Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis
Abstract
:1. Introduction
2. Patients and Methods
2.1. Type of Study
2.2. Patients
2.3. Ethics
2.4. Data Collection
2.5. Clinical Presentation Categories
2.6. Sequencing Technique
2.6.1. Panel Design
2.6.2. Technical Validation of the Targeted Gene Panel NGS
2.6.3. DNA Extraction
2.6.4. Libraries Constitution
2.6.5. Sequencing Device
2.7. Bioinformatics Analysis
2.7.1. Selection of Variants of Interest
2.7.2. Classification of Variants
2.8. Variants Reported
2.9. Diagnostic Categories
3. Results
3.1. Patients
3.2. Technical Validation Phase of Gene Panel
3.3. Depth and Coverage of Sequenced Regions
3.4. Patients with a Certain Diagnosis
3.5. Patients with a Suggested Diagnosis
a | ||||
Phenotype | Gene | Patient | Mutation | Notes |
Transient neonatal cholestasis | ATP8B1 | 1 | c.3040C>T:p.Arg1014Ter | TJP2: p.Gly538Ala (He)—Pathogenic MYO5B: p.Glu144Gly (He) -VOUS |
2 | Complete gene deletion | |||
ABCB11 | 3 | c.3691C>T:p.Arg1231Trp | ||
4 | c.1445A>G:p.Asp482Gly | |||
5 | c.2873_2874insCG:p.Phe959GlyfsTer49 | |||
6 | c.3329C>T:Ala1110Val | |||
7 | c.1243C>T:p.Arg415Ter | |||
8 | c.3181_3184del:p.Ile1061ValfsTer35 | |||
9 | c.2061C>G:p.Tyr687Ter | Neonatal cholestasis with pale stool and hypoglycemia, normal cholangiogram, advanced fibrosis on LB (at the age of 2 months), normalization of LFT at 1 year old with UDCA treatment. Persistent normal LFT after UDCA discontinuation. | ||
10 | c.3752C>T:p.Thr1251Ile | |||
11 | c.896-897GA>TT:p.Arg299Ile | |||
12 | c.890A>G:p.Glu297Gly | Inherited from his mother who presented ICP—Neonatal CMV infection. | ||
13 | c.3148C>T:p.Arg1050Cys | |||
14 | c.1396C>A:p.Gln466Lys | Neonatal CMV infection. | ||
ABCB4 | 15 | c.140G>A:p.Arg47Gln | ||
16 | c.2800G>A:p.Ala934Thr | Neonatal CMV infection. | ||
17 | c.2800G>A:p.Ala934Thr | |||
18 | c.2800G>A:p.Ala934Thr | |||
19 | c.101C>T:p.Thr34Met | |||
20 | c.1769G>A:p.Arg590Gln * [10,11] | Mild perinatal anoxo-ischemia. | ||
21 | c.3280-2A>G:p(?) | |||
22 | c.3676T>G:p.Cys1226Gly | |||
b | ||||
Phenotype | Patient | Mutation | Status | Notes |
Chronic or recurrent high GGT level cholestasis | 23 | ABCB4: c.1436C>T:p.Pro479Leu | He: Pathogenic | Recurent episodes of cholestasis and pruritus. Normalization of LFT with UDCA treatment. |
24 | ABCB4: c.1769G>A:p.Arg590Gln * | He: Likely Pathogenic [10,11] | Anicteric cholestasis associtaed with abdominal pain. Normal abdominal US images, especially no lithiasis. Normalization of LFT with UDCA treatment. | |
25 | ABCB4:c.1714C>T:p.Gln572Ter (inherited from the father) | He: Pathogenic | Chronic cholestasis and pruritus. Hydrocholecystis with possible compression of extrahepatic bile ducts. Family history of liver disease (father: LPAC syndrome). | |
26 | ABCB4:c.1769G>A:p.Arg590Gln* | He: Likely Pathogenic [10,11] | Trisomy 21, neonatal cholestasis with intra vesicular sludge, cirrhosis and ascitis. Complete atrioventricular canal. Duodenal atresia and necrotizing enterocolitis requiring parenteral nutrition. Possible ischemic cholangiopathy due to complicated surgeries during neonatal period. Normalization of LFT at 1 year old, no discontinuation. | |
27 | ABCB4:c.2800G>A:p.Ala934Thr | He: Likely pathogenic | Chronic cholestasis, cirrhosis. | |
28 | ABCB4: c.574G>T:p.Val192Phe (inherited from the mother) ABCB4: c.3655-6C>G:p.(?) (de novo) | He: Likely pathogenic He: VOUS | Neonatal cholestasis, pale stool, normal cholangiogram, family history of liver disease (mother and maternal aunt: ICP). Partial improvement of LFT with UDCA treatment. | |
29 | ABCB4: c.662T>C:p.Met221Thr (inherited from the father) | He: Likely pathogenic | Fallot’s tetralogy, nephrocalcinosis, persistent abnormal LFT with UDCA treatment, normal cholangiogram, cirrhosis. No information on neonatal period. No family history of liver disease. | |
30 | ABCB4:c.2800G>A:p.Ala934Thr (inherited from the mother) ATP8B1:c.2097+1G>A: p.(?) (inherited from the father) | He: Pathogenic He: Likely Pathogenic | Chronic cholestasis, cirrhosis, portal hypertension, aortic arch abnormalities. Family history of liver disease (mother: ICP). | |
31 | ABCB4:c.2144C>T:p.Thr715Ile | He: Likely Pathogenic | Neonatal cholestasis, deceased during neonatal period (multiorgan failure). | |
32 | ABCB4:c.1769G>A:p.Arg590Gln * [10,11] | He: Likely Pathogenic | Mental retardation, butterfly vertebrae. Lost of follow-up. | |
33 | ABCB4:c.1769G>A:p.Arg590Gln * [10,11] | He: Likely Pathogenic | Chronic cholestasis, cirrhosis, liver histology compatible with neonatal sclerosing cholangitis, LT at 2 years old. | |
34 | ABCB4:c.1769G>A:p.Arg590Gln * [10,11] ABCB11:c.470A>G:p.Tyr157Cys (inherited from the mother) | He: Likely Pathogenic He: VOUS-LP | Extreme prematurity with severe anoxo-ischemia and long term parenteral nutrition. Neonatal cholestasis. Deceased during neonatal period (multiorgan failure). Post mortem LB: panlobular dissecting fibrosis, ductopenia, hepatocellular cholestasis, disseminated intravascular coagulopation. Possible consequences of a submassive destruction of liver parenchyma. Family history of liver disease (mother: ICP; twin brother: TNC (carrying only ABCB11 variant); healthy older sister (same genotype): asymptomatic vesicular lithiasis). | |
35 | ABCB4:c.959C>T:p.Ser320Phe | He: Likely Pathogenic | Complex cardiac malformation, chronic cholestasis, exsudative enteropathy. | |
36 | ABCB4:c.140G>A:p.Arg47Gln | He: Pathogenic | Patient also diagnosed with a glycogenose storage disease type III and deafness. | |
c | ||||
Phenotype | Gene | Patient | Mutation | Status |
Oestro-progestative induced cholestasis | ABCB11 | 37 | c.890A>G:p.Glu297Gly (He) (inherited from her mother) c.403G>A:p.Glu135Lys (He) (de novo or inherited from her father) | CHe |
38 | c.150+3A>C:p(?) | He | ||
39 | c.3130delG:p.Ala1044LeufsTer53 | He | ||
