Categories: Skeleton phene (incl. short stature & teeth) , Growth / size / body region phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 130070 (trait) , 604327 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2016

Cross-species summary: Renamed from  'Dwarfism, Friesian' to 'Dwarfism, B4GALT7-related' [04/06/2024]

History: Back et al. (2008) reported six disproportionate dwarfs in the Friesian breed.

Inheritance: Consistent with the variant being causal, Leegwater et al. (2016) reported that "All 29 dwarfs of which DNA was available were homozygous for the mutation . . . [and] The 8 obligate carriers were heterozygous". (FN thanks Elizabeth Huffman, who substantially enhanced this section, working under the supervision of Professor Ernie Bailey; 23 April 2020)

Mapping: By conducting a GWAS on 10 affected and 10 normal Friesian horses, each genotyped with the equine SNP50 chip (yielding 34,429 informative SNPs), Orr et al. (2010) mapped this disorder to a 2Mb region (3.8–5.4 MB; EquCab2.0) of chromosome ECA14. Leegwater et al. (2016) mapped this disorder to a similar, slightly-larger region of ECA14 via an independent GWAS involving 19 Friesian dwarfs and 65 non-affected Friesian controls, each genotyped with the Illumina® EquineSNP50 Genotyping BeadChip (yielding 29,840 informative SNPs), specifying the region as "between positions 3151847 and 6229282 on ECA14" (Equcab 2.0). (FN thanks Elizabeth Huffman, who substantially enhanced this section, working under the supervision of Professor Ernie Bailey; 23 April 2020)

Molecular basis: Whole genome sequencing was conducted on 4 dwarf Friesians and 3 non-affected Friesian controls, and the resultant sequences were compared in the candidate region with sequence from the horse reference genome and a Quarter Horse (a breed in which dwarfism has not been reported) (Leegwater et al., 2016). The authors identified a likely causal (missense) variant in Friesians as g.4535550C>T; c.50G>A; p.Arg17Lys in B4GALT7. The point mutation concerns the last nucleotide of exon 1 and Leegwater et al. (2016) demonstrate that it leads to a splicing deficiency of B4GALT7 transcripts. (FN thanks Elizabeth Huffman, who substantially enhanced this section, working under the supervision of Professor Ernie Bailey; 23 April 2020)

Clinical features: As summarised by Orr et al. (2010), "the Friesian dwarf phenotype results from physeal growth retardation in both limbs and ribs, reflected in a characteristic disproportional growth disturbance. The potential for post-natal growth in these animals, albeit at a reduced rate, is responsible for mature dwarfs having a head of the same size as unaffected animals, a broader chest with narrowing at the costochondral junction, a disproportionally long back and abnormally short limbs. Furthermore, radiographs reveal a dysplastic metaphysis of the distal metacarpus and metatarsus. Light microscopy of growth plates at the costochondral junction demonstrates an irregular transition from cartilage to bone, and thickening and disturbed formation of chondrocyte columns, which is similar to findings in osteochondrodysplasia".

Prevalence: 177 Friesian horses were tested, with discovery of 22 carriers and 155 homozygotes for the reference allele. Not tested in other breeds. (Leegwater et al., 2016). (FN thanks Elizabeth Huffman, who substantially enhanced this section, working under the supervision of Professor Ernie Bailey; 23 April 2020)

Breed: Friesian (Horse) (VBO_0000969).
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: