Novel insights on GTPBP3‐associated hypertrophic cardiomyopathy

Abstract

About 100 genes have been associated with cardiomyopathies with genotypephenotype correlations often hard to establish. Genetic testing may help to confirm the genetic diagnosis and assess the risk of inheritance in the family. A 25-year old male with hypertrophic cardiomyopathy and fasciculoventricular accessory pathway was referred for genetic testing by his cardiologist. Targeted PRKAG2 screening and whole-exome sequencing were performed, followed by Sanger sequencing segregation analysis in the family. The PRKAG2 gene screening was negative. Whole-exome sequencing revealed the following four variants in the patient: c.181G>C (p. Ala61Pro) and c.1199C>T (p.Thr400Met) in the GTPBP3 gene, as well as c.752C>T (p.Thr251Ile) and c.1760C>T (p.Pro587Leu) in the POLG gene. Family segregation analysis showed that the patient's mother is a carrier of variant c.181G>C and the patient's paternal grandmother is a carrier of variant c.1199C>T in the GTPBP3 gene, which is in accordance with an autosomal recessive model of inheritance of the disease. Both variants in the POLG are found paternally inherited in the patient's healthy half-brother, thus are not considered disease-causing. GTPBP3 variants have been

Biallelic variants in GTPBP3: New patients, phenotypic spectrum, and outcome

“…Table 1 (and Table S1 for more details) shows the main clinical characteristics of patients affected by COXPD23 reported by the literature so far. Twenty cases have been described 2 , 3 , 4 , 5 , 6 , 7 clustering around two prevalent phenotypes: an early‐onset presentation with severe fatal encephalopathy, cardiogenic shock, and decompensated metabolic acidosis (in 8 patients) and a milder presentation (12 patients) with developmental delay leading to intellectual disability, with (5) or without (8) drug‐responsive epilepsy, and exercise intolerance (3). Bilateral thalamic lesions, suggesting metabolic edema, is a possible neuroimaging clue of this condition occurring in 2 out of 2 patients with severe and in 6 out of 10 patients with a milder phenotype undergoing a brain MRI.…”

“…COXPD23 is an ultrarare mitochondrial encephalopathy 2 ; in fact, less than 20 patients with biallelic pathogenic variants in GTPBP3 have been so far reported presenting with a large phenotypical spectrum. 2 , 3 , 4 , 5 , 6 , 7 A genotype–phenotype correlation has been recently suggested. 3 , 6 …”