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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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