IRCCS Mondino Foundation
Published February 20, 2022 | Version v1
Dataset Open

Recurrent, founder and hypomorphic variants contribute to shaping the genetic landscape of Joubert syndrome

Authors/Creators

  • 1. IRCCS Mondino Foundation, Pavia (Italy)
  • 2. University of Pavia (Italy)
  • 3. University of Washington, Seattle (USA)
  • 4. IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo (Italy)
  • 5. IRCCS Bambino Gesù Children's Hospital, Rome (Italy)
  • 6. IRCCS Stella Maris Foundation, Pisa, (Italy); University of Pisa (Italy)
  • 7. IRCCS Ospedale Pediatrico Bambino Gesù, Rome (Italy)
  • 8. University Children's Hospital Zürich (Switzerland)
  • 9. IRCCS Mondino Foundation, Pavia; University of Pavia (Italy)
  • 10. Georg August University, Göttingen,(Germany)
  • 11. IRCCS Istituto Neurologico "C Besta", Milan, (Italy)
  • 12. Giovanni XXIII Children's Hospital, Bari (Italy)
  • 13. University of Naples Federico II (Italy)
  • 14. Regional Hospital of Bozen (Italy)

Description

Introduction: This database includes the raw data linked with the paper “Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome”. In this paper we reported eleven recurrent variants in seven distinct JS genes occurring in our large European JS cohort, including a previously unreported variant in KIAA0586 (c.1006C>T).

Methods: We evaluated the frequencies of these variants in our cohort of >500 European JS patients and compared them with controls (from three large Italian non-JS cohorts and from the gnomAD database), and with an independent cohort of about 600 JS probands from the United States.

Results: All variants were markedly enriched in the European JS cohort compared to all controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazi Jewish founder variant (TMEM216 c.218G>T) was significantly enriched in American JS compared to European JS patients, while the MKS1 c.1476T>G variant was about ten times more frequent among European JS. Frequencies of all remaining variants were comparable in the two cohorts. Genotyping of several microsatellite markers across the gene loci in carriers of seven variants identified four novel founder haplotypes. Of note, MKS1 c.1476T>G was consistently detected in compound heterozygosity with deleterious variants in JS patients, while it was found in homozygosity in an unaffected parent. Functional studies on fibroblasts from this healthy carrier and her affected son showed a similarly reduced percentage of ciliated cells compared to unaffected controls, but much shorter cilia in the patient than in the unaffected homozygous parent, consistent with a hypomorphic effect.

Notes

Funding: Ricerca Corrente 2021 and Ricerca Finalizzata, Ministry of Health (Italy); Italian Ministry of University and Research; Telethon

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Additional details

Related works

Is published in
Journal article: 10.1136/jmg-2022-108725 (DOI)