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: