Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 609053 (trait) , 611360 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Haplotype HH0

Species-specific symbol: HH0

Mapping: In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA21 at 20-25Mb (UMD 3.0 genome assembly). Genotyping six affected Holstein-Friesian calves and 15 normal H-F controls with a custom-made 50K bovine SNP chip, followed by autozygosity mapping, enabled Charlier et al. (2012) to map this disorder to a 2.46Mb region of chromosome BTA21, which contains 56 annotated genes. Fritz et al. (2013) confirmed the existence and location of this deleterious haplotype. By genotyping each of 7,937 Nordic Holstein bulls with the BovineSNP50 BeadChip, yielding 36,387 informative autosomal SNPs, and then searching for 25-marker haplotypes that never occur as a homozygote where the minimum expectation is 6 occurrences, Sahana et al. (2013) "identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles". One of the eight regions (marked by haplotypes 21-276, 21-301 and 21-326) seems to coincide with Brachyspina.

Molecular basis: Using mate-pair libraries from one affected and three controls, Charlier et al. (2012) obtained around 3.4Gb of sequence from each animal. Comparison of sequence in the candidate BTA21 region "revealed a 3.3 Kb deletion removing exons 25–27 of the 37 composing the FANCI (Fanconi anemia complementation-group I) gene". Noting that the carrier frequency is far too high (up to 7.4%) to be consistent with a relatively rare autosomal recessive disorder, Charlier et al. (2012) also showed that a large proportion of affected calves die in utero. Thus this causal mutation also contributes to natural abortions and hence to reduced fertility.

Clinical features: As summarised by Charlier et al. (2012), "Affected animals are characterized by severely reduced body weight, growth retardation, extensive vertebral malformations causing a significant shortening of the spine (brachyspina) and long and slender limbs. In addition, affected calves exhibit inferior brachygnatism (i.e. uneven alignment of the upper and lower teeth), as well as malformation of the inner organs, in particular the heart, kidneys and gonads."

Breed: Holstein (black and white) (Cattle) (VBO_0000237).
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: