In-house multiplex ligation-dependent probe amplification assay for citrin deficiency: analytical validation and novel exonic deletions in SLC25A13

Lau, Nike Kwai Cheung; Lee, Han-Chih Hencher; Chen, Sammy Pak Lam; Ng, Candy Wai Yan; Mak, Chloe Miu; Chong, Yeow Kuan; Tong, Tammy Tsz Yan; Leung, Mei Tik; Shek, Chi Chung; Yuen, Yuet-Ping; Ching, Chor Kwan

doi:10.1016/j.pathol.2021.02.010

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…If only one or none such mutation was identified in NICCD highly suspicious patients, Sanger sequencing or target Next Generation Sequencing (NGS) of all the SLC25A13 exons and their flanking sequences [1,7,17,21, or entire open frames of SLC25A13 cDNA would be performed to identify the possible novel mutation [28]. Multiplex Ligation-dependent Probe Amplification (MLPA) should be considered a test of choice for molecular diagnosis of CD when the sequencing result is inconclusive [29]. In the current study, four mutations I, III, X, and XIX were the target mutations screened by PCR-RFLP, subsequently, undetected patients would be sequenced for whole 18 exons and their adjacent introns of the SLC25A13 gene.…”

Section: Discussion Mutation Identification and Genotypementioning

confidence: 99%

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis

Nguyen

Ngo

et al. 2023

J Hum Genet

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BACKGROUND: Citrin deficiency (CD), a disorder caused by mutations in the SLC25A13 gene, may result in neonatal intrahepatic cholestasis. This study was purposely to explore the mutation spectrum of SLC25A13 gene in Vietnamese CD patients. METHODS: The 292 unrelated CD patients were first screened for four high-frequency mutations by PCR/PCR-RFLP. Then, Sanger sequencing was performed directly for heterozygous or undetected patients. Novel mutations identified would need to be confirmed by their parents. RESULTS: 12 pathogenic SLC25A13 mutations were identified in all probands, including three deletions c.851_854del (p.R284Rfs*3), c.70-63_133del (p.Y24_72Ifs*10), and c. [1956C>A;1962del] (p.[N652K;F654Lfs*45]), two splice-site mutations (IVS6+5G>A and IVS11+1G>A), one nonsense mutations c.1399C>T (p.R467*), one duplication mutation c.1638_1660dup (p.A554fs*570), one insertion IVSl6ins3kb (p.A584fs*585), and four missense mutation c.2T>C (p.M1T), c.1231G>A (p.V411M), c.1763G>A (p.R588Q), and c.135G>C (p.L45F). Among them, c.851_854del (mut I) was the most identified mutant allele (91.78%) with a total of 247 homozygous and 42 heterozygous genotypes of carriers. Interestingly, two novel mutations were identified: c.70-63_133del (p.Y24_72Ifs*10) and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]).CONCLUSION: The SLC25A13 mutation spectrum related to intrahepatic cholestasis infants in Vietnam revealed a quite similar pattern to Asian countries' reports. This finding supports the use of targeted SLC25A13 mutation for CD screening in Vietnam and contributed to the SLC25A13 mutation spectra worldwide. It also helps emphasize the role of DNA analysis in treatment, genetic counseling, and prenatal diagnosis.

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Section: Discussion Mutation Identification and Genotypementioning

