Categories: Mortality / aging (incl. embryonic lethal)

Possibly relevant human trait(s) and/or gene(s) (MIM number): 607344 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

Cross-species summary: Phenes previously called ‘Abortion due to halplotype ….. ’ or ‘Abortion (embryonic lethality)’ , have been renamed to ‘Haplotype with homozygous deficiency, …’ or a phene name that is descriptive of the phenotype observed in homozygous affected animals [14/1/2022]

Species-specific symbol: BH2

History: After consultation with Schwarzenbacher and colleagues, this haplotype was named BH2 (Braunvieh haplotype 2) by VanRaden et al. (2013). It was previously called 424.49 by Vanraden et al. (2011) and BTA19-1 by Schwarzenbacher et al. (2012).

Mapping: Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new potential recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. One of these haplotypes (424.49) was roughly mapped to the region 7-16Mb on chromosome BTA19), but was not pursued further, by VanRaden et al. (2011). A subsequent study of another 2,959 Brown Swiss from Austria and Germany enabled Schwarzenbacher et al. (2012) to confirm the existence of this lethal haplotype and to refine its location to a region 10.140-11.049Mb on BTA19. However, its effect was still not clear: these authors noted that this haplotype "is suspect and needs further research". FN thanks Cole et al. (2014) for alerting him to the latter results.

In a preprint posted on the Cold Spring Harbor bioRxiv preprint server on 1st March 2016, Schwarzenbacher et al. (2016) documented the quite marked effects of this haplotype on mortality, and reported the discovery of its causal mutation as "a missense mutation in TUBD1 (rs383232842[T>C], p.H210R)". This is the first result from a preprint to be included in OMIA. A refereed version of this paper was published three months later in BMC Genomics (see reference list).

Häfliger et al. (2021) identified the same haplotype and same likely causal variant in Brown Swiss cattle in their investigation of Brown Swiss and Original Braunvieh populations reared in Switzerland - see OMIA002513-9913 for more detail.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: As reported by Schwarzenbacher et al. (2016),"Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia." As pointed out carefully by Schwarzenbacher et al. (2016), not all homozygotes die, i.e. the lethal allele has incomplete penetrance.

Prevalence: Wu et al. (2020) reported the frequency for this lethal haplotype as 4.4% in 19,309 Nordic Red Dairy cattle. Noting an inconsistency in this breed between the occurrence of the lethal haplotype and the likely causal variant (p.H210R) in Brown Swiss reported by Schwarzenbacher et al. (2016), Wu et al. (2020) noted that "it is highly likely that an additional recessive lethal mutation is segregating in this region in" Nordic Red Dairy cattle.

Breeds: Brown Swiss (Cattle) (VBO_0000166), Nordic Red (Cattle) (VBO_0016847).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: