Publications by authors named "Nguyen Pham Anh Hoa"

4 Publications

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Biliary atresia combined Wilson disease identified by whole exome sequencing in Vietnamese patient with severe liver failure.

Medicine (Baltimore) 2022 Jan;101(2):e28547

Institute of Genome Research, Vietnam Academy of Science and Technology, 18 - Hoang Quoc Viet Str., Caugiay, Hanoi, Vietnam.

Rationale: Hepatobiliary diseases such as biliary atresia (BA), Wilson disease, and progressive familial intrahepatic cholestasis are common causes of morbidity and mortality in young children. Affected patients progress rapidly to end-stage cirrhosis and require liver transplantation or die. Mutations in many genes have been identified to play an important role in the pathogenesis of hepatobiliary diseases.

Patient Concerns And Diagnosis: In this study, we identified mutations in an 8-year-old girl who had severe liver failure. The patient was first diagnosed with BA at 2.5 months of age and has undergone Kasai surgery to connect the umbilical cord and jejunum. After that, the patient suddenly had unusual developments with symptoms of jaundice, acute liver failure with hemolysis. She was tested and diagnosed with Wilson disease.

Interventions And Outcomes: She was treated according to the regimen for a patient with Wilson disease but had abnormal progress leading to severe liver failure. Genetic analysis was performed by whole exome sequencing and Sanger sequencing methods. The genetic analysis revealed that the patient had a homozygous mutation (p.Gly17Glyfs77∗) in the KRT18 gene, a double heterozygous mutation (p.Ser105∗ and p.Pro992Leu) in the ATP7B gene, and a homozygous variant (p.Val444Ala) in the ABCB11 gene. In silico prediction of mutations indicated that these mutations are the cause of the severe liver failure in the patient.

Lesson: This is a rare clinical case of a BA patient combined with Wilson disease. Our results suggested that whole exome sequencing is an effective diagnostic tool and emphasizes the importance of early diagnosis and appropriate management to save lives and prevent serious complications in the patient.
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January 2022

The role of p.Val444Ala variant in the ABCB11 gene and susceptibility to biliary atresia in Vietnamese patients.

Medicine (Baltimore) 2021 Nov;100(47):e28011

Institute of Genome Research, Vietnam Academy of Science and Technology, Vietnam.

Abstract: Biliary atresia (BA) is the most serious type of obstructive cholangiopathy that occurs in infants. BA can be the cause of death in children under 2 years if untreated early. However, the etiology of the disease is not known. BA is considered to be the result of the destruction of the bile duct system including the accumulation of bile acids. The bile salt export pump, a transporter protein encoded by the ABCB11 gene, plays the main role in the exportation and accumulation of bile acids. The p.Val444Ala variant in this gene is known to be associated with many cholestatic diseases. However, to date no study have been performed to evaluate the association of this variant with susceptibility to the risk of BA. In this study, we aimed to identify the frequency of p.Val444Ala variant and the risk of BA in Vietnamese patients.The polymerase chain reaction (PCR)- restriction fragment length polymorphism method was used to determine the frequency of alleles c.1331T>C (p.Val444Ala, rs2287622) in the ABCB11 gene in 266 Vietnamese patients with BA and 150 healthy people. The gene segment containing the variant was amplified by PCR with specific primers, after that the PCR products were cut by HaeIII restriction enzyme and analyzed on agarose gel to determine the genotypes. The frequency of alleles was assessed statistically to determine the association between these alleles and the risk of disease in patients.In our study, the frequency of alleles c.1331T>C (p.Val444Ala, rs2287622) in the ABCB11 gene was investigated the first time in the patients with BA. The results showed that CC and TC genotypes were significantly different between BA patients and healthy people (P < .01), and the C allele was associated with an increased risk of BA (odds ratio = 2.47; 95% confidence interval: 1.84-3.32; P < .01). The initial results of clinical, biochemical, and genetic analysis in our study suggested that the p.Val444Ala variant in the ABCB11 gene may be a susceptibility factor for the disease in Vietnamese patients with BA. These results provided new insights into the role of this ABCB11 variant in the pathogenesis of BA.
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November 2021

Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism.

EBioMedicine 2021 Sep 27;71:103530. Epub 2021 Aug 27.

Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China. Electronic address:

Background: Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution, especially for nonsyndromic BA (common form: > 85%) remains poorly defined.

Methods: We conducted whole exome sequencing on 89 nonsyndromic BA trios to identify rare variants contributing to BA etiology. Functional evaluation using patients' liver biopsies, human cell and zebrafish models were performed. Clinical impact on respiratory system was assessed with clinical evaluation, nasal nitric oxide (nNO), high speed video analysis and transmission electron microscopy.

Findings: We detected rare, deleterious de novo or biallelic variants in liver-expressed ciliary genes in 31.5% (28/89) of the BA patients. Burden test revealed 2.6-fold (odds ratio (OR) [95% confidence intervals (CI)]= 2.58 [1.15-6.07], adjusted p = 0.034) over-representation of rare, deleterious mutations in liver-expressed ciliary gene set in patients compared to controls. Functional analyses further demonstrated absence of cilia in the BA livers with KIF3B and TTC17 mutations, and knockdown of PCNT, KIF3B and TTC17 in human control fibroblasts and cholangiocytes resulted in reduced number of cilia. Additionally, CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Abnormally low level of nNO was detected in 80% (8/10) of BA patients carrying deleterious ciliary mutations, implicating the intrinsic ciliary defects.

Interpretation: Our findings support strong genetic susceptibility for nonsyndromic BA. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis.

Funding: The study is supported by General Research Fund, HMRF Commissioned Paediatric Research at HKCH and Li Ka Shing Faculty of Medicine Enhanced New Staff Start-up Fund.
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September 2021

Three novel mutations in the ATP7B gene of unrelated Vietnamese patients with Wilson disease.

BMC Med Genet 2018 06 18;19(1):104. Epub 2018 Jun 18.

Institute of Genome Research, Vietnam Academy of Science and Technology, 18 - Hoang Quoc Viet str., Caugiay, Hanoi, Vietnam.

Background: Wilson disease (OMIM # 277900) is a autosomal recessive disorder characterized by accumulation of copper in liver and brain. The accumulation of copper resulting in oxidative stress and eventually cell death. The disease has an onset in a childhood and result in a significant neurological impairment or require lifelong treatment. Another serious consequence of the disease is the development of liver damage and acute liver failure leading to liver transplant. The disorder is caused by mutations in the ATP7B gene, encoding a P-type copper transporting ATPase.

Case Presentation: We performed genetic analysis of three unrelated patients from three different Vietnamese families. These patients had clinical features such as numbness of hands and feet, vomiting, insomnia, palsy, liver failure and Kayser-Fleischer (K-F) rings and were diagnosed with Wilson disease in the Human Genetics Department, Vietnam National Children's Hospital. The entire coding region and adjacent splice sites of ATP7B gene were amplified and sequenced by Sanger method. Sequencing data were analyzed and compared with the ATP7B gene sequence published in Ensembl (ENSG00000123191) by using BioEdit software to detect mutations.

Conclusions: In this study, five mutations in the ATP7B gene were found. Among of these, three mutations were novel: c.750_751insG (p.His251Alafs*19) in exon 2, c.2604delC (p.Pro868Profs*5) in exon 11, and c.3077 T > A (p.Phe1026Tyr) in exon 14. Our results of the mutations associated with Wilson disease might facilitate the development of effective treatment plans.
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June 2018