High-depth next-generation sequencing panel testing in the evaluation of arteriovenous malformations

Area of Science:

• Genetics
• Vascular Biology
• Genomic Medicine

Background:

• Arteriovenous malformations (AVMs) are complex vascular anomalies characterized by abnormal direct connections between arteries and veins.
• Understanding the genetic underpinnings of AVMs is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To evaluate the molecular diagnostic yield of a high-depth next-generation sequencing (NGS) panel for Disorders of Somatic Mosaicism (DoSM) in patients with AVMs.
• To identify common genetic variants associated with AVMs.

Main Methods:

• Retrospective review of 54 patients with AVMs.
• High-depth NGS panel analysis targeting the Disorders of Somatic Mosaicism (DoSM) gene panel.
• Classification of identified variants as pathogenic, likely pathogenic, or of uncertain clinical significance.

Main Results:

• A molecular diagnostic yield of 68.5% (37 out of 54 patients) was achieved.
• Pathogenic and/or likely pathogenic (P/LP) variants were identified in 37 cases.
• MAP2K1, KRAS, and TEK variants were among the most frequently identified alterations. Somatic alterations were present in 32 cases, while 5 cases had germline P/LP variants.

Conclusions:

• The high-depth DoSM NGS panel demonstrates significant utility in identifying molecular diagnoses for patients with AVMs.
• Genetic variants, particularly somatic alterations, play a key role in the pathogenesis of AVMs.
• Further research into the identified genetic pathways may lead to improved diagnostic and therapeutic approaches for AVMs.