confidence: 99%

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis

Nguyen

Ngo

et al. 2023

J Hum Genet

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“…According to the ACMG guidelines, the pathogenicity analysis is PVS1 + PM2 + PP4, so it is likely pathogenic. Exon deletion is a rare variant type among SLC25A13 variants, which are mainly caused by large fragment deletion, including exon deletion, such as c.329–154_468 + 2352del2646bp (deletion of exon 5) ( 12 ), c.70–862_c.212 + 3527 del4532bp (deletion of exon 3) ( 13 ), Ex16 + 74_IVS17-32del516 (deletion of exon 17) ( 14 ), c.329–1687 -c.468 + 3865del5692bp (deletion of exon 5) ( 15 ), c.1019_1177 + 893del (deletion of exon 11) ( 16 ), c.1312–2860_1452 + 988del (deletion of exon 14) ( 17 ), c.1312–4144_1452 + 3373del (deletion of exon 14) ( 17 ) and c.3251 _c.15 + 18443del21709bp (deletion of exon 1) ( 18 ). Partial abnormal splicing of partially intron regions leads to exome deletions in mRNA, such as IVS4ins6 kb (skipping of exon 5) ( 19 ), IVS11+1 G > A (skipping of exon 11) ( 20 ), IVS15 + 1G > T (skipping of exon 15) ( 21 ) and IVS13+1G > A (skipping of exon 13) ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Zou²,

Chen³

et al. 2023

Front. Pediatr.

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BackgroundNeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a common clinical phenotype of citrin deficiency in infants. Its phenotype is atypical, so genetic testing is quite necessary for the diagnosis.Case presentationWe report 4 patients with jaundice and low body weight. Furthermore, the biochemical examination of all showed abnormal liver function and metabolic changes. DNA samples of the patients were extracted and subjected to genetic screening. All candidate pathogenic variants were validated by Sanger sequencing, and CNVs were ascertained by qPCR. The genetic screening revealed 6 variants in 4 patients, and all patients carried compound heterozygous variants of SLC25A13. Importantly, 3 variants were newly discovered: a nonsense mutation in exon17 (c.1803C > G), a frameshift mutation in exon 11(c.1141delG) and a deletion of the whole exon11. Thus, four NICCD patients were clearly caused by variants of SLC25A13. Biochemical indicators of all patients gradually returned to normal after dietary adjustment.ConclusionsOur study clarified the genetic etiology of the four infants, expanded the variant spectrum of SLC25A13, and provided a basis for genetic counseling of the family. Early diagnosis and intervention should be given to patients with NICCD.

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“…Thus far, research on citrin deficiency has mainly focused on pathogenesis [9,10], genetic diagnosis [11,12], and dietary treatment strategies [13,14]. There is no research study investigating the difficulties caregivers experience in dietary management, and the reasons underlying for these challenges.…”

Section: Introductionmentioning

confidence: 99%

Obstacles to home-based dietary management for caregivers of children with citrin deficiency: a qualitative study

Zhang

Cai

et al. 2022

Orphanet J Rare Dis

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Background Dietary management is the most important and effective treatment for citrin deficiency, as well as a decisive factor in the clinical outcome of patients. However, the dietary management ability of caregivers of children with citrin deficiency is generally poor, especially in East Asia where carbohydrate-based diets are predominant. The aim of this study was to identify the difficulties that caregivers encounter in the process of home-based dietary management, and the reasons responsible for these challenges. Results A total of 26 caregivers of children with citrin deficiency were recruited, including 24 mothers, one father, and one grandmother. Grounded theory was employed to identify three themes (covering 12 sub-themes) related to the dilemma of dietary management: dietary management that is difficult to implement; conflicts with traditional concepts; and the notion that children are only a part of family life. The first theme describes the objective difficulties that caregivers encounter in the process of dietary management; the second theme describes the underlying reasons responsible for the non-adherent behavior of caregivers; the third theme further reveals the self-compromise by caregivers in the face of multiple difficulties. Conclusions This study reflects the adverse effects of multi-dimensional contradictions on the adherence of caregivers to dietary management. These findings reveal that the dietary management of citrin deficiency is not only a rational process, rather it is deeply embedded in family, social, and dietary traditions.

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In-house multiplex ligation-dependent probe amplification assay for citrin deficiency: analytical validation and novel exonic deletions in SLC25A13

Cited by 4 publications

References 21 publications

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis

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

Obstacles to home-based dietary management for caregivers of children with citrin deficiency: a qualitative study

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