An FBN1 Deep Intronic Variant Is Associated With Pseudoexon Formation and a Variable Marfan Phenotype in a Five Generation Family

Authors

Dong-Chuan Guo
Xueyan Duan
Kathleen Mimnagh
Alana C Cecchi
Isabella C Marin
Yang Yu
Walter V Velasco
Kwanghyuk Lee
Xue Zhu
David R Murdock
Suzanne M Leal
Marsha M Wheeler
Josh Smith
Michael J Bamshad
Dianna M Milewicz

Publication Date

6-1-2023

Journal

Clinical Genetics

Abstract

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies.

Keywords

Humans, Marfan Syndrome, Fibrillin-1, Mutation, Phenotype, Aortic Diseases

Comments

Supplementary Materials

Data Availability Statement

PMID: 36861389