[Clinical and genetic analysis of a patient with Ataxia and vitamin E deficiency due to homozygous variant of TTPA gene].

Objective: To explore the clinical phenotype and genetic characteristics of a patient with Ataxia and vitamin E deficiency syndrome (AVED) due to a variant of TTPA gene.

Methods: A patient diagnosed with AVED (proband), intended for assisted reproductive technology for pregnancy in Zhongnan Hospital of Wuhan University in July 2023, was selected as research subject. Clinical data of the proband were collected, and 2 mL of peripheral venous blood samples were collected from the proband and her father and siblings for serum vitamin E level testing. Whole exome sequencing (WES) was carried out. Pathogenic variants were selected based on American public archive of interpretations of clinically relevant variants (ClinVar). Sanger sequencing was performed to validate the candidate variants detected by WES. Pathogenicity of variants was classified based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), and the impact of variants was analyzed using multiple bioinformatics tools including SIFT, Mutation Taster, CADD, and SpliceAI. Information on the protein domains was obtained from ClinVar and dbSNP databases, and a hotspot map for the variants of protein-coding region was constructed. This study was approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2023068K).

Results: The proband has a significantly low serum level of vitamin E (5.186 μg/mL), while her father and siblings were normal. WES revealed that she has harbored a homozygous missense c.2T>A (p.0?) variant of the TTPA gene, for which her father and younger sister were heterozygous carriers. Based on the guidelines from the ACMG, the missense c.2T>A (p.0?) variant of the TTPA gene was classified as pathogenic (PVS1+PM2+PM3). Multiple bioinformatics tools had predicted this variant to be located in the initiation codon region and may lead to abnormal synthesis of the TTPA protein, indicating it was deleterious. The hotspot map based on ClinVar and dbSNP databases showed an even distribution of variants across 5 structural domains of the TTPA protein, with high conservation of the first amino acid residue across various species.

Conclusion: The homozygous c.2T>A (p.0?) variant of the TTPA gene probably underlie the AVED in the proband. Above discovery has enriched the mutational spectrum of AVED and provided a basis for the diagnosis, genetic counseling, and assisted reproductive strategies for this family.