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Functional analysis of a novel FBN1 deep intronic variant causing Marfan syndrome in a Chinese patient
Qingming Wang1, Fang Zhang1, Xinlong Zhou1
1Key Laboratory for Precision Diagnosis and Treatment of Severe Infectious Diseases in Children, Dongguan Maternal and Child Health Hospital, Dongguan, China.
Abstract:
Marfan syndrome (MFS MIM#154700), due to pathogenic variants in the FBN1 gene, is an autosomal dominant connective tissue disorder, typically involving the skeletal, cardiovascular and ocular systems. Currently, over 3000 MFS patients were reported, and approximately 1800 pathogenic variants in FBN1 were identified. However, the molecular diagnosis still remains challenging for 8%-10% of patients with clinical features suggestive of MFS. In this study, we reported a 2-month-old Chinese female patient whose clinical features were compatible with the MFS. Whole-exome sequencing (WES) identified a novel de novo deep intronic variant, c.4943-8_4943-7insTATGTGATATTCAT TCAC in intron 40 of FBN1 that was predicted to affect the RNA splicing. Minigene analysis showed that this variant causes skipping of exon 41, leading to the deletion of 41 amino acids (c.4943_5065del, p.Val1649_Asp1689del). It confirmed the pathogenic nature of the variant and established the genotype-phenotype relationship. Our study expands the mutation spectrum of FBN1 and emphasizes the importance of deep intronic variant interpretation and the need for additional functional studies to verify the pathogenicity of these variants.
Insights
A novel deep intronic variant in the FBN1 gene was identified in a Marfan syndrome patient, expanding the known FBN1 mutation spectrum. This finding highlights the importance of interpreting intronic variants for accurate molecular diagnosis.
Area of Science:
- Genetics and Molecular Biology
- Medical Genetics
- Connective Tissue Disorders
Background:
- Marfan syndrome (MFS) is an autosomal dominant disorder caused by FBN1 gene variants, affecting skeletal, cardiovascular, and ocular systems.
- Despite over 3000 reported MFS cases and 1800 identified FBN1 variants, molecular diagnosis remains challenging for 8-10% of patients.
- Deep intronic variants are increasingly recognized as a cause of genetic disorders but require specialized interpretation.
Purpose of the Study:
- To investigate the genetic cause of Marfan syndrome in a patient with suggestive clinical features but no identifiable pathogenic variants through standard methods.
- To identify and functionally characterize a novel deep intronic variant in the FBN1 gene.
- To establish the genotype-phenotype correlation for the identified variant.
Main Methods:
- Whole-exome sequencing (WES) was performed to identify genetic variants.
- A novel deep intronic variant (c.4943-8_4943-7insTATGTGATATTCAT TCAC) in intron 40 of FBN1 was identified.
- Minigene analysis was conducted to assess the impact of the variant on RNA splicing.
Main Results:
- The identified deep intronic variant was confirmed to cause skipping of exon 41 in the FBN1 gene.
- This splicing defect leads to a deletion of 41 amino acids (p.Val1649_Asp1689del), confirming its pathogenic nature.
- The study established a genotype-phenotype relationship for this novel variant in the reported patient.
Conclusions:
- The study identified a novel pathogenic deep intronic FBN1 variant, expanding the known spectrum of mutations causing Marfan syndrome.
- The findings underscore the critical importance of interpreting deep intronic variants and performing functional studies for accurate molecular diagnosis of MFS.
- This research highlights the need for comprehensive genetic analysis, including deep intronic regions, for challenging cases of Marfan syndrome.
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