Contribution of Whole-Genome Sequencing and Transcript Analysis to Decipher Retinal Diseases Associated with MFSD8...

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Biallelic defects in MFSD8 are linked to neuronal ceroid lipofuscinosis and rare retinal degeneration.
• Understanding MFSD8 variant pathogenicity is crucial for diagnosing inherited retinal diseases.

Purpose of the Study:

• To investigate the clinical and genetic spectrum of MFSD8 variants in patients with inherited retinal degeneration.
• To elucidate the molecular mechanisms underlying MFSD8-associated retinal dystrophies.

Main Methods:

• Next-generation sequencing and whole-genome sequencing were employed to identify MFSD8 variants.
• Transcript analysis using patient lymphoblastoid cell lines assessed splice site alterations.
• In silico and in cellulo studies were performed to determine variant pathogenicity.

Main Results:

• Twelve MFSD8 variants were identified in nine patients, including seven novel variants.
• A deep intronic variant (c.998+1669A>G) created a pseudoexon, and a silent change (c.750A>G) caused exon skipping.
• Variant combinations influenced disease presentation: severe + moderate variants caused isolated retinal dystrophy, while two severe variants led to early-onset severe retinal dystrophy.

Conclusions:

• MFSD8 variants are a significant cause of both late-infantile neuronal ceroid lipofuscinosis and isolated retinal degeneration.
• The severity of retinal dystrophy is correlated with the combination of MFSD8 variant types (severe vs. moderate).
• Molecular analysis is essential for understanding genotype-phenotype correlations in MFSD8-related disorders.