Neonatal cholestasis

Gene: POLG

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 6 variants reported in Mitochondrial DNA depletion syndrome 4A (Alpers type) 203700.

Created: 14 Aug 2018, 9:20 a.m.

Comment on list classification: Based on rating by clinical fellow Helen Brittain (Genomics England Curator).

Created: 14 Aug 2018, 9:17 a.m.

Green List (high evidence)

Neonatal hepatic dysfunction is a feature of Mitochondrial DNA depletion syndrome 4A (Alpers type). This is therefore within the anticipated scope of the panel, and genes causing related presentations are rated green (MPV17 & DGUOK). It does however present with severe neurological manifestations in addition e.g. neurodevelopmental delay / seizures. If the panel is refined with the aim of fulfilling a more focal / isolated hepatic presentation in infancy then this gene would need to be re-considered.

Created: 27 Jul 2018, 1:39 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 4A (Alpers type) 203700

PMID: 20142534 - reported variability in features reported in 4 cases (two sets of sblings) of Alpers-like hepatocerebral syndrome who were compound heterozygous (all sharing one of the same variants) - one boy displayed cholestasis. All patients had liver disease. In OMIM, Mitochondrial DNA depletion syndrome 4A (Alpers type) has the features Liver failure, Abnormal bile duct architecture and Bile duct proliferation. I am unsure whether this gene should be Green on this panel. This is Green on the Mitochondrial disorders Version 1.66, Neonatal and familial gastrointestinal neuromuscular disorders Version 1.7, Undiagnosed metabolic disorders Version 1.77 panels. A literature search did not reveal any further cases linked to cholestasis.

Created: 25 Jul 2018, 1:33 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial disease; cholestasis; liver failure