40 | c.477+6T>G:p(?) | Ho |
3.6. Patients with an Uncertain Diagnosis
a | |||
Patient | Genotype | ACMG Classification | Phenotype |
41 | NOTCH2:c.1396C>T:p.Gln466Ter (He) | Pathogenic | Chronic cholestasis, no extra-hepatic AGS feature, neonatal occlusion, neonatal CMV infection, no bile duct paucity in a LB containing only 6 portal spaces. |
42 | NOTCH2:c.5002+2T>C:p.(?) (He) | Pathogenic | Transient neonatal cholestasis, No extra-hepatic AGS feature. No LB, no UDCA treatment. |
43 | NOTCH2:c.6101C>A:p.Ala2034Asp (He) | VOUS-LP | Chronic cholestasis, No extra-hepatic AGS feature, no bile duct paucity on LB. |
44 | HNF1B:1.32Mb deletion including HNF1B (He) | Pathogenic | Acute hepatitis with anicteric cholestasis, spontaneous resolution, no relapse (3 years of follow-up). No diabetes. Normal renal function. Slight perisinusoidal fibrosis, moderate hyperplasia of stellate cells and normal bile ducts in LB. Normal liver and renal ultrasound. |
45 | ATP7B:c.4135C>T:p.Pro1379Ser* (Ho) [13] | VOUS | Chronic cholestasis, cirrhosis, normal cupric balance but elevated cupric levels in LB. |
46 | ABCB4:c.2581T>G:p.Leu861Val (He) ABCB4:c.1584G>C:p.Glu528Asp ¤ (He) [14] | VOUS-LP VOUS | Chronic cholestasis, cirrhosis on LB (MDR3 staining: not available). |
47 | NR1H4: c.920-2A>G:p.(?) (He) DGUOK: c.353G>A:p.Arg118His (He) | Pathogenic Likely Pathogenic | Neonatal cholestasis with hypoglycemia; steatosis and hepatocellular cholestasis on LB. Treated with UDCA: normal LFT and abdominal US at age 2 years. No discontinuation of UDCA. |
48 | MYO5B: c.3190C>T:p.Arg1064Ter (He) (inherited from the father) CFTR: c.3485G>T p.Arg1162Leu (He) (inherited from the mother) | Pathogenic RD CAUSING | Pruritus, chronic diarrhea, chronic bronchial congestion, normal cholangiogram. |
49 | ABCB11:c.1408C>T:p.Arg470Ter (He) | Pathogenic | Chronic cholestasis persistent with UDCA treatment, cirrhosis. |
50 | ABCB11:c.890A>G:p.Glu297Gly (He) | Likely Pathogenic | Neonatal cholestasis. Lost of follow-up. |
b | |||
Patient | Genotype | CFTR-France Classification | Phenotype |
51 | CFTR:[c.2002C>T:p.Arg668Cys c.1727G>C:p.Gly576Ala] (He) | RD CAUSING RD CAUSING | Transient neonatal cholestasis |
52 | CFTR:c.2991G>C:p.Leu997Phe (He) | RD CAUSING | |
53 | CFTR:c.3909C>G:p.Asn1303Lys (He) | CF-causing | |
54 | CFTR:[c.220C>T:p.Arg74Trp; c.3808G>A:p.Asp1270Asn] (Ho) | RD-VOUS4 RD-VOUS4 | |
55 | CFTR:[c.220C>T:p.Arg74Trp; c.3808G>A:p.Asp1270Asn; c.601G>A: p.Val201Met] (He) | RD-VOUS4 RD-VOUS4 RD-VOUS4 | Chronic cholestasis |
56 | CFTR: c.1523T>G:p. Phe508Cys (He) [c.1727G>C:p.Gly576Ala; c.2002C>T:p.Arg668Cys] (He) | RD CAUSING RD CAUSING RD CAUSING | |
57 | CFTR:c.2991G>C:p.Leu997Phe (He) | RD CAUSING | |
58 | CFTR:c.2991G>C:p.Leu997Phe (He) | RD CAUSING | |
59 | CFTR:c.3485G>T:p.Arg1162Leu (He) | RD CAUSING | |
60 | CFTR:c.2173G>A:p.Glu725Lys (He) | RD CAUSING | |
61 | CFTR: c.1516A>G:p.Ile506Val (He) | RD-VOUS4 |
3.7. Patients with No Diagnosis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Harpavat, S.; Garcia-Prats, J.A.; Anaya, C.; Brandt, M.L.; Lupo, P.J.; Finegold, M.J.; Obuobi, A.; ElHennawy, A.A.; Jarriel, W.S.; Shneider, B.L. Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements. JAMA 2020, 323, 1141–1150. [Google Scholar] [CrossRef]
- Fawaz, R.; Baumann, U.; Ekong, U.; Fischler, B.; Hadzic, N.; Mack, C.L.; McLin, V.A.; Molleston, J.P.; Neimark, E.; Ng, V.L.; et al. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 154–168. [Google Scholar]
- Nicastro, E.; Di Giorgio, A.; Marchetti, D.; Barboni, C.; Cereda, A.; Iascone, M.; D’Antiga, L. Diagnostic Yield of an Algorithm for Neonatal and Infantile Cholestasis Integrating Next-Generation Sequencing. J. Pediatr. 2019, 211, 54–62.e4. [Google Scholar] [CrossRef]
- Bahassi, E.M.; Stambrook, P.J. Next-generation sequencing technologies: Breaking the sound barrier of human genetics. Mutagenesis 2014, 29, 303–310. [Google Scholar] [CrossRef]
- Herbst, S.M.; Schirmer, S.; Posovszky, C.; Jochum, F.; Rödl, T.; Schroeder, J.A.; Barth, T.F.; Hehr, U.; Melter, M.; Vermehren, J. Taking the next step forward-Diagnosing inherited infantile cholestatic disorders with next generation sequencing. Mol. Cell. Probes 2015, 29, 291–298. [Google Scholar] [CrossRef]
- Nicastro, E.; D’Antiga, L. Next generation sequencing in pediatric hepatology and liver transplantation. Liver Transplant. 2018, 24, 282–293. [Google Scholar] [CrossRef] [Green Version]
- Chappell, K.; Francou, B.; Habib, C.; Huby, T.; Leoni, M.; Cottin, A.; Nadal, F.; Adnet, E.; Paoli, E.; Oliveira, C.; et al. Galaxy Is a Suitable Bioinformatics Platform for the Molecular Diagnosis of Human Genetic Disorders Using High-Throughput Sequencing Data Analysis: Five Years of Experience in a Clinical Laboratory. Clin. Chem. 2022, 68, 313–321. [Google Scholar] [CrossRef]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef] [Green Version]
- Castellani, C.; Cuppens, H.; Macek, M.; Cassiman, J.J.; Kerem, E.; Durie, P.; Tullis, E.; Assael, B.M.; Bombieri, C.; Brown, A.; et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J. Cyst. Fibros. 2008, 7, 179–196. [Google Scholar] [CrossRef] [Green Version]
- Ziol, M.; Barbu, V.; Rosmorduc, O.; Frassati-Biaggi, A.; Barget, N.; Hermelin, B.; Scheffer, G.L.; Bennouna, S.; Trinchet, J.-C.; Beaugrand, M.; et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 2008, 135, 131–141. [Google Scholar] [CrossRef]
- Dong, C.; Condat, B.; Picon-Coste, M.; Chrétien, Y.; Potier, P.; Noblinski, B.; Arrivé, L.; Hauuy, M.-P.; Barbu, V.; Maftouh, A.; et al. Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities. JHEP Rep. Innov. Hepatol. 2021, 3, 100201. [Google Scholar] [CrossRef]
- Roelandt, P.; Antoniou, A.; Libbrecht, L.; Van Steenbergen, W.; Laleman, W.; Verslype, C.; Van der Merwe, S.; Nevens, F.; De Vos, R.; Fischer, E.; et al. HNF1B deficiency causes ciliary defects in human cholangiocytes. Hepatology 2012, 56, 1178–1181. [Google Scholar] [CrossRef]
