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".
