Biallelic TSEN2 variants causing pontocerebellar hypoplasia type 2.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Pontocerebellar hypoplasia type 2 (PCH2) is a severe neurodegenerative disorder.
• It is typically caused by variants in TSEN genes, with TSEN54 variants being most common.
• TSEN2-related PCH2B is exceptionally rare.

Purpose of the Study:

• To report a novel case of TSEN2-related PCH2B.
• To characterize the identified TSEN2 variants using exome sequencing and structural modeling.
• To refine genotype-phenotype correlations in PCH2B.

Main Methods:

• Exome sequencing was performed on a patient presenting with PCH2 features.
• Identified variants were analyzed using structural modeling to predict their impact.
• Clinical data was correlated with genetic findings.

Main Results:

• A 7-year-old girl with PCH2 symptoms was found to have compound heterozygous TSEN2 variants: a known missense (p.Tyr309Cys) and a novel nonsense (p.Arg350*).
• Structural modeling indicated p.Tyr309Cys destabilizes the TSEN2-TSEN54 interface and p.Arg350* truncates the catalytic domain.
• The p.Tyr309Cys variant, despite minor predicted structural impact, correlated with severe clinical presentation.

Conclusions:

• This case expands the known spectrum of TSEN2 pathogenic variants.
• The findings underscore the importance of integrating structural modeling with clinical data for accurate genotype-phenotype correlation in PCH2B.
• This research contributes to a better understanding of the genetic basis of rare neurodegenerative disorders.