- Yi, F.; Poskanzer, S.A.; Myers, C.T.; Thies, J.; Collins, C.J.; Dayuha, R.; Duong, P.; Houwen, R.; Hahn, S.H. p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease. JIMD Rep. 2020, 54, 32–36. [Google Scholar] [CrossRef]
- Khabou, B.; Durand-Schneider, A.-M.; Delaunay, J.-L.; Aït-Slimane, T.; Barbu, V.; Fakhfakh, F.; Housset, C.; Maurice, M. Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases. Int. J. Biochem. Cell Biol. 2017, 89, 101–109. [Google Scholar] [CrossRef] [Green Version]
- Karpen, S.J.; Kamath, B.M.; Alexander, J.J.; Ichetovkin, I.; Rosenthal, P.; Sokol, R.J.; Dunn, S.; Thompson, R.J.; Heubi, J.E. Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults. J. Pediatr. Gastroenterol. Nutr. 2021, 72, 654–660. [Google Scholar] [CrossRef]
- Matte, U.; Mourya, R.; Miethke, A.; Liu, C.; Kauffmann, G.; Moyer, K.; Zhang, K.; Bezerra, J.A. Analysis of gene mutations in children with cholestasis of undefined etiology. J. Pediatr. Gastroenterol. Nutr. 2010, 51, 488–493. [Google Scholar] [CrossRef] [Green Version]
- Wang, N.-L.; Lu, Y.-L.; Zhang, P.; Zhang, M.-H.; Gong, J.-Y.; Lu, Y.; Xie, X.-B.; Qiu, Y.-L.; Yan, Y.-Y.; Wu, B.-B.; et al. A Specially Designed Multi-Gene Panel Facilitates Genetic Diagnosis in Children with Intrahepatic Cholestasis: Simultaneous Test of Known Large Insertions/Deletions. PLoS ONE 2016, 11, e0164058. [Google Scholar] [CrossRef] [Green Version]
- Togawa, T.; Sugiura, T.; Ito, K.; Endo, T.; Aoyama, K.; Ohashi, K.; Negishi, Y.; Kudo, T.; Ito, R.; Kikuchi, A.; et al. Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing. J. Pediatr. 2016, 171, 171–177.e4. [Google Scholar] [CrossRef]
- Stalke, A.; Skawran, B.; Auber, B.; Illig, T.; Schlegelberger, B.; Junge, N.; Goldschmidt, I.; Leiskau, C.; von Neuhoff, N.; Baumann, U.; et al. Diagnosis of monogenic liver diseases in childhood by next-generation sequencing. Clin. Genet. 2018, 93, 665–670. [Google Scholar] [CrossRef] [Green Version]
- Chen, H.-L.; Li, H.-Y.; Wu, J.-F.; Wu, S.-H.; Chen, H.-L.; Yang, Y.-H.; Hsu, Y.-H.; Liou, B.-Y.; Chang, M.-H.; Ni, Y.-H. Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges. J. Pediatr. 2019, 205, 153–159.e6. [Google Scholar] [CrossRef]
- Shagrani, M.; Burkholder, J.; Broering, D.; Abouelhoda, M.; Faquih, T.; El-Kalioby, M.; Subhani, S.N.; Goljan, E.; Albar, R.; Monies, D.; et al. Genetic profiling of children with advanced cholestatic liver disease. Clin. Genet. 2017, 92, 52–61. [Google Scholar] [CrossRef]
- Lipiński, P.; Ciara, E.; Jurkiewicz, D.; Pollak, A.; Wypchło, M.; Płoski, R.; Cielecka-Kuszyk, J.; Socha, P.; Pawłowska, J.; Jankowska, I. Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders-Single-Center Experience. Front. Pediatr. 2020, 8, 414. [Google Scholar] [CrossRef]
- Fickert, P.; Fuchsbichler, A.; Wagner, M.; Zollner, G.; Kaser, A.; Tilg, H.; Krause, R.; Lammert, F.; Langner, C.; Zatloukal, K.; et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004, 127, 261–274. [Google Scholar] [CrossRef]
