Identification of a novel SUOX pathogenic variants as the cause of isolated sulfite oxidase deficiency in a Chinese pedigree

Abstract

Background Isolated sulfite oxidase deficiency (ISOD) is a life‐threatening rare autosomal recessive disorder caused by pathogenic variants in SUOX (OMIM 606887) gene. The aim of our study was to establish a comprehensive genetic diagnosis strategy for the pathogenicity analysis of the SUOX gene within a limited time and to lay the foundation for precise genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis. Methods Two offspring from one set of parents were studied. Next‐generation sequencing (NGS) was used to screen for disease‐causing gene variants in a family with ISOD. Then, Sanger sequencing was performed to verify the presence of candidate variants. Sulfite, homocysteine and uric acid levels were detected in the patients. According to the ACMG/AMP guidelines, the pathogenicity level of novel variants was annotated. Results The nonsense pathogenic variant (c.1200C > G (p.Y400*)) and a duplication (c.1549_1574dup (p.I525 Mfs*102)) were found in the SUOX gene in the proband. The nonsense mutation (c.1200C > G (p.Y400*), pathogenic, isolated sulfite oxidase deficiency, autosomal recessive) has been reported as pathogenic and the duplication (c.1549_1574dup (p.I525 Mfs*102), pathogenic, isolated sulfite oxidase deficiency, autosomal recessive) was novel, which was classified as pathogenic according to the ACMG/AMP Standards and Guidelines. Conclusion We established the pathogenicity assessment in ISOD patients based on ACMG/AMP Standards and Guidelines and this is the first ISOD patient reported in mainland China. We also discovered that ISOD is caused by SUOX gene duplication mutation, which enriches the spectrum of SUOX pathogenic variants.

Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency and literature review

“…30 Recently, Du et al, two offspring identi ed with a heterozygous nonsense pathogenic variant (c.1200C>G, p.Y400*) and a heterozygous duplication (c.1549_1574dup, p.I525 Mfs*102) in the SUOX gene in the proband. 27 Lastly, Zhao et al, reported a Chinese new born patient presented with homocysteine and uric acid in plasma, cysteine and total homocysteine in the blood and S-sulfocysteine was abnormally elevated in urine. 28 The proband was manifested with progressive encephalopathy, tonic seizures, abnormal muscle tone, di culties in feeding, progressive neuropathological ndings, intermittent convulsions and axial dystonia.…”

“…Among 32 reported variants, 20 variants are missense, 4 variants are nonsense, 6 variants are deletion which result into frameshift and one duplication. 4,[9][10][11][12][13][14][15][16][17][18][19][20]27,28 One deletion leads to loss of the wild type stop codon and followed by formation of a prolonged protein (Table 6). 13 ISOD is a very rare and extremely heterogenous disorder in terms of both genotype and phenotype.…”

“…During literature review, we found that 27 reports of SUOX gene associated ISOD has been published till date. [4][5][6] Recently, ve early-onset ISOD patients have been reported in Chinese population 4,6,21,24,29 , two early-onset patient in Chinese mainland 27,28 , and one late-onset ISOD pedigree including three patients have been reported in Chinese mainland 30 .…”

Cross‐talk Between (Hydrogen)Sulfite and Metalloproteins: Impact on Human Health

“…This inborn error arises from either mutations of SO protein (so‐called isolated SO deficiency (ISOD)) or inability to correct synthesis the pyranopterindithiolate cofactor (so‐called Moco deficiency (MoCD)) in vivo, resulting in the accumulation of excess toxic sulfite in serum [84–86] . Both ISOD and Moco deficiencies have been reported in several patients [87–91] . In 1967, Mudd et al., first reported the ISOD and then it is known as a rare autosomal recessive disorder in human [92] …”

Novel Compound Heterozygous Pathogenic Variants in SUOX Cause Isolated Sulfite Oxidase Deficiency in a Chinese Han Family

“…The incidence of ISOD has not been reported epidemiologically. To date, < 50 cases have been reported worldwide (van der Klei-van Moorsel et al, 1991;Rupar et al, 1996;Garrett et al, 1998;Johnson et al, 2002a;Lee et al, 2002;Seidahmed et al, 2005;Claerhout et al, 2018;Chen et al, 2014;Rocha et al, 2014;Zaki et al, 2016;Brumaru et al, 2017;Lee et al, 2017;Mhanni et al, 2020;Sharawat et al, 2020;Du et al, 2021). Recently, four early-onset ISOD patients have been reported in Hong Kong and Taiwan, China (Chan et al, 2002;Lee et al, 2002Lee et al, , 2017Chen et al, 2014), one early-onset patient in Chinese mainland (Du et al, 2021), and one late-onset ISOD pedigree including three patients have been reported in Chinese mainland (Tian et al, 2019).…”