HYLS1 – Hydrolethalus syndrome

This summary synthesizes evidence linking HYLS1 to hydrolethalus syndrome, a rare, lethal malformation disorder characterized by severe brain malformations. Multiple clinical reports and case series have consistently implicated biallelic, autosomal recessive mutations in HYLS1 in the pathogenesis of this disorder (PMID:26830932, PMID:18648327).

Genetic evidence is robust. In several independent studies, homozygous and compound heterozygous variants in HYLS1 have been reported. A notable recurrent variant, c.632A>G (p.Asp211Gly), has been observed in multiple probands across unrelated families (PMID:18648327, PMID:34212369). This variant was selected as a representative marker of the mutation spectrum observed in these patients.

Functional studies support a pathomechanism that centralizes HYLS1 in the regulation of ciliogenesis. Experimental assays have demonstrated that mutations in HYLS1 lead to aberrant protein localization and impaired primary cilium assembly, which is consistent with the clinical phenotype of hydrolethalus syndrome (PMID:15843405, PMID:34162535).

In addition, segregation data from familial case reports, including living siblings with the mutation, reinforce autosomal recessive inheritance and the critical role of HYLS1 in disease manifestation (PMID:26830932). The co‐segregation of the HYLS1 variant with disease across different families further substantiates its pathogenic impact.

Collectively, the genetic and experimental evidence is coherent. Studies involving over 21 probands provide strong case-level data, and functional investigations affirm that a disruption in HYLS1 function leads to the severe developmental defects observed in hydrolethalus syndrome. The integration of multi‐patient investigations with mechanistic cell and animal models elevates the confidence in this gene–disease relationship.

Key take‑home sentence: The strong association between HYLS1 mutations, particularly c.632A>G (p.Asp211Gly), and hydrolethalus syndrome underpins its clinical utility in diagnosis, further guiding genetic counseling and potential therapeutic research.

References

• Clinical Genetics • 2016 • A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome PMID:26830932
• Journal of Neuropathology and Experimental Neurology • 2008 • Hydrolethalus syndrome: neuropathology of 21 cases confirmed by HYLS1 gene mutation analysis PMID:18648327
• Clinical Genetics • 2021 • The first two non-Finnish HYLS1 variants: Expanding the phenotypic spectrum of hydrolethalus syndrome PMID:34212369
• Human Molecular Genetics • 2005 • Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1 PMID:15843405
• Science Advances • 2021 • Ciliopathy protein HYLS1 coordinates the biogenesis and signaling of primary cilia by activating the ciliary lipid kinase PIPKIγ PMID:34162535

Evidence Based Scoring (AI generated)