- Fickert, P.; Zollner, G.; Fuchsbichler, A.; Stumptner, C.; Weiglein, A.H.; Lammert, F.; Marschall, H.-U.; Tsybrovskyy, O.; Zatloukal, K.; Denk, H.; et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 2002, 123, 1238–1251. [Google Scholar] [CrossRef]
- Jacquemin, E.; De Vree, J.M.; Cresteil, D.; Sokal, E.M.; Sturm, E.; Dumont, M.; Scheffer, G.L.; Paul, M.; Burdelski, M.; Bosma, P.J.; et al. The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001, 120, 1448–1458. [Google Scholar] [CrossRef]
- Schatz, S.B.; Jüngst, C.; Keitel-Anselmo, V.; Kubitz, R.; Becker, C.; Gerner, P.; Pfister, E.-D.; Goldschmidt, I.; Junge, N.; Wenning, D.; et al. Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. Hepatol. Commun. 2018, 2, 504–514. [Google Scholar] [CrossRef]
- Wendum, D.; Barbu, V.; Rosmorduc, O.; Arrivé, L.; Fléjou, J.-F.; Poupon, R. Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchows Arch. 2012, 460, 291–298. [Google Scholar] [CrossRef]
- Benzimra, J.; Derhy, S.; Rosmorduc, O.; Menu, Y.; Poupon, R.; Arrivé, L. Hepatobiliary anomalies associated with ABCB4/MDR3 deficiency in adults: A pictorial essay. Insights Imaging 2013, 4, 331–338. [Google Scholar] [CrossRef] [Green Version]
- Qiu, Y.-L.; Liu, T.; Abuduxikuer, K.; Hao, C.-Z.; Gong, J.-Y.; Zhang, M.-H.; Li, L.-T.; Yan, Y.-Y.; Li, J.-Q.; Wang, J.-S. Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome. Hum. Mutat. 2019, 40, 2247–2257. [Google Scholar] [CrossRef]
- Aamann, L.; Ørntoft, N.; Vogel, I.; Grønbaek, H.; Becher, N.; Vilstrup, H.; Ott, P.; Lildballe, D.L. Unexplained cholestasis in adults and adolescents: Diagnostic benefit of genetic examination. Scand. J. Gastroenterol. 2018, 53, 305–311. [Google Scholar] [CrossRef]
- Hertel, P.M.; Bull, L.N.; Thompson, R.J.; Goodrich, N.P.; Ye, W.; Magee, J.C.; Squires, R.H.; Bass, L.M.; Heubi, J.E.; Kim, G.E.; et al. Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis. J. Pediatr. Gastroenterol. Nutr. 2021, 73, 169–177. [Google Scholar] [CrossRef]
- Zhou, J.; Yao, Y.; Huang, X.; Chen, D.; Zhang, T.; Zhang, Y. Association between bile salt export pump polymorphisms and intrahepatic cholestasis of pregnancy susceptibility: A meta-analysis of case-control studies. Gynecol. Endocrinol. 2019, 35, 179–183. [Google Scholar] [CrossRef]
- Jacquemin, E.; Lykavieris, P.; Chaoui, N.; Hadchouel, M.; Bernard, O. Transient neonatal cholestasis: Origin and outcome. J. Pediatr. 1998, 133, 563–567. [Google Scholar] [CrossRef]
- Champion, V.; Carbajal, R.; Lozar, J.; Girard, I.; Mitanchez, D. Risk factors for developing transient neonatal cholestasis. J. Pediatr. Gastroenterol. Nutr. 2012, 55, 592–598. [Google Scholar] [CrossRef]
- Liu, L.-Y.; Wang, X.-H.; Lu, Y.; Zhu, Q.-R.; Wang, J.-S. Association of variants of ABCB11 with transient neonatal cholestasis. Pediatr. Int. 2013, 55, 138–144. [Google Scholar] [CrossRef]
