Categories: Hearing / vestibular / ear phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 612109 (trait) , 142992 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant with variable expressivity

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific name: Notched ears; Nicked ears

Species-specific symbol: CE

Species-specific description: Koch et al. (2013) suggested the following nomenclature: CE-0 for homozygous wild type; CE-1 for heterozygotes; and CE-2 for homozygous duplication.

History: This disorder was first documented by Yamane (1915).

Inheritance: In the original report, Yamane (1915) provided pedigree evidence that implied Mendelian inheritance. Later reports (Wriedt, 1925; MacDonald, 1957; Scheider et al., 1994) were consistent with autosomal dominance with variable expressivity (suggestive of a multifactorial underlying trait, with one gene of large effect). Koch et al. (2013) reached the same conclusion from a pedigree analysis, and were able to trace all cases back to a single bull born in 1943.

Mapping: From a GWAS on 32 affected and 36 control Highland cattle, each genotyped with the Illumina bovine HD SNP chip (yielding 519,828 informative SNPs), Koch et al. (2013) mapped this trait to a 4Mb region of chromosome BTA6 (106Mb to 110Mb; UMD3 assembly).

Molecular basis: Among the 64 genes in the mapped region (see Mapping section), Koch et al. (2013) reported that HMX1 (which encodes a transcription factor) stood out as a "striking functional [comparative] candidate" (based on known mutations in humans, mice and rats). Whole-genome sequencing of a severely affected cow (assumed to be homozygous) revealed "6 non-synonymous DNA variants within the two coding exons of HMX1 and two structural variants within the downstream highly conserved region". Genotyping by sequencing in other animals excluded all but one of the structural variants, namely a 76bp duplication (Copy Number Variant; CNV), which was confirmed as the causal mutation by subsequent genotyping in 40 affecteds and 80 control Highland cattle, as well as in 144 cattle from a range of other breeds. As reported by Koch et al. (2013), "The affected ultra-conserved enhancer is located 148 kb apart of the coding region of HMX1 . . . . The sequence of the 76 bp duplication is highly conserved . . . . In silico prediction revealed several transcription factor binding sites indicating the potential functional relevance of this region".

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

Clinical features: As reported by Koch et al. (2013): "Crop ears in Highland cattle generally affect both ears more or less symmetrically, with a nick on the tip of the ear . . . . Crop ears are already present at birth and occur both in male and female cattle. We classified the crop ear phenotype into 2 general categories of varying severity: in category 1 the notches are mild to moderate and the ear cartilage appears normal or is only mildly deformed . . . . Category 2 is defined by clearly shortened ears, large notches and prominent (and slightly caudally twisted) upper edges of the ear cartilage above the notches . . . . However, the phenotypic severity of crop ears varies greatly within both categories."

Breeds: Ayrshire (Cattle) (VBO_0000120), Highland (Cattle) (VBO_0000234), Jersey (Cattle) (VBO_0000250).
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: