Categories: Cardiovascular system phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 217095 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: no

Species-specific description: Conotruncal defects are a type of congenital heart defect characterized by abnormal formation and union of the endocardial cushions that normally divide the atrioventricular canal during development. The severity of the defect can vary from subclinical to life threatening. Clinical signs include exercise intolerance, cyanosis, and a systolic murmur. Edited by Meg Sleeper, VMD and Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Inheritance: Conotruncal defects are inherited as a complex trait in the Keeshond, involving multiple loci and environmental influences (Werner et al., 2005).

Mapping: There is some evidence that predisposing alleles on CFA2, CFA9, and CFA15 act synergistically to cause conotruncal defects in the Keeshond (Werner et al., 2005). However, none of these three loci alone are responsible for inheritance of the condition.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Clinical signs include exercise intolerance with cyanosis and a systolic murmur. Radiographs may show reduced circulation in the pulmonary vessels along with right ventricular hypertrophy. Diagnosis can be obtained by echocardiogram or angiogram.

Pathology: Opposing areas of mesenchymal tissue known as the atrioventricular endocardial cushions divide the atrioventricular canal during cardiac development. Abnormal septation is caused by abnormal formation and fusion of these cushions. Conotruncal defects include varying degrees of abnormality in the septation of the heart during development, which are divided into four grades of severity Patterson et al., 1974). Grade 1: The defects are subclinical, and include a persistent conus septum fusion line, an aneurysm in the ventricular septum, and absence of the papillary muscle of the conus. Otherwise, the heart is normal and no murmurs are present. Grade 2: Affected animals have a ventricular septal defect. Grade 3: Affected dogs have Tetralogy of Fallot, which is the combination of pulmonic stenosis, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Grade 4: Affected animals have a persistent truncus arteriosus, where the pulmonary artery and aorta arise from the truncus and there is no supraventricular crest. Occasionally, affected dogs also have anomalies of the aortic arch system, such as persistent ductus arteriosus, retroesophageal right subclavian artery, lateral origin of the aortic arch branches, and persistent left cranial vena cava (Patterson et al., 1974).

Prevalence: Conotruncal defects in the Keeshond have been studied extensively (Werner et al., 2005).

Control: The recommendation is that affected dogs with congenital heart defects should not be bred, even if they are only mildly affected. At this time, there are neither good statistical models to predict risks nor reliable methods to detect all carriers. Dogs will the subclinical form (Grade1) are not reliably detected by clinical evaluation. Nevertheless, a complete cardiovascular workup should be performed prior to breeding of any relatives of affected dogs. Test matings, with evaluation of all offspring, can be used to evaluate breeding animals.

Genetic testing: Not available.

Breed: Keeshond (Dog) (VBO_0200759).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below