- Hermeziu, B.; Sanlaville, D.; Girard, M.; Léonard, C.; Lyonnet, S.; Jacquemin, E. Heterozygous bile salt export pump deficiency: A possible genetic predisposition to transient neonatal cholestasis. J. Pediatr. Gastroenterol. Nutr. 2006, 42, 114–116. [Google Scholar] [CrossRef]
- Jacquemin, E.; Malan, V.; Rio, M.; Davit-Spraul, A.; Cohen, J.; Landrieu, P.; Bernard, O. Heterozygous FIC1 deficiency: A new genetic predisposition to transient neonatal cholestasis. J. Pediatr. Gastroenterol. Nutr. 2010, 50, 447–449. [Google Scholar] [CrossRef]
- Santos Silva, E.; Almeida, A.; Frutuoso, S.; Martins, E.; Valente, M.J.; Santos-Silva, A.; Lopes, A.I. Neonatal Cholestasis Over Time: Changes in Epidemiology and Outcome in a Cohort of 154 Patients From a Portuguese Tertiary Center. Front. Pediatr. 2020, 8, 351. [Google Scholar] [CrossRef]
- Jung, C.; Driancourt, C.; Baussan, C.; Zater, M.; Hadchouel, M.; Meunier-Rotival, M.; Guiochon-Mantel, A.; Jacquemin, E. Prenatal molecular diagnosis of inherited cholestatic diseases. J. Pediatr. Gastroenterol. Nutr. 2007, 44, 453–458. [Google Scholar] [CrossRef]
- Aleksandrova, M.I.; Kushnareva, N.S.; Smirnova, O.V. Manifestation of cystic fibrosis transmembrane regulator (CFTR) in hepatic ductal structures and renal tubules of female rats with experimental cholestasis of pregnancy. Bull. Exp. Biol. Med. 2014, 156, 654–657. [Google Scholar] [CrossRef]
- Miller, A.C.; Comellas, A.P.; Hornick, D.B.; Stoltz, D.A.; Cavanaugh, J.E.; Gerke, A.K.; Welsh, M.J.; Zabner, J.; Polgreen, P.M. Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions. Proc. Natl. Acad. Sci. USA 2020, 117, 1621–1627. [Google Scholar] [CrossRef] [Green Version]
- Mann, D.A. Epigenetics in liver disease. Hepatol. Baltim. Md 2014, 60, 1418–1425. [Google Scholar] [CrossRef] [Green Version]
ABCB11 (NM_003742.2) | ABCB4 (NM_000443.3) | ABCC2 (NM_000392.3) | ACOX2(NM_003500) * | AIRE (NM_000383) |
AKR1D1 (NM_005989.3) | AMACR (NM_014324.5) | ATP7B (NM_000053) | ATP8B1 (NM_005603.4) | BAAT (NM_001701.3) |
CFTR (NM_000492.3) | CIRH1A (NM_032830.2) | CLDN1 (NM_021101.4) | CYP27A1 (NM_000784.3) | CYP7B1 (NM_004820.3) |
DCDC2 (NM_016356) * | GBE1 (NM_000158) | GPBAR1 (NM_001077191) | HSD3B7 (NM_025193.3) | JAG1 (NM_000214.2) |
MYO5B (NM_001080467) | NOTCH2 (NM_024408.3) | NR1H4 (NM_00512) | SERPINA1(NM_000295) * | SCYL1 (NM_020680) * |
SLCO1B1/SLCO1B3 (NM_006446/NM_019844) | SLC25A13 (NM_014251.2) | SLC27A5 (NM_012254.2) | TJP2 (NM_004817.3) | TTC37 (NM_014639.3) |
UGT1A1 (NM_000463.2) | UNC45A (NM_018671) | VIPAS39 (NM_022067.3) | VPS33B (NM_018668.3) |
Gene | Transmission Mode | Disease (OMIM/Orphanet Number) | Number of Patients |
---|---|---|---|
Cholestasis with High GGT Activity | 92 | ||
JAG1 | AD | Alagille syndrome (118450/261619) | 48 |
NOTCH2 | AD | Alagille syndrome (610205/261629) | 7 |
ABCB4 | AR | PFIC3 (602347/79305) | 17 |
DCDC2 | AR | Neonatal sclerosing cholangitis (617394/480556) | 9 |
