Argininosuccinate lyase (ASL) deficiency is an autosomal recessive disorder of the urea cycle with a diverse spectrum of clinical presentation that is detectable in newborn screening. We report an 8-year-old girl with ASL deficiency who was detected through newborn screening and was confirmed using biochemical and functional assay. She is compound heterozygous for a likely pathogenic variant NM_000048.4(ASL):c.283C>T (p.Arg95Cys) and a likely benign variant NM_000048.4(ASL): c.1319T>C (p.Leu440Pro). Functional characterisation of the likely benign genetic variant in ASL was performed. Genomic sequencing was performed on the index patient presenting with non-specific symptoms of poor feeding and lethargy and shown to have increased serum and urine argininosuccinic acid. Functional assay using HEK293T cell model was performed. ASL enzymatic activity was reduced for Leu440Pro. This study highlights the role of functional testing of a variant that may appear benign in a patient with a phenotype consistent with ASL deficiency, and reclassifies NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) variant as likely pathogenic.

中文翻译：

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To B(enign) 或 Not to B：通过新生儿筛查发现的轻度精氨酸琥珀酸裂解酶缺陷的变体的功能化。

精氨基琥珀酸裂解酶 (ASL) 缺乏症是一种尿素循环常染色体隐性遗传疾病，具有多种临床表现，可在新生儿筛查中检测到。我们报告了一名 8 岁女孩患有 ASL 缺陷，她是通过新生儿筛查发现的，并通过生化和功能检测确诊。她是可能致病性变异 NM_000048.4(ASL):c.283C>T (p.Arg95Cys) 和可能良性变异 NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) 的复合杂合子。对 ASL 中可能的良性遗传变异进行了功能表征。对表现出进食不良和嗜睡等非特异性症状的指示患者进行基因组测序，结果显示血清和尿液精氨酸琥珀酸升高。使用 HEK293T 细胞模型进行功能测定。Leu440Pro 的 ASL 酶活性降低。这项研究强调了对表型与 ASL 缺陷一致的患者中可能表现为良性的变异的功能测试的作用，并将 NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) 变异重新分类为可能的致病性。