Childhood onset hereditary spastic paraplegia

Gene: RINT1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:34 p.m. | Last Modified: 24 Feb 2025, 5:34 p.m.

Panel Version: 7.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: Three unrelated cases and functional evidence are available in support of the association of this gene with early-onset hereditary spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 11 Oct 2024, 11:38 a.m. | Last Modified: 11 Oct 2024, 11:38 a.m.

Panel Version: 6.7

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. Their age of onset ranged from around 7 months to 17 months.

Previously, three patients harbouring biallelic RINT1 variants were reported with infantile liver failure syndrome-3 (MIM #618641) and the phenotypes reported in PMID:37463447 have not previously been reported. One of the individual died at 14 months due to acute liver failure, probably before the development of a neurological phenotype. The episodic liver dysfunction in two other patients was very similar to that previously reported in PMID:31204009 (MIM #618641).

In addition, functional and lipidomic analysis highlights a pivotal role for RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

PMID:38990652 reported a girl with early-onset pure hereditary spastic paraplegia and with compound heterozygous truncating variants in RINT1 gene. Functional evidence is available for these variants.

Created: 11 Oct 2024, 11:35 a.m. | Last Modified: 11 Oct 2024, 11:35 a.m.

Panel Version: 6.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
hereditary spastic paraplegia, MONDO:0019064

Publications

• 37463447
• 38990652

Green List (high evidence)

The PMID: 38990652 reports fourth case with HSP and bialellic RINT1 variants. They also note:
"The exon-intron boundaries around intron 11 may represent a mutational hotspot, given variation at c.1671+2 and c.1672-1 in all reported cases thus far."
Enough evidence for the green rating!
Sources: Literature

Created: 15 Sep 2024, 3:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
HSP

Publications

• PMID: 38990652