Categories: Respiratory system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 131241 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific symbol: GRL syndrome

History: Eusebi et al. (2022) provided the first report of this syndrome.

Inheritance: Eusebi et al. (2022) conducted a detailed pedigree analysis which suggested an "hypothesis of a variant that severely affects the function of a major gene following a classic Mendelian recessive mode of inheritance".

Mapping: Eusebi et al. (2022) "performed a genome-wide association study on a cohort of 13 affected calves and 24 putative non-carrier parents, mapping the disease to a wide 6 cM region on bovine chromosome 3 (p< 10−7)."

Molecular basis: Eusebi et al. (2022): "Whole genome resequencing of three affected calves and three putative non-carrier parents identified a novel missense variant (c.149G>A|p.Cys50Tyr) in exon 2 of the endothelin 2 (EDN2) gene. Bioinformatic analyses of p.Cys50Tyr effects predicted them to be damaging for both the structure and the function of the edn2 protein, and to create a new site of splicing that may also affect the pattern of pre-mRNA splicing and exon definition. Sanger sequencing of this variant on the rest of the sample set confirmed the segregation pattern obtained with whole genome re-sequencing".

Clinical features: Eusebi et al. (2022): "The first five affected calves appeared in 2004 in a Lidia herd and were reported to be suffering from a novel bovine syndrome exhibiting severe growth retardation, respiratory alterations and juvenile lethality. Various systems were affected, including muscular, skeletal and respiratory abnormalities. At the muscular level, the calves displayed weakness, muscular atrophy, impaired mobility and prostration. Skeletal alterations include arched posture and convex frontonasal profile . . . . The respiratory tract was affected by malformation of the nasal turbinate, which may be the cause of the notorious snoring described in these calves, and trachea, with a progressive reduction of the endotracheal lumen . . . and the fusion of tracheal cartilage rings . . . . Finally, feeding difficulties and dehydration were also reported in these calves, probably as a consequence of the abnormalities previously described. This GRL syndrome can be diagnosed at birth in most cases, and all affected calves died before 1 year of age."

Breed: Lidia, Spain (Cattle) (VBO_0002878).
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: