Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review

Abstract

Background Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder of the urea cycle caused by a deficiency in the argininosuccinate synthetase (ASS1) enzyme due to mutations in the ASS1 gene. Only a few Chinese patients with CTLN1 have been reported, and ASS1 gene mutations have been identified sporadically in China. Case presentation A Chinese family with one member affected with mild CTLN1 was enrolled. Targeted exome sequencing was performed on the proband, and Sanger sequencing was used to validate the detected mutation. We also reviewed the genetic and clinical characteristics of CTLN1 in Chinese patients that have been published to date. Newborn screening showed remarkably increased concentrations of citrulline with elevated ratios of citrulline/arginine and citrulline/phenylalanine, and the patient presented with a speech delay at age three. The urinary organic acid profiles were normal. A novel homozygous splicing variant c.773 + 4A > C in the ASS1 gene was identified in the proband, and it was predicted to affect splicing by in silico analysis. To date, only nine Chinese patients with CTLN1 have been reported, with a total of 15 ASS1 mutations identified and no high frequency or hot spot mutations found; the mutation spectrum of Chinese patients with CTLN1 was heterogeneous. Conclusions We described a mild Chinese CTLN1 case with a novel homozygous splicing variant c.773 + 4A > C and reviewed previous genotypes and phenotypes in Chinese patients with CTLN1. Thus, our findings contribute to understanding the molecular genetic background and clinical phenotype of CTLN1 in this population. Electronic supplementary material The online version of this article (10.1186/s12881-019-0836-5) contains supplementary material, which is available to authorized users.

Identification of Novel Mutations in Chinese Infants With Citrullinemia

“…The OXCT1 c.1248+5G > A mutation, IKBKAP c.2204+6T > C mutation, and CDHR1 c.2040+5G > T mutation were previously found to cause exon skipping ( Ibrahim et al, 2007 ; Hori et al, 2013 ; Stingl et al, 2017 ). Moreover, the ATF6 c.82+5G > T mutation led to intron retention ( Kohl et al, 2015 ), while ASS1 mutations c.773+4A > C and c.970+5G > A were identified in patients with citrullinemia ( Kobayashi et al, 1995 ; Lin et al, 2019 ). Second, the MutationTaster predicted that the mutation was disease-causing.…”

Whole exome sequencing make a definitive diagnosis of a Vietnamese patient with a late onset urea cycle disorder

“…Due to eight genes involved in UCDs and their multiple coding regions, researchers have turned to apply the next generation sequencing to detect variants in UCDs cases (Choi et al, 2017;Zhao et al, 2019;Lin et al, 2019;Yan et al, 2019). Here, we report a female patient with a prior diagnosis of urea cycle disorders.…”

Application of Next Generation Sequencing Genetic Studies of Urea Cycle Disorders

“…Argininosuccinate synthetase (ASS1) xúc tác cho phản ứng kết hợp giữa citrulline và aspartate tạo ra argininosuccinate trong tế bào chất của các tế bào gan. Gen ASS1 nằm trên cánh dài của nhiễm sắc thế số 9 tại vị trí 9q34.1, có kích thước 63 kb, 16 exon, trong đó quá trình dịch mã bắt đầu từ exon 3, mã hóa cho chuỗi popypeptide gồm 412 amino acid [27]. Cơ sở dữ liệu Clinvar đã cập nhật 255 đột biến trên gen ASS1 gây bệnh Citrullinemia typ 1.…”

“…Hai biến thể, đồng hợp tử c.725C>T, p.T242I; c.971G>T, p.G324V trên gen ASS1 đã được xác định, có thể là nguyên nhân của các dấu hiệu bất thường não khi chụp cộng hưởng và là cơ sở để chẩn đoán bệnh Citrullinemia ở thai nhi, 23 tuần tuổi [28]. Tiến hành sàng lọc bằng WES trong 1 gia đình người Trung Quốc, có 1 thành viên được chẩn đoán mắc bệnh Citrullinemia typ 1, Lin và cộng sự (2019) đã xác định được 1 đột biến tại vị trí mối nối, thể đồng hợp tử, c.773+4A>C và được di truyền từ bố và mẹ [27]. Kết quả này là cơ sở để hiểu rõ mối tương quan giữa kiểu gen và kiểu hình của bệnh Citrullinemia typ 1 trong cộng đồng người Trung Quốc [23].…”