Autosomal Recessive ACTG2-Related Visceral Myopathy in Brothers

Area of Science:

• Genetics
• Gastroenterology
• Molecular Biology

Background:

• Pediatric intestinal pseudo-obstruction (PIPO) is a complex disorder affecting gut motility.
• Autosomal dominant ACTG2-related visceral myopathy is a common cause of primary PIPO.
• Genetic heterogeneity contributes to variable PIPO severity and presentation.

Purpose of the Study:

• To investigate the genetic basis of a family with severe PIPO and bladder dysfunction.
• To identify novel genetic variants associated with pediatric intestinal pseudo-obstruction.
• To explore the role of ACTG2 gene variations in PIPO pathogenesis.

Main Methods:

• Clinical genome sequencing was performed on affected individuals and their mother.
• Immunohistochemistry was utilized to assess ACTG2 expression in intestinal tissues.
• Analysis of both coding and noncoding regions of the ACTG2 gene.

Main Results:

• A 6.8 kb deletion encompassing the ACTG2 gene was identified in the affected individuals.
• A maternally inherited missense variant (p.Val10Met) in ACTG2 was also found.
• The study revealed biallelic inheritance of mild ACTG2 variants leading to severe PIPO.

Conclusions:

• Monoallelic hypomorphic ACTG2 variants can cause mild gastrointestinal symptoms.
• Biallelic inheritance of mild ACTG2 variants can result in severe PIPO and bladder dysfunction.
• Non-coding ACTG2 exon deletions are an under-recognized cause of PIPO, emphasizing genome sequencing for comprehensive diagnosis.