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Published on: December 16, 2022
A Prevalent TMEM260 Deletion Causes Conotruncal Heart Defects, Including Truncus Arteriosus
Naoya Saijo1, Hisao Yaoita1, Jun Takayama2,3,4,5
1Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Insights
Genetic variants in TMEM260 are a leading cause of truncus arteriosus (TA) in Japan, potentially explaining over half of TA cases. This finding highlights TMEM260
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Conotruncal heart defects, including truncus arteriosus (TA), are severe congenital malformations.
- The 22q11.2 deletion syndrome is a known contributor to TA, but other major causes remain elusive.
- TMEM260 was recently identified as a significant cause of TA in the Japanese population.
Purpose of the Study:
- To investigate TMEM260 as a potential major genetic cause of TA in the Japanese population.
- To identify novel TMEM260 variants and assess their prevalence and phenotypic spectrum.
- To evaluate the role of TMEM260 in familial cases of TA and related conotruncal defects.
Main Methods:
- Genetic analysis of a family with TA and double-outlet right ventricle (DORV).
- Identification and characterization of compound heterozygous TMEM260 variants, including a large deletion and a nonsense mutation.
- Population-based allele frequency analysis of identified TMEM260 variants in the Japanese population.
Main Results:
- A family presented with compound heterozygous TMEM260 variants: a 7066-bp deletion (exons 6-7) and c.1393C>T (p.Gln465*).
- The allele frequency of the 7066-bp deletion was 0.17% in the Japanese population.
- Combined with the previously reported c.1617del variant (0.36% allele frequency), TMEM260 variants may account for over 50% of Japanese TA cases.
- TMEM260 variants were associated with a spectrum of phenotypes, including DORV.
Conclusions:
- Pathogenic TMEM260 variants are likely the most common genetic cause of TA in the Japanese population.
- TMEM260 mutations explain a significant proportion of TA cases and a range of conotruncal heart defects.
- Genetic testing for TMEM260 variants is valuable for diagnosing Japanese patients with TA and related congenital heart disease.
Abstract:
Conotruncal heart defects are severe congenital malformations of the outflow tract, including truncus arteriosus (TA) and double-outlet right ventricle (DORV). TA is a severe congenital heart disease (CHD) in which the main arterial outflow tract of the heart fails to separate. We recently reported TMEM260 (NM_017799.4), c.1617del (p.Trp539Cysfs*9), as a major cause of TA in the Japanese population (TMEM260 Keio-Tohoku variant) comparable to the prevalence of the 22q11.2 deletion syndrome, which accounts for 12%-35% of TA. However, no other major causes of TA have not been identified. Here, we report a family that included a TA patient and a DORV patient, harboring the compound heterozygous variants of TMEM260, a 7066-bp deletion encompassing exons 6-7 and c.1393C > T, p.(Gln465*). The allele frequency of the 7066-bp deletion was particularly high in the Japanese population (0.17%). Based on the allele frequency of this deletion and c.1617del (0.36%) in the Japanese population, TMEM260 variants might be associated with more than half of the Japanese patients with TA. This study showed that TMEM260 pathogenic variants might be the most common cause of TA in the Japanese population and could explain the wide spectrum of phenotypes associated with TMEM260-related CHD, including DORV, demonstrating the usefulness of genetic testing in Japanese patients with TA.
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