Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611177 (gene) , 611263 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Cross-species summary: This phene was previously called ‘Abortion due to halplotype HH2' and has been renamed to ‘Haplotype with homozygous deficiency-HH2, IFT80-related’.

Species-specific name: Haplotype HH2

Species-specific symbol: Hh2

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 recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. Three of these haplotypes occur in Holsteins only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named them HH1, HH2 and HH3, where the first H stands for Holstein and the second H for haplotype. The disorder described in this OMIA entry is HH2, which is located in chromosome BTA1, at 92-97Mb (UMD 3.0 genome assembly). McClure et al. (2014) refined the mapping of haplotype HH2 on chromosome BTA1 to 94,860,836 to 96,553,339 (UMD3.1).

Molecular basis: In an extensive study involving exome capture and next-gen sequencing, McClure et al. (2014) were not able to discover any potentially causal variant for haplotype HH2. Yang et al. (2021): "Short- and long-read WGS was performed on four carriers and four non-carriers of HH2 to screen for variants in concordance with HH2 haplotype status.Sequence variation analysis revealed five putative functional variants of protein-coding genes, including a frameshift mutation (g.107172616delT) in intraflagellar transport protein 80 (IFT80) gene. Transcriptome analysis of whole blood indicated that no gene exhibited significantly differential expression or allele-specific expression between carriers and non-carriers in the candidate region. This evidence points to g.107172616delT as the highest priority causative mutation for HH2." In presenting "a comprehensive framework for identification and validation of . . . [harmful recessive] genetic defects, including haplotype-based detection, variant selection from sequence data, and validation using knockout embryos", Ortega et al. (2022) confirmed that the IFT80 variant g.107172616delT (OMIA variant 1396) is the cause of homozygous lethality of haplotype HH2, and providing supporting evidence by showing that the development of IFT80-null embryos created via a CRISPR-Cas9 system is arrested at the 8-cell stage, when IFT80 is normally activated. The authors concluded that the "frameshift in IFT80 on chromosome 1 at 107,172,615 bp (p.Leu381fs) disrupts WNT and hedgehog signaling, and is responsible for the death of homozygous embryos".

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: