Asymptomatic ASS1 carriers with high blood citrulline levels. Issue 9 (21st June 2022)

• Record Type: Journal Article
• Authors: Chen, Hui‐An; Hsu, Rai‐Hseng; Chang, Kai‐Ling; Huang, Yi‐Chen; Chiang, Yun‐Chen; Lee, Ni‐Chung; Hwu, Wuh‐Liang; Chiu, Pao‐Chin; Chien, Yin‐Hsiu
• Is Part Of: Molecular genetics & genomic medicine. Volume 10:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-21
• Subjects: ASS1 -- carriers -- citrullinemia -- newborn screening -- tandem mass analysis; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.2007
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Introduction: Citrullinemia Type 1 (CTLN1) is an autosomal recessive disorder caused by variants in the ASS1 gene. This study intends to clarify the etiology of false positives in newborn screening for citrullinemia. Method: Newborns who had elevated dried‐blood spot citrulline levels were enrolled, and medical records were reviewed retrospectively. Common ASS1 variants were screened using high‐resolution melting analysis. Result: Between 2011 and 2021, 130 newborns received confirmatory testing for citrullinemia, 4 were found to be patients for CTLN1; 11 were patients with citrin deficiency; and 49 newborns were confirmed to be carrying one pathogenic ASS1 variant. The incidence of CTLN1 was 1 in 188, 380 (95% confidence interval: 1 in 73, 258 to 1 in 484, 416). All ASS1 variants studied in this cohort were located in exons 11 to 15, which encode the tetrameric interface regions of the ASS1 protein. Among 10 ASS1 carriers with elevated citrulline levels and complete sequence data, four (40%) revealed additional non‐benign ASS1 variants; in contrast, only 2 of the 26 controls (7.7%), with normal citrulline levels, had additional ASS1 variants. Conclusion: Heterozygote ASS1 variants may lead to a mild elevation of blood citrulline levels: about 2–6 times the population mean. Molecular testing and family studies remain critical for precise diagnosis, genetic counseling, and management. Abstract : This is the first research characterizing and classifying the different etiology causing elevated citrulline levels on newborn screening. Some ASS1 variants may be hypomorphic dominant and lead to a mild elevation of blood citrulline level in carriers. Carriers with persistently elevated citrulline levels remain asymptomatic into adulthood and require no additional treatment.