Taking the next step forward – Diagnosing inherited infantile cholestatic disorders with next generation sequencing

Herbst, Saskia M.; Schirmer, S.; Posovszky, Carsten; Jochum, Frank; Rödl, Thomas; Schroeder, Josef; Barth, Thomas F.E.; Hehr, Ute; Melter, Michael; Vermehren, Jan

doi:10.1016/j.mcp.2015.03.001

Cited by 40 publications

(36 citation statements)

References 32 publications

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“…The bioinformatic tools PolyPhen-2, MutationTaster and SIFT, did not detect any ‘deleterious’ or ‘damaging’ variations among the NGS data of the 93 genes which were associated with inherited infantile cholestatic disorders (16). When focusing on the 51 genes that affect bile acid homeostasis uniquely, only 12 exonic nonsynonymous SNPs were detected (Table III).…”

Section: Resultsmentioning

confidence: 99%

“…As the genetic determinants of hypercholanemia are complex (16), whole genome sequencing was performed in the present study in order to evaluate the possible involvement of other genes, the collective testing of which was prohibitively time-consuming and cost-expensive. The sequencing revealed that no other genetic mutations were causing perturbations of bile acid metabolism other than the SLC10A1 gene, and this further supports the diagnosis of NTCP deficiency in the patient.…”

Section: Discussionmentioning

confidence: 99%

“…The variants that were causing abnormal splicing or amino acid changes (including stop-loss and stop-gain variants), in particular those with minor allele frequencies (MAFs) <1%, were recorded as possible candidates of the causative mutations. In view of the intractable and marked hypercholanemia observed in the patient, a panel of genes that may uniquely affect bile acid homeostasis were assembled for candidate mutation analysis using PubMed, The Online Mendelian Inheritance in Man record and primarily by reference to previous publications (12–16). …”

Section: Methodsmentioning

confidence: 99%

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Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency

Deng

Mao

Guo

et al. 2016

Experimental and Therapeutic Medicine

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The human solute carrier family 10 member 1 (SLC10A1) gene encodes sodium taurocholate cotransporting polypeptide (NTCP), the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although the function of NTCP has been studied extensively and a number of SLC10A1 variations have been identified in humans, information regarding NTCP deficiency is limited. To date, only one patient with NTCP deficiency has been described; however, in the present study a pediatric patient who experienced intractable and striking hypercholanemia is presented. Analysis of the SLC10A1 gene in the patient revealed a homozygous p.Ser267Phe (c.800C>T) variation, which proved to be a single-nucleotide polymorphism (SNP) in the allele frequency of 4.7% of healthy controls. This variation involved a conserved amino acid residue on the orthologous alignment that was predicted to be ‘disease-causing’ by functional analysis using a number of bioinformatic tools. Next generation sequencing was performed; however, no other genetic causes were identified that would affect the bile acid homeostasis in the patient. Moreover, an adult, with the same genotype as the pediatric patient, was identified for the first time as experiencing mild hypercholanemia. The molecular and clinical findings in the present study suggest, for the first time, that there is an association between p.Ser267Phe SNP and hypercholanemia, and this information may be used to clinically identify NTCP deficiency worldwide.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency

Deng

Mao

Guo

et al. 2016

Experimental and Therapeutic Medicine

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“…Our patients with ABCB11 spectrum liver disorders were treated with 4-PBA instead of rifampicin. As a clinically approved pharmacological chaperone drug, 4-PBA has been shown to target some mislocalized BSEP mutants to the canalicular membrane [1819]. The drug enhances cell surface protein expression for some of the missense mutations found in ATP8B1 and ABCB11 deficiency [2021], and one study showed that bile acids act as pharmacological chaperones of E297G BSEP [22].…”

Section: Discussionmentioning

confidence: 99%

“…Diagnosing genetically heterogeneous cholestatic disorders is challenging due to the large number of candidate genes [18]. Until a decade ago, a number of cases of infantile cholestasis had been considered idiopathic [19].…”

Section: Discussionmentioning

confidence: 99%

Early Diagnosis ofABCB11Spectrum Liver Disorders by Next Generation Sequencing

Lee

Kim

Choe

et al. 2017

Pediatr Gastroenterol Hepatol Nutr

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PurposeThe goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis.MethodsFifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members.ResultsIdiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis.ConclusionABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

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Molecular Genetics and Liver Disease

Gissen

2017

Diseases of the Liver and Biliary System in Children

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Taking the next step forward – Diagnosing inherited infantile cholestatic disorders with next generation sequencing

Cited by 40 publications

References 32 publications

Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency

Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency

Early Diagnosis ofABCB11Spectrum Liver Disorders by Next Generation Sequencing

Molecular Genetics and Liver Disease

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