Fetal anomalies
Gene: HYLS1 Green List (high evidence)Green List (high evidence)
ClinGen classification: Moderate
HYLS1 was first reported in relation to autosomal recessive hydrolethalus in 2005 (Mee et al., PMID: 15843405). This is often a fatal fetal condition that results in stillbirth, or death shortly after birth. Prenatal features have been identified as early as the first trimester, and phenotypes include FGR (fetal growth restriction), brain anomalies, skeletal features (like femoral bowing and polydactyly/syndactyly), congenital heart disease, and genital anomalies. The most frequent features of this condition in probands with the founder missense mutation include hydrocephalus, small mandible, polydactyly, congenital heart defects, and respiratory anomalies. Affected probands compound heterozygous for the recurrent missense variant and another missense or nonsense variant have also been reported. Three variants (missense, nonsense) that have been reported in over 40 probands in 3 publications (PMIDs: 15843405, 18648327, 34212369) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. There were also two homozygous stop loss variants reported in 2 probands from 2 publications (PMID: 26830932, 36580738), but these were not scored because the phenotype does not fully match that of the other cases and and their disease mechanism similarity cannot be confirmed. This gene-disease relationship is also supported by experimental evidence (mouse model, drosophila model, expression-level data, interaction evidence, cell culture evidence, functional alteration evidence; PMIDs: 15843405, 19656802, 32509774, 40009365). Homozygous mutant mice exhibit perinatal lethality, brain anomaly, polydactyly, and kidney complications. The drosophila model showed ciliary dysfunction and atypical spermatogenesis in mutants. The gene is widely expressed in mice, including in specific brain regions such as the medulla. HYLS1 interacts with SAS-4 (CENPJ), which is definitively associated with autosomal recessive microcephaly 6 with/without short stature. Other experimental evidence indicates the key role of HYLS1 in centriole stability and ciliogenesis. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 8/06/2025 (SOP Version 11).Created: 14 Aug 2025, 11:32 p.m. | Last Modified: 14 Aug 2025, 11:32 p.m.
Panel Version: 1.388
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hydrolethalus syndrome MONDO:0006037
Green List (high evidence)
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.
Overall, sufficient evidence that variants in this gene cause a ciliopathy.Created: 6 Aug 2020, 11:47 p.m. | Last Modified: 14 Jan 2022, 10:26 p.m.
Panel Version: 0.2257
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hydrolethalus syndrome (MIM#236680); Ciliopathy
Publications
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 listCreated: 13 May 2020, 2:26 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hydrolethalus syndrome 236680
Publications
Gene: hyls1 has been classified as Green List (High Evidence).
Phenotypes for gene: HYLS1 were changed from HYDROLETHALUS SYNDROME TYPE 1 to Hydrolethalus syndrome (MIM#236680); Ciliopathy
Publications for gene: HYLS1 were set to
Tag founder tag was added to gene: HYLS1.
gene: HYLS1 was added gene: HYLS1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: HYLS1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HYLS1 were set to HYDROLETHALUS SYNDROME TYPE 1
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.