Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 609909 (trait) , 613874 (trait) , 172405 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0012362: dilated cardiomyopathy 1P

Mendelian trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Molecular basis: Yost et al. (2019) "characterized genetic aspects of familial DCM in a [Welsh springer spaniel] canine model with a high incidence of sudden death. A missense G > A mutation in exon 1 of the phospholamban [PLN] gene that changed . . . [the 9th] amino acid from arginine to histidine [R9H] was identified in affected dogs. This variant was predicted to be deleterious. . . . The dam . . . , the sire's parents . . . and the sire's sister . . . were all homozygous wild type for the variant suggesting that this was likely a de novo mutation in the sire who died suddenly at 48 months of age. The proband . . . , [all] four [accessible] affected littermates . . ., and three of four offspring of the proband were heterozygous for the variant . . . . The proband and mutation positive littermates all demonstrated the disease phenotype after 20 months of age. The mutation positive offspring of the proband are all only 14 months of age and appear to be below the age of disease development. An additional 100 Welsh Springer Spaniels and one of the proband's offspring did not have the variant." Yost et al. (2019) note that three missense variants at the same (9th) amino acid in the human PLN gene, namely R9C, R9L and R9H, are associated with DCM in humans; see MIM entry 609909 for a description of the first of these three variants.

Clinical features: Yost et al. (2019): "Clinical evaluation of the proband and four littermates demonstrated echocardiographically evident left ventricular dilation, systolic dysfunction and ventricular arrhythmias . . . . One affected female littermate is still alive at 44 months of age and is managed with routine medical care including an ace inhibitor (enalapril), inodilator (pimobendan) and an antiarrhythmic (sotalol)."

Pathology: Yost et al. (2019): "Necropsy evaluation of the dogs that died suddenly identified gross findings of mild biventricular dilation, and histologic findings of moderate to diffuse fatty infiltration of the left ventricle, myofiber loss and interstitial edema, mild interstitial fibrosis and mild lymphocytic infiltration".

Breed: Welsh Springer Spaniel (Dog) (VBO_0201411).
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: