Phenotypic characterisation of SMAD4 variant carriers

Area of Science:

• Genetics and Genomics
• Vascular Biology
• Gastroenterology

Background:

• Hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are linked to SMAD4 pathogenic variants.
• Overlapping symptoms and additional connective tissue disorders are observed in some patients.
• This study focuses on SMAD4 variant carriers within an HHT reference center cohort.

Purpose of the Study:

• To delineate the phenotype of SMAD4 variant carriers followed in an HHT reference center.
• To investigate the spectrum of clinical manifestations associated with SMAD4 variants.

Main Methods:

• Observational study utilizing data from the Clinical Investigation for the Rendu-Osler Cohort database.
• Analysis of 1114 HHT patients to identify SMAD4 variant carriers.
• Phenotypic characterization based on established diagnostic criteria for HHT, JPS, and connective tissue disorders.

Main Results:

• 33 participants (3%) out of 1114 HHT patients carried a SMAD4 variant.
• High frequencies of HHT symptoms (epistaxis, telangiectases, AVMs) and JPS criteria were observed.
• Significant prevalence of digestive angiodysplasia (59%), gastric polyposis (81%), and connective tissue disorders (61%), including aortic dilation (15%).

Conclusions:

• SMAD4 variant carriers present a broad phenotype including HHT, JPS, and connective tissue disorders.
• Frequent and early digestive complications warrant biennial endoscopic screening.
• Systematic screening for pulmonary/hepatic AVMs and cardiac/skeletal complications is recommended.