ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency
A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-...
Published in: | Genes |
---|---|
Main Authors: | , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
MDPI AG
2022
|
Subjects: | |
Online Access: | https://doi.org/10.3390/genes13101847 https://doaj.org/article/7d0787eedc8f4bcdbda649660d9e16e3 |
id |
ftdoajarticles:oai:doaj.org/article:7d0787eedc8f4bcdbda649660d9e16e3 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:7d0787eedc8f4bcdbda649660d9e16e3 2023-05-15T15:50:55+02:00 ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency Matthias Christen Jos Bongers Déborah Mathis Vidhya Jagannathan Rodrigo Gutierrez Quintana Tosso Leeb 2022-10-01T00:00:00Z https://doi.org/10.3390/genes13101847 https://doaj.org/article/7d0787eedc8f4bcdbda649660d9e16e3 EN eng MDPI AG https://www.mdpi.com/2073-4425/13/10/1847 https://doaj.org/toc/2073-4425 doi:10.3390/genes13101847 2073-4425 https://doaj.org/article/7d0787eedc8f4bcdbda649660d9e16e3 Genes, Vol 13, Iss 1847, p 1847 (2022) Canis lupus familiaris dog neurology metabolism fatty acid disorder seizure Genetics QH426-470 article 2022 ftdoajarticles https://doi.org/10.3390/genes13101847 2022-12-30T23:06:56Z A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. We sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6). Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs. The acylcarnitine C8/C12 ratio was elevated ~43.3 fold in homozygous mutant dogs as compared to homozygous wild type dogs. Based on available clinical and biochemical data together with current knowledge in humans, we propose the ACADM frameshift variant as causative variant for the MCAD deficiency with likely contribution to the neurological phenotype in the index case. Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency. Further prospective studies are warranted to assess the clinical consequences of this enzyme defect. Article in Journal/Newspaper Canis lupus Directory of Open Access Journals: DOAJ Articles Cavalier ENVELOPE(-69.462,-69.462,-67.825,-67.825) Genes 13 10 1847 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Canis lupus familiaris dog neurology metabolism fatty acid disorder seizure Genetics QH426-470 |
spellingShingle |
Canis lupus familiaris dog neurology metabolism fatty acid disorder seizure Genetics QH426-470 Matthias Christen Jos Bongers Déborah Mathis Vidhya Jagannathan Rodrigo Gutierrez Quintana Tosso Leeb ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
topic_facet |
Canis lupus familiaris dog neurology metabolism fatty acid disorder seizure Genetics QH426-470 |
description |
A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. We sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6). Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs. The acylcarnitine C8/C12 ratio was elevated ~43.3 fold in homozygous mutant dogs as compared to homozygous wild type dogs. Based on available clinical and biochemical data together with current knowledge in humans, we propose the ACADM frameshift variant as causative variant for the MCAD deficiency with likely contribution to the neurological phenotype in the index case. Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency. Further prospective studies are warranted to assess the clinical consequences of this enzyme defect. |
format |
Article in Journal/Newspaper |
author |
Matthias Christen Jos Bongers Déborah Mathis Vidhya Jagannathan Rodrigo Gutierrez Quintana Tosso Leeb |
author_facet |
Matthias Christen Jos Bongers Déborah Mathis Vidhya Jagannathan Rodrigo Gutierrez Quintana Tosso Leeb |
author_sort |
Matthias Christen |
title |
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
title_short |
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
title_full |
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
title_fullStr |
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
title_full_unstemmed |
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency |
title_sort |
acadm frameshift variant in cavalier king charles spaniels with medium-chain acyl-coa dehydrogenase deficiency |
publisher |
MDPI AG |
publishDate |
2022 |
url |
https://doi.org/10.3390/genes13101847 https://doaj.org/article/7d0787eedc8f4bcdbda649660d9e16e3 |
long_lat |
ENVELOPE(-69.462,-69.462,-67.825,-67.825) |
geographic |
Cavalier |
geographic_facet |
Cavalier |
genre |
Canis lupus |
genre_facet |
Canis lupus |
op_source |
Genes, Vol 13, Iss 1847, p 1847 (2022) |
op_relation |
https://www.mdpi.com/2073-4425/13/10/1847 https://doaj.org/toc/2073-4425 doi:10.3390/genes13101847 2073-4425 https://doaj.org/article/7d0787eedc8f4bcdbda649660d9e16e3 |
op_doi |
https://doi.org/10.3390/genes13101847 |
container_title |
Genes |
container_volume |
13 |
container_issue |
10 |
container_start_page |
1847 |
_version_ |
1766385947634565120 |