Molecular epidemiologic study of citrin deficiency by screening for four reported pathogenic SLC25A13 variants in the Shaanxi and Guangdong provinces, China

Abstract

Background: Citrin deficiency (CD) is an autosomal recessive disease resulting from biallelic mutations of the SLC25A13 gene. This study aimed to investigate the molecular epidemiological features of CD in the Guangdong and Shaanxi provinces of China.Methods: A total of 3,409 peripheral blood samples from Guangdong and 2,746 such samples from Shaanxi province were collected. Four prevalent SLC25A13 mutations NG_012247.2 (NM_014251.3): c.852_855del, c.1638_1660dup, c.615+5G>A, and c.1751-5_1751-4ins(2684) were screened by using the conventional polymerase chain reaction (PCR)/PCR-restriction fragment length polymorphism and newly-developed multiplex PCR methods, respectively. The mutated SLC25A13 allele frequencies, carrier frequencies, and CD morbidity rates were calculated and then compared with the Chi-square and Fisher's exact tests. Results:The mutations were detected in 68 out of 6,818 SLC25A13 alleles in Guangdong and 29 out of 5,492 alleles in the Shaanxi population. The carrier frequencies were subsequently calculated to be 1/51 and 1/95, while the CD morbidity rates were 1/10,053 and 1/35,865, in the 2 populations, respectively. When compared with the Shaanxi population, Guangdong exhibited a higher frequency of mutated SLC25A13

Case report: Three novel variants on SLC25A13 in four infants with neonatal intrahepatic cholestasis caused by citrin deficiency

“…Compound heterozygous variants from SLAC25A13 were detected in all four probands; all variants were classified as likely pathogenic or pathogenic according to ACMG guidelines ( 3 ) ( Table 2 ): Patient 1 [NM001160210: c.1803C > G, p.Y601X ( Figure 1A ) and IVS16ins3kb, p.A584fs]; Patient 2 [NM001160210: c.1803C > G, p.Y601X ( Figure 1B ) and c.1663_1664insGAGATTACAGGTGGCTGCCCGGG, p.A555fs] ( Figure 1C ) ]; Patient 3 [NM_014251: c.1141delG, p.V381Cfs*27 ( Figure 1D ) and c.1750_1751 ins3Kb ( Figure 1E ), patient 4 [NM_014251: c.852_855del, p.M285Pfs*2 ( Figure 1F ) and exon11 del ( Figure 1G )].…”

“…SLC25A13 is the pathogenic gene of NICCD, which encodes the citrin protein. Citrin plays significant roles in the urea cycle, malic acid-aspartate shuttle, and gluconeogenesis ( 3 ). As a result, variants of SLC25A13 can lead to metabolic abnormalities such as citrullinemia, hyperammonemia, hypoglycemia, and hyperlipidemia.…”

Rare liver diseases are not rare in China

“…Province with an estimated CD prevalence of 1/10 053, whereas a lower carrier frequency (1/95) is observed in Shaanxi Province with a theoretical incidence of 1/35 865, 24 showing a latitudinal gradient with a higher prevalence reported in lower latitudes. patients is more prevalent in Hong Kong, indicating a regional difference between SLC25A13 mutation spectra.…”

“…The overall mutation carrier rates among newborns could be as high as 2% (107/5332) in southern China 23 . In addition, the mutation carrier rate is 1/51 in Guangdong Province with an estimated CD prevalence of 1/10 053, whereas a lower carrier frequency (1/95) is observed in Shaanxi Province with a theoretical incidence of 1/35 865, 24 showing a latitudinal gradient with a higher prevalence reported in lower latitudes.…”

Citrin Deficiency: Clinical and Nutritional Features

“…The overall mutation carrier rates among newborns could be as high as 2% (107/5332) in southern China [ 10 ]. The mutation carrier rate is 1/51 in Guangdong Province, with an estimated CD prevalence of 1/10,053, whereas a lower carrier frequency (1/95) is observed in Shaanxi Province, with a theoretical incidence of 1/35,865 [ 11 ], showing a big regional difference in the frequency of mutation even in China. Recently, these mutations have been reported in various races and many non-Asian countries, such as the UK, France, and Canada [ 12 , 13 , 14 ], so CD is recognized as a pan-ethnic global disease.…”