Skeletal dysplasia

Gene: HYLS1

Comment when marking as ready: Borderline Amber/Green and mechanism unclear. However, given at least two variants reported with a ciliopathy phenotype and supporting functional data from multiple animal models all indicative of ciliopathy, keep Green.

Created: 6 Aug 2020, 11:40 p.m. | Last Modified: 6 Aug 2020, 11:40 p.m.

Panel Version: 0.3707

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 cells have shown mislocalisation of the protein to the nucleus (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. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.

Created: 6 Aug 2020, 11:08 p.m. | Last Modified: 7 Aug 2020, 2:12 a.m.

Panel Version: 0.3713

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hydrolethalus syndrome (MIM#236680)

Publications

• 15843405
• 18648327
• 19400947
• 19656802
• 32509774

Mode of pathogenicity
Other

I don't know

OMIM notes Dandy Walker anomaly as a neurological feature. All patients results in either stillbirths or neonatal death, so limited information available. Almost all patients have the same recurring missense (p.Asp211Gly)

PMID: 18648327 - describes many patients with the recurring missense mutation. Summary table describes brain features of 19 patients, none appear to be consistent with JS

PMID: 26830932 - 2 homozygous living siblings (stop-loss, extension) both diagnosed with JS. Patients had molar tooth signs and dysplasia of cerebellar vermis

Single reported family, but likely due to a unique mutational spectrum separate from the recurring missense
Sources: Expert list

Created: 13 May 2020, 2:26 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hydrolethalus syndrome 236680

Publications

• PMID: 26830932