Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects

Area of Science:

• Genetics
• Rare Diseases
• Human Physiology

Background:

• Structural heart defects and renal anomalies syndrome (SHDRA) is a rare genetic disorder.
• Previously, only two families with biallelic TMEM260 variants were reported.
• The full spectrum of genetic variants and clinical manifestations of SHDRA remains incompletely understood.

Purpose of the Study:

• To identify additional families with SHDRA.
• To expand the mutational spectrum of TMEM260 in SHDRA.
• To further delineate the clinical features and prognosis of SHDRA.

Main Methods:

• Genome and exome sequencing were performed on affected individuals.
• RNA studies were utilized to investigate variant effects.
• Clinical data from identified patients and previously reported cases were analyzed.

Main Results:

• Eight individuals from five families with biallelic TMEM260 variants were identified.
• A spectrum of TMEM260 variants including deletions, nonsense, frameshift, splicing, and missense changes were found.
• Consistent clinical features included ventricular septal defects (often secondary to truncus arteriosus), elevated creatinine, and variable renal anomalies (e.g., horseshoe kidneys, renal cysts).
• High mortality was observed, with 6/12 patients dying between 6 weeks and 5 years of age.
• Carrier frequency for SHDRA was estimated between 0.0007-0.007.

Conclusions:

• This study confirms TMEM260 as a key gene in SHDRA.
• The genetic and clinical spectrum of SHDRA has been significantly expanded.
• SHDRA is a severe early-childhood condition characterized by congenital cardiac malformations and variable renal phenotypes.