Cholestasis

Gene: RINT1

Red List (low evidence)

The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 2:45 p.m. | Last Modified: 10 Dec 2025, 2:45 p.m.

Panel Version: 3.14

As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients.

PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported.

PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia.

As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/) this panel includes neonatal conjugated hyperbilirubinaemia, unexplained cholestasis or cholestasis of pregnancy-onset.

As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.

Created: 18 Jun 2025, 5:07 p.m. | Last Modified: 23 Jun 2025, 3:24 p.m.

Panel Version: 3.7

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile liver failure syndrome 3, OMIM:618641

Publications

• 31204009
• 37463447
• 39186236

Red List (low evidence)

Recurrent episodes of acute liver failure rather than cholestasis.

Created: 8 Dec 2024, 9:46 a.m. | Last Modified: 8 Dec 2024, 9:46 a.m.

Panel Version: 3.6

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 4:18 p.m. | Last Modified: 3 Mar 2022, 4:18 p.m.

Panel Version: 1.105

Green List (high evidence)

PMID: 31204009 3 unrelated probands with biallelic RINT1 variants and infantile liver failure; proband 3 had focal hepatocellular cholestasis therefore sufficient overlap in phenotype to rate as green

Created: 20 Jan 2022, 1:27 p.m. | Last Modified: 20 Jan 2022, 1:27 p.m.

Panel Version: 1.103

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile liver failure syndrome 3

Publications

• PMID: 31204009

Green List (high evidence)

Comment on list classification: Promoting this gene from red to amber, but with recommendation for green rating, pending review of whether the phenotype is within the scope of this panel.

Created: 27 Jan 2021, 4:45 p.m. | Last Modified: 27 Jan 2021, 4:45 p.m.

Panel Version: 1.78

Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.
Sources: Literature

Created: 27 Jan 2021, 4:44 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile liver failure syndrome 3 OMIM:618641; infantile liver failure syndrome 3 MONDO:0032844

Publications

• 31204009