OMIA 002374-9913 : Charcot Marie Tooth disease, FGD4-related in Bos taurus

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 611104 (gene) , 609311 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Mapping: Reynolds et al. (2021) “report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts [on body weight, stature or body condition score] generally exceeding the largest-effect variants identified from additive genome-wide association studies … [and] detail six novel putative causative mutations with effects ranging from mild (3.5% reduction in body weight) to severe (>25% reduction in body weight and increased early-life mortality)." The authors "detected a significant locus for bodyweight on bovine chromosome 5 at 77.6 Mbp. This signal was represented by a single, significant variant at the locus, representing a non-sense mutation in the FYVE, RhoGEF and PH domain containing 4 gene (FGD4 ....), a gene for which non-sense variants in humans have been proposed to underlie Charcot Marie Tooth disease (CMT)."

Molecular basis: Reynolds et al. (2021) report a FGD4 c.1671+1G>A splice donor mutation in New Zealand dairy cattle as likely causal variant for the the bodyweight QTL and Charcot Marie Tooth disease.

Clinical features: Reynolds et al. (2021) “conducted a genotypic screen of 568 animals to identify calves homozygous for the FGD4 (and other) mutations. … Nine of these homozygous mutant animals were then recruited for the farm trial… . Growth rates of FGD4 homozygotes were significantly reduced …, with the bodyweight difference between these animals and controls widening to 49.7kg by 24 months of age … . At the end of the farm trial (~27 months of age), FGD4 mutant animals subjectively demonstrated behavioural differences and instances of loss of motor control. In these cases, routine animal handling procedures such as confinement in a cattle crush and head bail appeared to lead to increased restlessness and agitation in FGD4 mutant animals, with some animals collapsing to a ‘kneeling’ position – a behaviour not observed in controls ... .”

Pathology: Histopathological findings of peripheral nerves from FGD4 homozygotes included hypercellularity, Schwann cell hyperplasia, axonal swelling and degeneration, and lack of myelin staining consistent with demyelination (Reynolds et al., 2021).

Prevalence: The alternative allele frequency in New Zealand dairy cattle was reported as 0.039 in Holstein Friesian cattle, 0.001 in Jersey cattle and 0.024 in the 25,239 dairy cattle genotyped (Reynolds et al., 2021).

Breeds: Holstein Friesian, Jersey.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
FGD4 FYVE, RhoGEF and PH domain containing 4 Bos taurus 5 NC_037332.1 (77463045..77219790) FGD4 Homologene, Ensembl, NCBI gene


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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 Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
1326 Holstein Friesian Jersey Charcot Marie Tooth disease FGD4 splicing Naturally occurring variant ARS-UCD1.2 5 g.77262490C>T c.1671+1G>A Splice donor mutation based on XM_005206883.3 2021 34045765


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.
2022 Dittmer, K.E., Neeley, C., Perrott, M.R., Reynolds, E., Garrick, D.J., Littlejohn, M.D. :
Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in <i>FGD4</i>. Vet Pathol 59:442-450, 2022. Pubmed reference: 35300540. DOI: 10.1177/03009858221083041.
2021 Reynolds, E.G.M., Neeley, C., Lopdell, T.J., Keehan, M., Dittmer, K., Harland, C.S., Couldrey, C., Johnson, T.J.J., Tiplady, K., Worth, G., Walker, M., Davis, S.R., Sherlock, R.G., Carnie, K., Harris, B.L., Charlier, C., Georges, M., Spelman, R.J., Garrick, D.J., Littlejohn, M.D. :
Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes. Nat Genet 53:949-54, 2021. Pubmed reference: 34045765. DOI: 10.1038/s41588-021-00872-5.

Edit History

  • Created by Imke Tammen2 on 09 Aug 2021
  • Changed by Imke Tammen2 on 09 Aug 2021