KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf

Abstract

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.

MYH3 ‐associated non‐syndromic palatoschisis (cleft palate, CP) in Limousine cattle

“…Whole-genome sequencing was performed as previously described (Jacinto et al, 2022). Reads were mapped to the ARS-UCD1.2 assembly (Rosen et al, 2020), resulting in an average read depth of 13×, and then processed as previously reported (Jacinto et al, 2021). This identified 30 homozygous private protein-changing variants that were present exclusively in the genome of the affected calf and absent in 942 controls from the ongoing Swiss Comparative Bovine Resequencing Project, including 28 genomes from purebred Limousine cattle (Table S1).…”

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MYH3-associated non-syndromic palatoschisis (cleft palate, CP) in Limousine cattle

BACKGROUNDPalatoschisis (also called cleft palate) is an opening or cleft in the upper lip, the roof of the palate, or both, and is a common defect in both humans and domestic animals (Mossey & Modell, 2012;Mulvihill et al, 1980). It can also occur in cattle as an isolated (non-syndromic) birth defect (OMIA 000197-9913), or it is associated with familial or sporadic genetic syndromes, such as the recessively inherited CHRNB1-related arthrogryposis multiplex congenita in Red dairy cattle (Agerholm et al, 2016; OMIA 000070-9913), or the reported isolated case of KCNG1-related neuromuscular channelopathy (Jacinto et al, 2021; OMIA 002483-9913).

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A de novo start‐lost variant in ANKRD28 in a Holstein calf with dwarfism

“…A whole‐genome sequencing (WGS) approach was performed as described before (Jacinto et al, 2022 ) using genomic DNA extracted from blood of the affected calf, her dam, and from semen of her sire. Reads were mapped to the ARS‐UCD1.2 assembly (Rosen et al, 2020 ) resulting in an average read depth of 20.7× in the calf, 21.8× in the dam, and 22.1× in the sire, and then processed as reported earlier (Jacinto et al, 2021 ). We hypothesized that the affected calf had a novel form of dwarfism and investigated the genetic origin.…”

Is a heterozygous missense variant in SGSH the cause of a syndromic form of congenital amastia in an Original Braunvieh calf?

“…Reads were mapped to the ARS‐UCD1.2 assembly (Rosen et al, 2020), resulting in an average read depth of 14.7×. The WGS data were evaluated as previously described (Jacinto et al, 2021). Variant filtering did not reveal any private homozygous protein‐changing variants present in the genome of the affected calf, making a possible recessive inheritance unlikely.…”