ABCMdb

ABCB11 p.Val1112Phe

Predicted by SNAP2:	A: D (75%), C: N (53%), D: D (95%), E: D (91%), F: D (91%), G: D (91%), H: D (91%), I: D (71%), K: D (91%), L: D (85%), M: D (71%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (91%), T: D (80%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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Publications
[hide] Taking the next step forward - Diagnosing inherite... Mol Cell Probes. 2015 Oct;29(5):291-8. doi: 10.1016/j.mcp.2015.03.001. Epub 2015 Mar 13. Herbst SM, Schirmer S, Posovszky C, Jochum F, Rodl T, Schroeder JA, Barth TF, Hehr U, Melter M, Vermehren J
Taking the next step forward - Diagnosing inherited infantile cholestatic disorders with next generation sequencing.
Mol Cell Probes. 2015 Oct;29(5):291-8. doi: 10.1016/j.mcp.2015.03.001. Epub 2015 Mar 13., [PMID:25771912]

Abstract [show]
Identifying rare genetic forms of infantile cholestasis is challenging due to their similar clinical presentation and their diverse etiology. After exclusion of common non-genetic causes a huge list of rare differential diagnosis remains to be solved. More than 90 genes are associated with monogenic forms of infantile cholestasis, thus preventing routine genetic workup by Sanger sequencing. Here we demonstrate a next generation sequencing approach to discover the underlying cause in clinically well characterized patients in whom common causes of infantile cholestasis have been excluded. After validation of the analytical sensitivity massive parallel sequencing was performed for 93 genes in six prospectively studied patients. Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611+1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Three exemplary clinical cases of infants with cholestasis are presented and discussed in the context of their genetic and histopathological findings (autosomal recessive polycystic kidney disease, atypical PFIC and Niemann-Pick syndrome type C1). These case reports highlight the critical impact of integrating clinical, histopathological and genetic data during the process of multi gene panel testing to ultimately pinpoint rare genetic diagnoses.

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5 Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611&#fe;1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Login to comment
129 Pat Gene Sequence alteration Coverage (reads) Interpretation OMIM phenotype Mode of inheritance Reference 1 PKHD1 c.2330C > T p.Thr777Met 11/30 Heterozygous VUS 4 AR Polycystic Kidney Disease Autosomal rezessiv This report 1 PKHD1 c.6779A > G p.Tyr2260Cys 20/33 Heterozygous VUS 4 AR Polycystic Kidney Disease Autosomal rezessive This report 2 LBR c.1114C > T p.Arg372Cys 27/68 Heterozygous VUS 5 Reynolds-Syndrome Primary Biliary Cirrhosis Autosomal dominan [15] 2 ABCB11 c.3334G > T p.Val1112Phe 4/5 heterozygous VUS 4 Progressive familial intrahepatic cholestasis Autosomal rezessive This report 3 NPC1 c.346C > T p.Arg116* 21/56 Heterozygous VUS 5 NiemannePick Type C Autosomal rezessive [16] 3 NPC1 c.1171G > A p.Glu391Lys 12/34 Heterozygous VUS 4 NiemannePick Type C Autosomal rezessive This report 4 ABCB11 c.611&#fe;1G > A Splice site 35/76 heterozygous VUS 4 Progressive familiar intrahepatic cholestasis Autosomal recessive This report 4 ABCB11 c.1881dupT p.Gly628Trpfs*3 47/87 Heterozygous VUS 4 Progressive familiar intrahepatic cholestasis Autosomal recessive This report Fig. 1. Login to comment
144 Patient No. 2 was shown to carry a heterozygous ABCB11 mutation p.Val1112Phe, which so far has neither been described in healthy controls nor as a pathogenic mutation. Login to comment