[Genetic analysis of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant].

Objective: To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant.

Methods: A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children's Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children's Hospital of Ningbo University (Ethics No. EC2020-048).

Results: Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c.101C>A (p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c.101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+PVS1+PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c.101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein.

Conclusion: The c.101C>A (p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c.101C>A (p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.