RASopathies are a group of developmental disorders caused by dominant mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. The goal of this study was to characterize the pathological phenotype of a Romagnola stillborn calf with skeletal-cardio-enteric dysplasia and to identify a genetic cause by whole-genome sequencing (WGS). The calf showed reduced fetal growth, a short-spine, a long and narrow face, cardiac defects and heterotopy of the spiral colon. Genetic analysis revealed a private heterozygous missense variant in MAP2K2:p.Arg179Trp, located in the protein kinase domain in the calf, and not found in more than 4500 control genomes including its sire. The identified variant affecting a conserved residue was predicted to be deleterious and most likely occurred de novo. This represents the first example of a dominant acting, and most likely pathogenic, variant in MAP2K2 in domestic animals, thereby providing the first MAP2K2-related large animal model, especially in respect to the enteric malformation. In addition, this study demonstrates the utility of WGS-based precise diagnostics for understanding sporadic congenital syndromic anomalies in cattle and the general utility of continuous surveillance for rare hereditary defects in cattle.

Jacinto J.G.P., Hafliger I.M., Gentile A., Drogemuller C. (2021). A heterozygous missense variant in MAP2K2 in a stillborn romagnola calf with skeletal-cardio-enteric dysplasia. ANIMALS, 11(7), 1931-1931 [10.3390/ani11071931].

A heterozygous missense variant in MAP2K2 in a stillborn romagnola calf with skeletal-cardio-enteric dysplasia

Jacinto J. G. P.;Gentile A.;
2021

Abstract

RASopathies are a group of developmental disorders caused by dominant mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. The goal of this study was to characterize the pathological phenotype of a Romagnola stillborn calf with skeletal-cardio-enteric dysplasia and to identify a genetic cause by whole-genome sequencing (WGS). The calf showed reduced fetal growth, a short-spine, a long and narrow face, cardiac defects and heterotopy of the spiral colon. Genetic analysis revealed a private heterozygous missense variant in MAP2K2:p.Arg179Trp, located in the protein kinase domain in the calf, and not found in more than 4500 control genomes including its sire. The identified variant affecting a conserved residue was predicted to be deleterious and most likely occurred de novo. This represents the first example of a dominant acting, and most likely pathogenic, variant in MAP2K2 in domestic animals, thereby providing the first MAP2K2-related large animal model, especially in respect to the enteric malformation. In addition, this study demonstrates the utility of WGS-based precise diagnostics for understanding sporadic congenital syndromic anomalies in cattle and the general utility of continuous surveillance for rare hereditary defects in cattle.
2021
Jacinto J.G.P., Hafliger I.M., Gentile A., Drogemuller C. (2021). A heterozygous missense variant in MAP2K2 in a stillborn romagnola calf with skeletal-cardio-enteric dysplasia. ANIMALS, 11(7), 1931-1931 [10.3390/ani11071931].
Jacinto J.G.P.; Hafliger I.M.; Gentile A.; Drogemuller C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/827722
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