J. :
Description of breed ancestry and genetic health traits in arctic sled dog breeds. Canine Med Genet 8:8, 2021. Pubmed reference: 34544496. DOI: 10.1186/s40575-021-00108-z.
2019 Donner, J., Anderson, H., Davison, S., Hughes, A.M., Bouirmane, J., Lindqvist, J., Lytle, K.M., Ganesan, B., Ottka, C., Ruotanen, P., Kaukonen, M., Forman, O.P., Fretwell, N., Cole, C.A., Lohi, H. :
Correction: Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs. PLoS Genet 15:e1007938, 2019. Pubmed reference: 30657768. DOI: 10.1371/journal.pgen.1007938.
Kucharczyk, N., Cislo-Pakuluk, A., Bedford, P. :
Collie eye anomaly in Australian Kelpie dogs in Poland. BMC Vet Res 15:392, 2019. Pubmed reference: 31684941. DOI: 10.1186/s12917-019-2143-y.
2018 Brown, E.A., Thomasy, S.M., Murphy, C.J., Bannasch, D.L. :
Genetic analysis of optic nerve head coloboma in the Nova Scotia Duck Tolling Retriever identifies discordance with the NHEJ1 intronic deletion (collie eye anomaly mutation). Vet Ophthalmol 21:144-150, 2018. Pubmed reference: 28702949. DOI: 10.1111/vop.12488.
Donner, J., Anderson, H., Davison, S., Hughes, A.M., Bouirmane, J., Lindqvist, J., Lytle, K.M., Ganesan, B., Ottka, C., Ruotanen, P., Kaukonen, M., Forman, O.P., Fretwell, N., Cole, C.A., Lohi, H. :
Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs. PLoS Genet 14:e1007361, 2018. Pubmed reference: 29708978. DOI: 10.1371/journal.pgen.1007361.
Grosås, S., Lingaas, F., Prestrud, K.W., Ropstad, E.O. :
Compliance between clinical and genetic diagnosis of choroidal hypoplasia in 103 Norwegian Border Collie puppies. Vet Ophthalmol 21:371-375, 2018. Pubmed reference: 29111596. DOI: 10.1111/vop.12520.
2016 Fredholm, M., Larsen, R.C., Jönsson, M., Söderlund, M.A., Hardon, T., Proschowsky, H.F. :
Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish Rough Collies and Shetland Sheepdogs. Anim Genet 47:250-2, 2016. Pubmed reference: 26732749. DOI: 10.1111/age.12405.
Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. :
Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004.
2015 Bauer, B.S., Sandmeyer, L.S., Grahn, B.H. :
Diagnostic ophthalmology. Can Vet J 56:989-90, 2015. Pubmed reference: 26346323.
Palanova, A. :
Collie eye anomaly: a review. Veterinarni Medicina 60:345-350, 2015. DOI: https://doi.org/10.17221/8381-VETMED.
2014 Mizukami, K., Yabuki, A., Endoh, D., Chang, H.S., Lee, K.W., Nakayama, M., Kushida, K., Kohyama, M., Lee, J.I., Yamato, O. :
Investigation of parallel and simultaneous selection for collie eye anomaly and ivermectin toxicosis. Vet Rec 175:174, 2014. Pubmed reference: 24939474. DOI: 10.1136/vr.102015.
2012 Miyadera, K., Acland, G.M., Aguirre, G.D. :
Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61, 2012. Pubmed reference: 22065099. DOI: 10.1007/s00335-011-9361-3.
Mizukami, K., Chang, H.S., Ota, M., Yabuki, A., Hossain, M.A., Rahman, M.M., Uddin, M.M., Yamato, O. :
Collie eye anomaly in Hokkaido dogs: case study. Vet Ophthalmol 15:128-32, 2012. Pubmed reference: 22051190. DOI: 10.1111/j.1463-5224.2011.00950.x.
2010 Chang, HS., Mizukami, K., Yabuki, A., Hossain, MA., Rahman, MM., Uddin, MM., Arai, T., Yamato, O. :
A novel rapid genotyping technique for Collie eye anomaly: SYBR Green-based real-time polymerase chain reaction method applicable to blood and saliva specimens on Flinders Technology Associates filter paper. J Vet Diagn Invest 22:708-15, 2010. Pubmed reference: 20807925. DOI: 10.1177/104063871002200506.
Dostal, J., Horak, P., Hrdlicová, A., Stratil, A. :
Simplified PCR analysis of a mutation in the NHEJ1 gene causing Collie eye anomaly in some dog breeds. Czech Journal of Animal Science 55:346-350, 2010. DOI: 10.17221/259/2009-CJAS.
2009 Walser-Reinhardt, L., Hässig, M., Spiess, B. :
Collie Eye Anomaly in Switzerland. Schweiz Arch Tierheilkd 151:597-603, 2009. Pubmed reference: 19946851. DOI: 10.1024/0036-7281.151.12.597.
2007 Munyard, KA., Sherry, CR., Sherry, L. :
A retrospective evaluation of congenital ocular defects in Australian Shepherd dogs in Australia. Vet Ophthalmol 10:19-22, 2007. Pubmed reference: 17204124. DOI: 10.1111/j.1463-5224.2007.00486.x.
Parker, H.G., Kukekova, A.V., Akey, D.T., Goldstein, O., Kirkness, E.F., Baysac, K.C., Mosher, D.S., Aguirre, G.D., Acland, G.M., Ostrander, E.A. :
Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. Genome Res 17:1562-71, 2007. Pubmed reference: 17916641. DOI: 10.1101/gr.6772807.
2005 Rampazzo, A., D'Angelo, A., Capucchio, MT., Sereno, S., Peruccio, C. :
Collie eye anomaly in a mixed-breed dog. Vet Ophthalmol 8:357-60, 2005. Pubmed reference: 16178848. DOI: 10.1111/j.1463-5224.2005.00417.x.
2004 Pedersen, P. B., Nielsen, C. B., Heegaard, S. :
Collie eye anomaly in blind Collie pups Dansk Veterinaertidsskrift 87:27-29, 2004.
2003 Lowe, JK., Kukekova, AV., Kirkness, EF., Langlois, MC., Aguirre, GD., Acland, GM., Ostrander, EA. :
Linkage mapping of the primary disease locus for collie eye anomaly. Genomics 82:86-95, 2003. Pubmed reference: 12809679.
2002 Beuing, G., Erhardt, G. :
Influences on the frequency of estimated collie eye anomaly (CEA) in Collies and Shelties - results of a breeding club survey Kleintierpraxis 47:407-413, 2002.
2001 Sargan, D.R. :
Collie eye anomaly in the rough collie Journal of Small Animal Practice 42:204 only, 2001. Pubmed reference: 11327669.
2000 Wallin-Hakanson, B., Wallin-Hakanson, N., Hedhammar, A. :
Influence of selective breeding on the prevalence of chorioretinal dysplasia and coloboma in the rough collie in Sweden Journal of Small Animal Practice 41:56-59, 2000. Pubmed reference: 10701187.
Wallin-Hakanson, B., Wallin-Hakanson, N., Hedhammar, A. :
Collie eye anomaly in the rough collie in Sweden: genetic transmission and influence on offspring vitality Journal of Small Animal Practice 41:254-258, 2000. Pubmed reference: 10879403.
1999 Spadiut, H.W., Nell, B. :
Collie eye anomaly (CEA) in a Border Collie in Austria [German] Wiener Tierarztliche Monatsschrift 86:378-381, 1999.
1998 Bedford, P.G.C. :
Collie eye anomaly in the Lancashire Heeler Veterinary Record 143:354-356, 1998. Pubmed reference: 9800301.
1991 Bjerkas, E. :
Collie eye anomaly in the rough Collie in Norway. Journal of Small Animal Practice 32:89-92, 1991. DOI: 10.1111/j.1748-5827.1991.tb00925.x.
Sanders, G. :
Collie Eye Anomaly Australian Veterinary Practitioner 21:198, 1991.
1986 Wikstrom, B. :
[Collie eye anomaly. An account of ophthalmoscopic evaluations of Collies in central Sweden in 1974-84] Svensk Veterinartidning 38:140-143, 1986.
1982 Bedford, PG. :
Collie eye anomaly in the United Kingdom. Vet Rec 111:263-70, 1982. Pubmed reference: 7147637.
Bedford, PG. :
Collie eye anomaly in the border collie. Vet Rec 111:34-5, 1982. Pubmed reference: 6812274.
1981 Stades, F.C., Barnett, K.C. :
Collie eye anomaly in collies in the Netherlands. Vet Q 3:66-73, 1981. Pubmed reference: 6787732. DOI: 10.1080/01652176.1981.9693799.
1980 Bedford, P.G.C. :
Incidence of colie eye anomaly (Correspondence) Veterinary Record 107:95, 1980. Pubmed reference: 6777963.
Walde, I. :
Visual defects in dogs as the result of breed specific fundus diseases (progressive retinal atrophy and collie eye anomaly) Wiener Tierarztliche Monatsschrift 67:20-24, 1980.
1979 Barnett, KC. :
Collie eye anomaly (CEA). J Small Anim Pract 20:537-42, 1979. Pubmed reference: 480920.
Barnett, KC., Stades, FC. :
Collie eye anomaly in the Shetland sheepdog in the Netherlands. J Small Anim Pract 20:321-9, 1979. Pubmed reference: 120471.
1974 Albert, R.A., Wilder, D.T. :
The Collie eye anomaly Auburn Veterinarian 30:103-107, 1974.
1972 Yakely, W.L. :
Collie eye anomaly: decreased prevalence through selective breeding Journal of the American Veterinary Medical Association 161:1103-1107, 1972. Pubmed reference: 4631461.
1971 Mason, TA., Cox, K. :
Collie eye anomaly. Aust Vet J 47:38-40, 1971. Pubmed reference: 4994718.
1970 Blogg, JR. :
Collie eye anomaly. Aust Vet J 46:530-2, 1970. Pubmed reference: 4992161.
Cole, W.W. :
Breeding of Collies with Collie eye anomaly Journal of the American Veterinary Medical Association 156:4 only, 1970.
1969 Cello, R.M. :
Collie eye anomaly: comments Journal of the American Veterinary Medical Association 155:870-871, 1969. Pubmed reference: 4980212.
Wyman, M., Donovan, E.F. :
Eye anomaly of the Collie Journal of the American Veterinary Medical Association 155:866-870, 1969. Pubmed reference: 4980211.
1966 Roberts, S.R., Dellaporta, A., Winter, F.C. :
The Collie ectasia syndrome: pathology of the eyes of young and adult dogs American Journal of Ophthalmology 62:728-752, 1966. Pubmed reference: 4959239.
Roberts, SR., Dellaporta, A., Winter, FC. :
The collie ectasia syndrome. Pathologic alterations in the eyes of puppies one to fourteen days of age. Am J Ophthalmol 61:1458-65, 1966. Pubmed reference: 5949333.
1965 Donovan, E.F., Wyman, M. :
Ocular fundus anomaly in the collie. J Am Vet Med Assoc 147:1465-9, 1965. Pubmed reference: 5884039.
Roberts, S.R., Dellaporta, A. :
Congenital ectasia of the sclera in Collie dogs. I. Clinical features American Journal of Ophthalmology 59:180-186, 1965. Pubmed reference: 14268789.
1961 Roberts, S.R. :
Congenital posterior ectasia of the sclera in Collies. Veterinary Excerpts 21:63-67, 1961. DOI: 10.1016/0002-9394(60)90684-x.
1960 Roberts, S.R. :
Congenital posterior ectasia of the sclera in Collie dogs Am J Ophthalmol 50:451-65, 1960. Pubmed reference: 14437837. DOI: 10.1016/0002-9394(60)90684-x.

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