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Background <p>Argininosuccinic aciduria (ASA) is an autosomal recessive disorder resulting from a lack of argininosuccinate lyase (ASL). ASL facilitates the fourth phase of the urea cycle, when argininosuccinic acid breaks down to provide arginine and fumarate. <i>ASL</i> (NM_000048.3) is the sole gene identified with mutations linked to ASA.</p> Methods <p>This study involved a clinical and genetic assessment of an Iranian family with a newborn girl diagnosed with ASA, who died at 40 days of age. Whole Exome Sequencing (WES) was conducted on the proband’s parents to identify the genetic problem, followed by Sanger sequencing. Then, genetic testing was performed on Chorionic villus sampling (CVS) of two fetuses from this family during separate pregnancies spaced one year apart, and the detected variation was verified using Sanger sequencing in both of them. The next step involved examining the stability of the protein pre- and post-variation, alongside doing molecular docking investigations for the ASL protein.</p> Results <p>In the WES analysis, the c.919T &gt; C (p.Cys307Arg) variant was identified in the <i>ASL</i> gene, present in the parents as heterozygotes and in both fetuses as homozygotes. The stability of the protein in the variant state was observed to be diminished in comparison to the wild state. Additionally, the binding site of the 2-(N-omega)-L-arginino succinate ligand and the chemical bonds established with the normal and variant proteins were completely changed.</p> Conclusion <p>This study facilitated the reclassification of this variant from VUS to likely pathogenic, considerably helping specialists in decision-making about this variety.</p>

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Identification of the potential pathogenicity of a VUS in the ASL gene associated with argininosuccinic aciduria in an Iranian family

  • 期刊论文

  • 发表日期：

    2025年8月29日

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  • Elaheh Hasani,
  • Maryam Naghinejad,
  • Sima Mansoori Derakhshan,
  • Akbar Amirfiroozy,
  • Maghsood Mehri,
  • Mahmoud Shekari Khaniani

摘要

Background

Argininosuccinic aciduria (ASA) is an autosomal recessive disorder resulting from a lack of argininosuccinate lyase (ASL). ASL facilitates the fourth phase of the urea cycle, when argininosuccinic acid breaks down to provide arginine and fumarate. ASL (NM_000048.3) is the sole gene identified with mutations linked to ASA.

Methods

This study involved a clinical and genetic assessment of an Iranian family with a newborn girl diagnosed with ASA, who died at 40 days of age. Whole Exome Sequencing (WES) was conducted on the proband’s parents to identify the genetic problem, followed by Sanger sequencing. Then, genetic testing was performed on Chorionic villus sampling (CVS) of two fetuses from this family during separate pregnancies spaced one year apart, and the detected variation was verified using Sanger sequencing in both of them. The next step involved examining the stability of the protein pre- and post-variation, alongside doing molecular docking investigations for the ASL protein.

Results

In the WES analysis, the c.919T > C (p.Cys307Arg) variant was identified in the ASL gene, present in the parents as heterozygotes and in both fetuses as homozygotes. The stability of the protein in the variant state was observed to be diminished in comparison to the wild state. Additionally, the binding site of the 2-(N-omega)-L-arginino succinate ligand and the chemical bonds established with the normal and variant proteins were completely changed.

Conclusion

This study facilitated the reclassification of this variant from VUS to likely pathogenic, considerably helping specialists in decision-making about this variety.