SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). (October 2018)

• Record Type: Journal Article
• Authors: Lenz, Dominic; McClean, Patricia; Kansu, Aydan; Bonnen, Penelope; Ranucci, Giusy; Thiel, Christian; Straub, Beate; Harting, Inga; Alhaddad, Bader; Dimitrov, Bianca; Kotzaeridou, Urania; Wenning, Daniel; Iorio, Raffaele; Himes, Ryan; Kuloğlu, Zarife; Blakely, Emma; Taylor, Robert; Meitinger, Thomas; Kölker, Stefan; Prokisch, Holger; Hoffmann, Georg; Haack, Tobias; Staufner, Christian
• Is Part Of: Genetics in medicine. Volume 20:Number 10(2018)
• Page Start: 1255
• Page End: 1265
• Publication Date: 2018-10
• Subjects: acute liver failure -- CALFAN syndrome -- congenital disorder of intracellular trafficking -- low-GGT cholestasis -- SCYL1; Medical genetics -- Periodicals; Genetic disorders -- Periodicals; 616.04205
• DOI: 10.1038/gim.2017.260
• Languages: English
• ISSNs: 1098-3600

Abstract

Abstract Purpose Biallelic mutations inSCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype. Methods We aimed to identify patients withSCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed. Results Seven patients from five families with biallelicSCYL1 variants were identified. The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking. Conclusion SCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.