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Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease
M. Neřoldová, E. Ciara, J. Slatinská, S. Fraňková, P. Lišková, R. Kotalová, J. Globinovská, M. Šafaříková, L. Pfeiferová, H. Zůnová, L. Mrázová, V. Stránecký, A. Vrbacká, O. Fabián, E. Sticová, D. Skanderová, J. Šperl, M. Kalousová, T. Zima, M....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 2006
Free Medical Journals
od 2006
Public Library of Science (PLoS)
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PubMed Central
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ProQuest Central
od 2006-12-01
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od 2006-10-01
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od 2006-01-01
Open Access Digital Library
od 2006-01-01
Medline Complete (EBSCOhost)
od 2008-01-01
Nursing & Allied Health Database (ProQuest)
od 2006-12-01
Health & Medicine (ProQuest)
od 2006-12-01
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od 2006-12-01
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od 2006
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- cholestáza * genetika MeSH
- cytoskeletální proteiny genetika MeSH
- flavoproteiny genetika MeSH
- genotyp MeSH
- intrahepatální cholestáza * genetika diagnóza MeSH
- lidé MeSH
- mitochondriální proteiny genetika MeSH
- mutace MeSH
- protoporfyrinogenoxidasa genetika MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND AND AIM: Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis. PATIENTS AND METHODS: Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in ABCB11, ATP8B1, ABCB4 or JAG1 demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families. RESULTS: WES revealed biallelic variation in 3 ciliopathy genes (PKHD1, TMEM67 and IFT172) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in PPOX in one adult index subject, and homozygosity for an unreported splice-site variation in F11R in one child. Whereas phenotypes of the index patients with mutated PKHD1, TMEM67, and PPOX corresponded with those elsewhere reported, how F11R variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in IFT172, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for IFT172 rs780205001 c.167A>C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant IFT172 NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants IFT172 rs776310391 c.157T>A p.(Phe53Ile) and rs746462745 c.164C>G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations. CONCLUSION: Our findings suggest association of IFT172 variants with non-syndromic cholestatic liver disease.
Department of Medical Genetics The Children's Memorial Health Institute Warsaw Poland
Department of Pediatrics Hospital Poprad Poprad Slovak Republic
Diagnostik und Forschungsinstitut für Pathologie Medizinische Universität Graz Graz Austria
Institute for Clinical and Experimental Medicine Prague Czech Republic
Citace poskytuje Crossref.org
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