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Genotype-phenotype correlations
Short report
Novel HYLS1 variants associated with Joubert syndrome suggest potential genotype-phenotype correlates
  1. Simone Gana1,
  2. Fulvio D’Abrusco1,
  3. Roberta Nicotra2,3,
  4. Chiara Ghiberti2,
  5. Guido Catalano2,3,
  6. Elisa Rognone4,
  7. Anna Pichiecchio2,4,
  8. Sabrina Signorini3,
  9. Enza Maria Valente1,5
  1. 1 Neurogenetics Research Center, Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, Italy
  2. 2 Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Lombardia, Italy
  3. 3 Developmental Neuro-Ophthalmology Unit, Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, Italy
  4. 4 Department of Neuroradiology, Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, Italy
  5. 5 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  1. Correspondence to Professor Enza Maria Valente; enzamaria.valente{at}unipv.it

Abstract

Joubert syndrome (JS) is an inherited neurodevelopmental ciliopathy with wide clinical and genetic heterogeneity, whose paradigmatic sign is a peculiar cerebellar and brainstem malformation known as the ‘molar tooth sign’. Recessive pathogenic variants in the HYLS1 gene are associated with hydrolethalus syndrome (HLS), a severe disorder characterised by multiple developmental defects leading to intrauterine or perinatal death. However, HYLS1 biallelic variants were also reported in three individuals with JS.

Here, we report a fourth patient with a purely neurological JS carrying two compound heterozygous missense variants in the HYLS1 gene. Notably, while all patients with lethal HLS had both variants falling within the highly conserved HYLS-1 Box, the four patients with milder JS phenotype featured at least one variant external to this evolutionary conserved domain, suggesting a possible correlation between the mutation site and the severity of the phenotype.

  • Exome Sequencing

https://doi.org/10.1136/jmg-2024-110308

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    Footnotes

    • SG and FD’A are joint first authors.

    • SG and FD’A contributed equally.

    • Contributors SG and EMV performed the clinical evaluation, conceived the study and wrote the manuscript. FDA performed the genetic analysis and contributed to manuscript editing. RN, CG, GC and SS performed the clinical and neuropsychiatric evaluation and contributed to manuscript editing. ER and AP performed the neuroradiological evaluation and contributed to manuscript editing.

    • Funding This work has been funded by Italian Ministry of Health (RF-2019-12369368) and Telethon Foundation (GGP20070).

    • Competing interests The corresponding author EMV is an editor of the Journal of Medical Genetics.

    • Provenance and peer review Not commissioned; externally peer reviewed.