WES and Transcriptome Analysis Identifies FN1 as a Candidate Gene for Anterior Segment Dysgenesis.

Background: Anterior segment dysgenesis (ASD) disorders are phenotypically diverse and have multiple associated genes. This study reports on a Chinese family of three generations with ASD disorders and identifies several associated genes and pathways of the disorders.

Methods: The history of illnesses, clinical observations, and blood samples of all family members were collected. Whole exome sequencing (WES) and polymerase chain reaction (PCR) were conducted to detect the genetic variants between patients and control members in the family. Transcriptomic study and quantitative real-time PCR (qRT-PCR) were subsequently performed to validate the differentially expressed genes (DEGs) and investigate the possible mechanisms of ASD caused by the variations.

Results: The medical examination and illness history identified four members of the family diagnosed with ASD (III:3, II:3, II:2 and I:2). All four patients suffered various degrees of corneal opacity with abnormally thin cornea. Members II:3, II:2, and I:2 also had cataracts and iris hypoplasia and received an intraocular lens implant before the age of 20. We detected a heterozygous missense variation c.6122G > A (p.R2041Q and rs746145647) in fibronectin1 (FN1) in the four patients in this family that was absent in the other healthy members. The transcriptome and RT-PCR analysis revealed that the FN1 mRNA level was significantly upregulated in the blood samples of patients compared to healthy controls. A total of 909 DEGs were identified, including 607 upregulated genes and 302 downregulated genes. GO and KEGG annotation revealed that many DEGs were involved in biological processes closely related to focal adhesion, extracellular matrix-receptor interaction, TGF-β pathway, and the immune system.

Conclusion: This study identified an FN1 mutation associated with ASD patients and probed potential pathways related to it.