Hydrocephalus

Gene: HYLS1

Green List (high evidence)

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Green. Additional comments from reviewing GLHs: Single pathogenic variant multiple reports multiple families (Founder Finnish) multiple pathogenic reviews ClinVar. Known founder mutation associated with the phenotype - if we downgrade to Amber how will this be flagged when present?

Created: 2 May 2024, 10:48 a.m. | Last Modified: 2 May 2024, 10:48 a.m.

Panel Version: 4.6

Added the Q4_21_rating tag to make it clear that the rating is being assessed.

Created: 6 Oct 2022, 2:09 p.m. | Last Modified: 6 Oct 2022, 2:09 p.m.

Panel Version: 2.132

I don't know

As the recommendation is to demote HYLS1 from Green to Amber on this panel, the to_be_confirmed_NHSE tag has been added, as further NHSE review is required.

Created: 15 Mar 2022, 5:46 p.m. | Last Modified: 15 Mar 2022, 5:46 p.m.

Panel Version: 2.127

I don't know

A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in Drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome but no hydrocephalus. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Suggest Amber rating given only single founder variant reported with a hydrocephalus phenotype with supporting functional data from multiple animal models indicative of ciliopathy. It is unclear what phenotype other variants in this gene would be associated with at this stage.

Created: 7 Aug 2020, 11:58 p.m. | Last Modified: 7 Aug 2020, 11:58 p.m.

Panel Version: 2.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hydrolethalus syndrome (MIM#236680)

Publications

• 15843405
• 18648327
• 19400947
• 19656802
• 32509774

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 29 Jul 2019, 2:49 p.m. | Last Modified: 29 Jul 2019, 2:49 p.m.

Panel Version: 1.34

Green List (high evidence)

Comment when marking as ready: Recurrent missense reported to date; ASP211GLY  

Created: 25 May 2017, 2:39 p.m.

Prenatal relevance. Recurrent ASP211GLY  mutation

Created: 25 May 2017, 2:29 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hydrolethalus syndrome 236680

Mode of pathogenicity
Other