CFTR | AR | Cystic fibrosis (219700/586) | 3 |
ATP7B | AR | Wilson disease (277900/905) | 3 |
SERPINA1 | AR | Alpha-1-antitrypsine deficiency (613490/60) | 5 |
Cholestasis with Normal or LOW GGT Activity | 57 | ||
ATP8B1 | AR AR | PFIC1 (211600/79306) BRIC1 (243300/99960) | 1 1 |
ABCB11 | AR AR | PFIC2 (601847/79304) BRIC2 (605479/99961) | 19 3 |
TJP2 | AR | PFIC4 (615878/480483) | 8 |
NR1H4 | AR | PFIC5 (617049/480476) | 1 |
MYO5B | AR | Myosin 5b deficiency related cholestasis (in absence of MVID) (ND/480491) | 10 |
VPS33B | AR | ARC syndrome (208085/2697) | 5 |
AKR1D1 | AR | Primary bile acid synthesis defect (235555/79303) | 1 |
ACOX2 | AR | Primary bile acid synthesis defect (617308/ND) | 2 |
BAAT | AR | Primary bile acid synthesis defect (conjugation defect) (619232/238475) | 1 |
CYP27A1 | AR | Cerebrotendinous xanthomatosis (213700/909) | 1 |
SCYL1 | AR | Spinocerebellar ataxia (616719/466794) | 3 |
TTC37 | AR | Tricho-hepato-enteric syndrome (614602/84064) | 1 |
Genetic Hyperbilirubinemia | 20 | ||
UGT1A1 | AR | Gilbert syndrome (143500/357) | 1 |
AR | Crigler-Najjar syndrome (218800/79235) | 1 | |
ABCC2 | AR | Dubin-Johnson syndrome (237500/234) | 17 |
SLCO1B1/B3 | AR | Rotor syndrome (237450/3111) | 1 |
Reference | Number of Genes | Number of Patients | Age (Years) | NGS Indication | Diagnostic Rate (%) |
---|---|---|---|---|---|
Matte U et al. JPGN. 2010 | 5 | 51 | 0–17 | Chronic cholestasis | 27% |
Wang NL et al. PLoS One. 2016 | 61 | 141 | 0–17 | Chronic cholestasis | 22% |
Togawa T et al. J Pediatr. 2016 | 18 | 109 | <1 | Chronic cholestasis | 26% |
Stalke A et al. Clin Genet. 2018 | 21 | 135 | 0–20 | Chronic cholestasis | 17% |
Chen HL et al. J. Of Ped. 2018 | 52 | 102 | 0–18 | Cholestasis | 32,4% |
Shagrani et al. Clin Genet. 2018 | 189 | 98 | 0–17 | Severe cholestasis | 61% |
Lipinski et al. Front. Pediatr. 2020 | 53 | 22 | 0–18 | Chronic cholestasis | 68% |
Karpen et al. JPGN. 2021 | 66 | 2171 | 0–18 | Cholestasis | 12% |
Our study | 34 | 603 | 0–17 | Cholestasis | 28% |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Almes, M.; Spraul, A.; Ruiz, M.; Girard, M.; Roquelaure, B.; Laborde, N.; Gottrand, F.; Turquet, A.; Lamireau, T.; Dabadie, A.; et al. Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis. Diagnostics 2022, 12, 1169. https://doi.org/10.3390/diagnostics12051169
Almes M, Spraul A, Ruiz M, Girard M, Roquelaure B, Laborde N, Gottrand F, Turquet A, Lamireau T, Dabadie A, et al. Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis. Diagnostics. 2022; 12(5):1169. https://doi.org/10.3390/diagnostics12051169
Chicago/Turabian StyleAlmes, Marion, Anne Spraul, Mathias Ruiz, Muriel Girard, Bertrand Roquelaure, Nolwenn Laborde, Fréderic Gottrand, Anne Turquet, Thierry Lamireau, Alain Dabadie, and et al. 2022. "Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis" Diagnostics 12, no. 5: 1169. https://doi.org/10.3390/diagnostics12051169