Multisystemic Involvement in Autosomal Recessive Cerebellar Ataxia Type 8 Having a Novel SYNE1 Nonsense Variant

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Autosomal recessive cerebellar ataxia type 8 (SCAR8) is a progressive neurodegenerative disorder.
• It is caused by pathogenic variants in the SYNE1 gene.
• SCAR8 can present with multisystemic symptoms beyond cerebellar ataxia.

Purpose of the Study:

• To characterize a patient with SCAR8 and complex multisystemic symptoms.
• To identify the genetic variants underlying the patient's condition.
• To investigate the relationship between SYNE1 variants and respiratory dysfunction.

Main Methods:

• Whole-exome sequencing was performed to identify genetic variants.
• SYNE1 mRNA expression levels were quantified.
• A literature review was conducted to analyze variant clustering and clinical phenotypes.

Main Results:

• Compound heterozygous nonsense variants in the SYNE1 gene were identified, including a novel variant (c.18727C>T).
• The patient presented with a severe phenotype including cerebellar ataxia, motor neuron disease, vocal cord paralysis, and obesity.
• SYNE1 mRNA expression was reduced, and a literature review indicated a clustering of SYNE1 variants in the C-terminal region in patients with respiratory dysfunction.

Conclusions:

• This case highlights the diverse and severe clinical manifestations of SCAR8.
• Novel SYNE1 variants can lead to significant reductions in gene expression.
• C-terminal SYNE1 variants are associated with respiratory compromise in SCAR8 patients.