Neonatal cholestasis
Gene: BCS1LComment when marking as ready: A number of cases have been reported in association with biallelic variants in BCS1L. There is a Finnish population with founder effect associated with GRACILE syndrome, where cholestasis is a feature. Reports in other populations suggest complex III deficiency. The cause for the difference in presentation is not clear. In both phenotypes the outcome is poor in view of multi-system dysfunction with death reported in infancy. I think that further evidence is needed about the mutational spectrum and clinical presentation. At present I think that this severe multi-system presentation is more likely to be picked up through other presenting routes e.g. mitochondrial / undiagnosed metabolic rather than a more focused cholestasis panel. Amber at present pending further information.Created: 27 Jul 2018, 10:23 a.m.
Comment on list classification: Although GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) has been reported in multiple individuals in association with BCS1L, 17 of these were Finnish cases homozygous for the same variant. Functional studies showed some evidence of pathogenicity (possible reduction in protein stability, failure to rescue BCS1L-deficient yeast in complementation studies). Variants in BCS1L have been reported in 9 additional unrelated patients from 7 families, however only 4/9 of these presented with cholestasis; unlike the Finnish patients, these 9 patients had complex III deficiency. Because of these differences in the phenotype in the non-Finnish cases, there is not sufficient evidence for this gene as a cause of GRACILE syndrome.Created: 27 Jul 2018, 5:49 a.m.
Comment on publications: PIMD:11528392 reports 6 patients from 4 unrelated families with complex III deficiency, encephalopathy and renal tubulopathy; 2/6 also had cholestasis. PMID:12215968 reports 17 Finnish patients with GRACILE syndrome, homozygous for the same variant in BCS1L, and an additional 3 unrelated British patients, all compound heterozygotes for 5 additional variants (one was heterozygous for the Finnish variant); all Finnish patients and 2/3 British patients had cholestasis.Created: 27 Jul 2018, 5:36 a.m.
Gene added from King's College Hospital NHS Foundation Trust diagnostic cholestasis gene panel. This gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.Created: 25 Jul 2018, 4:15 p.m.
Mode of inheritance
Unknown
Phenotypes
GRACILE syndrome
This panel has been subjected to extensive internal and external review.
Gene: bcs1l has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: BCS1L was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Gene: bcs1l has been classified as Amber List (Moderate Evidence).
Publications for gene: BCS1L were set to 11528392; 9792866; 12215968
Phenotypes for gene: BCS1L were set to GRACILE syndrome; Cholestasis
Gene: bcs1l has been classified as Amber List (Moderate Evidence).
BCS1L was added to Neonatal cholestasis panel. Sources: Expert list
BCS1L was created by Louise Daugherty