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Diagnostic algorithm for citrullinemia type I found by newborn screening. Cit, Citrulline; NBS, newborn screening; NGS, next generation sequencing.
Source publication
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 retrospectiv...
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Herein, we report the aggregation properties of metabolites of urea cycle and uric acid pathway. The aggregation/ self-assembly properties of these metabolites were studied extensively via microscopic techniques. In this context the self-assembling properties of citrulline, ornithine, xanthine, hypoxanthine, cytosine and uracil were studied by asse...
Herein, we report the aggregation properties of metabolites of urea cycle and uric acid pathway. The aggregation/ self-assembly properties of these metabolites were studied extensively via microscopic techniques. In this context the self-assembling properties of citrulline, ornithine, xanthine, hypoxanthine, cytosine and uracil were studied by asse...
Citations
... Tandem mass spectrometrybased newborn screening (NBS) enables early diagnosis of CTLN1 by using elevated dried blood sport citrulline as a target marker (Sander et al. 2003). However, newborns with argininosuccinic acidemia, citrullinemia type II (citrin deficiency), pyruvate carboxylase deficiency (Diez-Fernandez et al. 2017), and heterozygous state for ASS1 pathogenic variants (Chen et al. 2022) also present with high blood citrulline levels. Some newborn screening-positive CTLN1 subjects may be asymptomatic. ...
... While these approaches have proven success in some conditions, false positive rates remained high for some other conditions, especially for those with low positive predictive value primary markers and no known secondary biochemical markers. Citrin deficiency (CD, MIM #605814, also known as citrullinemia type II), a common IEM locally, exemplifies this issue of a high false positive rate attributed to ASS1 carriers with no effective secondary biochemical marker [6,7]. Maintaining multiple second-tier biochemical tests is also time-and labor-intensive. ...
... Early treatment is life-saving and could prevent disastrous complications such as acute liver failure. Notably, newborn screening for citrin deficiency using citrulline as a biomarker has been notoriously challenging, with a high false positive rate owing to the carrier status of citrullinemia type I [6,7]. During the period, 19 cases had citrulline levels above 35 µmol/L, which would have been recalled and resulted in false positive NBS results if second-tier tests were not performed. ...
In this study, we evaluated the implementation of a second-tier genetic screening test using an amplicon-based next-generation sequencing (NGS) panel in our laboratory during the period of 1 September 2021 to 31 August 2022 for the newborn screening (NBS) of six conditions for inborn errors of metabolism: citrullinemia type II (MIM #605814), systemic primary carnitine deficiency (MIM #212140), glutaric acidemia type I (MIM #231670), beta-ketothiolase deficiency (#203750), holocarboxylase synthetase deficiency (MIM #253270) and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MIM # 246450). The custom-designed NGS panel can detect sequence variants in the relevant genes and also specifically screen for the presence of the hotspot variant IVS16ins3kb of SLC25A13 by the copy number variant calling algorithm. Genetic second-tier tests were performed for 1.8% of a total of 22,883 NBS samples. The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. The confirmed true positive cases were citrullinemia type II (n = 2) and systemic primary carnitine deficiency (n = 1). The false positives were later confirmed to be carrier of citrullinemia type II (n = 2), carrier of glutaric acidemia type I (n = 1) and carrier of systemic primary carnitine deficiency (n = 1). There were no false negatives reported. The incorporation of a second-tier genetic screening test by NGS greatly enhanced our program’s performance with 5-working days turn-around time maintained as before. In addition, early genetic information is available at the time of recall to facilitate better clinical management and genetic counseling.
... As compound heterozygous status was only clear in one case, the degree of linkage disequilibrium between these two variants should be further discussed and pedigree analysis must be strictly performed for definite diagnosis. The latter could also be verified indirectly using the Integrative Genomics Viewer (IGV) during next-generation sequencing as c.1261G > A was close to c.1244-2 A > C. The exact pathophysiology leading to abnormal NBS results for newborns with this haplotype also deserves further research, which might be similar to asymptomatic ASS1 carriers with high blood citrulline levels [21,22]. ...
Background
Population-specific variation database of inborn errors of metabolism (IEMs) is essential for precise genetic diagnosis and disease prevention. Here we presented a systematic review of clinically relevant variants of 13 IEMs genes reported among Chinese patients.
Methods
A systematic search of the following electronic databases for 13 IEMs genes was conducted: PubMed-NCBI, China national knowledge infrastructure and Wanfang databases. Patient data was extracted from articles eligible for inclusion and recorded in Excel electronic form using a case-by-case approach.
Results
A total of 218 articles, 93 published in English and 125 in Chinese, were retrieved. After variant annotation and deduplication, 575 unique patients (241 from articles published in Chinese) were included in the population-specific variation database. Patients identified by newborn screening and symptomatic presentation were 231 (40.17%) and 344 (59.83%), respectively. Biallelic variants were observed in 525/575 (91.3%). Among the 581 unique variants identified, 83 (14.28%) were described ≥ 3 times and 97 (16.69%) were not recorded in Clinvar or HGMD. Four variants were reclassified as benign and dozens of confusing variants deserved further research.
Conclusion
This review provides a unique resource of the well-characterized diseases and causative variants that have accumulated in Chinese population and is a preliminary attempt to build the Chinese genetic variation database of IEMs.
Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert “Bob” Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.
