Compound Heterozygous Loss-of-Function Variants in CCM2L in a Fetus With Tetralogy of Fallot

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart disease.
• The genetic underpinnings of TOF remain incompletely understood, necessitating further research into novel genetic factors.

Purpose of the Study:

• To investigate the genetic etiology of Tetralogy of Fallot (TOF).
• To identify potential genetic variants contributing to the development of TOF in affected individuals.

Main Methods:

• Whole exome sequencing (WES) and Sanger sequencing were employed on a family trio with diagnosed TOF.
• A minigene assay was utilized to confirm the functional impact of identified splice-site variants on RNA splicing.

Main Results:

• Compound heterozygous loss-of-function variants in the CCM2L gene were identified in a fetus with TOF.
• The identified variants, a nonsense variant and a splice-site variant, were absent in population databases and classified as likely pathogenic.
• The splice-site variant was demonstrated to cause exon skipping, leading to frameshift and premature termination of CCM2L translation.

Conclusions:

• This study reports the first instance of biallelic loss-of-function variants in the human CCM2L gene.
• The findings indicate a potential association between CCM2L gene variants and the pathogenesis of Tetralogy of Fallot.