A TMEM260 Biallelic Deletion Underlies Truncus Arteriosus

Area of Science:

• Genetics
• Cardiovascular Biology
• Developmental Biology

Background:

• Truncus arteriosus (TA) is a severe congenital heart defect characterized by a single ventricular outflow tract.
• Biallelic variants in the TMEM260 gene are associated with structural heart defects and renal anomalies syndrome (SHDRA), including TA.
• Previous studies identified founder variants in East Asian and Ashkenazi Jewish populations, but genotype-phenotype correlations require further clarification.

Purpose of the Study:

• To investigate the genetic basis of familial truncus arteriosus in a Japanese family.
• To characterize a novel TMEM260 biallelic structural variation.
• To assess the frequency and significance of this variant in the Japanese population.

Main Methods:

• Prenatal diagnosis of TA via ultrasound.
• Clinical management and outcome tracking of the affected infant.
• Whole-genome sequencing and analysis of a homozygous deletion in TMEM260 exons 6 and 7.
• Structural variation analysis using the ToMMo 8.3K JPN-SV dataset.

Main Results:

• A male infant with familial TA, whose sister also had TA, presented with heart failure and deceased at 53 days.
• Genetic analysis revealed a homozygous 7,066-bp deletion in TMEM260 (exons 6-7) inherited from heterozygous parents.
• This specific deletion was found to have a significant allele frequency (0.00173) in the Japanese population.

Conclusions:

• This is the first reported case of familial TA caused by a biallelic structural variation in TMEM260.
• The identified TMEM260 deletion represents a substantial genetic cause of TA in the Japanese population.
• This variant should be considered alongside previously identified TMEM260 mutations in the genetic diagnosis of TA.