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The HYLS1 gene, traditionally linked with hydrolethalus syndrome, has now been implicated in Joubert syndrome based on multiple lines of evidence. Notably, a case report described living siblings with Joubert syndrome harboring a homozygous no‑stop mutation in HYLS1, expanding its phenotypic spectrum from the typically lethal malformation to a non‑lethal, neurodevelopmental phenotype (PMID:26830932). This observation was significant because the affected siblings exhibited characteristic midline brain anomalies including agenesis of the cerebellar vermis (HP:0002335).
In addition, a multi‑patient study that evaluated a cohort of 22 Joubert syndrome patients also identified a HYLS1 variant among several causative genes. Although HYLS1 was not the most common culprit in that cohort, its presence in a patient with Joubert syndrome underlines its role in the genetic heterogeneity of ciliopathies (PMID:36580738). The report corroborated traditional genetic approaches by emphasizing how variants in HYLS1 can contribute to a milder, yet clinically significant, phenotype in contrast to the lethal variant found in hydrolethalus syndrome.
Another independent study further strengthened this association by reporting compound heterozygous missense variants in HYLS1 in a patient with Joubert syndrome. The investigators noted that the variant distribution relative to the evolutionarily conserved HYLS-1 Box might modulate the severity of the phenotype, thereby hinting at a potential genotype‑phenotype correlation (PMID:39626953). This finding supports the notion that not all HYLS1 mutations carry an identical clinical risk, and subtle differences in their molecular nature can pivot the clinical outcome between hydrolethalus syndrome and Joubert syndrome.
Genetic evidence has been bolstered further by the detailed description of the variant NM_145014.2:c.900A>C (p.Ter300TyrextTer11) identified in the affected siblings. This variant, which disrupts the stop codon, is especially compelling given that it appears to permit the translation of an elongated protein product with aberrant function that aligns with the ciliopathy features observed in Joubert syndrome (PMID:26830932). The precision in variant characterization using HGVS nomenclature underscores its clinical utility for diagnostic decision‑making.
Functional studies in HYLS1‐related disorders have provided mechanistic insights into how disruption of primary cilia formation and signaling can result in neural developmental anomalies. Specifically, experiments demonstrated that HYLS1 mutations can misdirect cellular protein localization and disturb ciliary assembly, thereby corroborating the clinical findings of cerebellar and brainstem malformations common to Joubert syndrome (PMID:34162535, PMID:19400947).
Collectively, these converging genetic and functional assessments indicate that the HYLS1 variant spectrum can be broader than previously thought, with clear evidence supporting its association with Joubert syndrome. The genetic evidence—from familial segregation in living siblings to observations in broader patient cohorts—and the corresponding functional assays all coalesce around a unified pathway involving ciliary dysfunction.
This integrated evidence not only refines our understanding of HYLS1 in the pathogenesis of ciliopathies but also carries significant implications for diagnostic evaluation, prognostication, and potential future therapeutic targeting in Joubert syndrome. Key take‑home: HYLS1 variants are now recognized as an important contributor to the Joubert syndrome spectrum, providing a critical marker for clinical genetic testing in ciliopathy diagnostics.
Gene–Disease AssociationStrongMultiple independent case reports and multi‑patient studies (including evidence in living siblings [PMID:26830932] and cohort analyses [PMID:36580738]) support a robust association between HYLS1 and Joubert syndrome, further augmented by genotype‑phenotype correlations ([PMID:39626953]). Genetic EvidenceStrongThe identification of a unique no‑stop mutation (c.900A>C) in affected siblings and confirmation in additional patient cohorts establishes solid genetic evidence for HYLS1’s role in Joubert syndrome. Functional EvidenceModerateCellular and animal model studies demonstrating disrupted ciliogenesis and altered protein localization in HYLS1 mutants provide mechanistic support that is consistent with the clinical ciliopathy phenotype observed in Joubert syndrome ([PMID:34162535], [PMID:19400947]). |