Skeletal Dysplasia_Fetal

Gene: HYLS1

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. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Amber rating on this panel as skeletal abnormalities including polydactyly and deformity of the skull base only described in those with the hydrolethalus phenotype, single founder variant and supporting functional data from multiple animal models all indicative of ciliopathy.

Created: 7 Aug 2020, 12:10 a.m. | Last Modified: 7 Aug 2020, 12:10 a.m.

Panel Version: 0.24

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hydrolethalus syndrome (MIM#236680)

Publications

• 15843405
• 18648327
• 19400947
• 19656802
• 32509774
• 26830932

I don't know

PMID: 34212369 - additional two fetuses with a phenotype of HLS with brain abnormalities, limbs malformations with pre and postaxial hexadactyly and abnormal genitalia. Probands were het for the Finnish founder variant (p.Asp211Gly) but each chet with a novel variant (p.(Arg221Pro, p.(Arg205*)). One fetus had occipital meningocele
molar tooth sign, the other craniorachischisis

Created: 16 Feb 2024, 4:54 a.m. | Last Modified: 16 Feb 2024, 4:54 a.m.

Panel Version: 0.212

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 MIM#236680

Publications

• PMID: 26830932
• 34212369
• 15843405
• 18648327
• 19400947
• 19656802
• 32509774