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Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma
Author(s) -
Blackburn Patrick R.,
Hickey Raymond D.,
Nace Rebecca A.,
Giama Nasra H.,
Kraft Daniel L.,
Bordner Andrew J.,
Chaiteerakij Roongruedee,
McCormick Jennifer B.,
Radulovic Maja,
Graham Rondell P.,
Torbenson Michael S.,
Tortorelli Silvia,
Scott C. Ronald,
Lindor Noralane M.,
Milliner Dawn S.,
Oglesbee Devin,
AlQabandi Wafa'a,
Grompe Markus,
Gavrilov Dimitar K.,
ElYoussef Mounif,
Clark Karl J.,
Atwal Paldeep S.,
Roberts Lewis R.,
Klee Eric W.,
Ekker Stephen C.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23047
Subject(s) - tyrosinemia , hepatocellular carcinoma , cirrhosis , biology , exome sequencing , liver disease , cancer research , tyrosine , medicine , genetics , mutation , gene , biochemistry
Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.