Expanding the Phenotypic Spectrum of TXNDC15 ‐Related Ciliopathies to Include Joubert Syndrome

ABSTRACT Biallelic loss‐of‐function variants in TXNDC15 are a known cause of the perinatally lethal ciliopathy Meckel syndrome (MKS). TXNDC15 encodes an endoplasmic reticulum (ER)‐resident thioredoxin‐domain protein required for ciliary transition zone integrity. Many ciliopathy genes show a spectrum of severity, producing a clinical continuum from lethal MKS to the less severe Joubert syndrome (JS). Using genome and exome sequencing analysis, we identified four unrelated children with JS who harbor rare biallelic variants in TXNDC15. In contrast to the biallelic truncating variants typical of MKS, all individuals with JS carried a missense variant in trans with a truncating variant. Three of four missense variants cluster within the functionally critical thioredoxin domain. In silico structural modeling using AlphaFold and variant effect prediction (AlphaMissense, DynaMut2) support a deleterious effect on protein stability and function for the majority of these missense variants. This work expands the phenotypic spectrum of TXNDC15 ‐related ciliopathies to include JS. All four individuals carried a missense allele in trans with a truncating allele. Our findings underscore the importance of including TXNDC15 in the genetic diagnosis of JS.

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Publication Details

Journal
American Journal of Medical Genetics Part A
Published
2026-10-05
DOI
https://doi.org/10.1002/ajmg.a.70317
Primary Topic
Genetic and Kidney Cyst Diseases
Type
article
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article

Expanding the Phenotypic Spectrum of TXNDC15 ‐Related Ciliopathies to Include Joubert Syndrome

Thomas M. Kitzler, Jennifer C. Dempsey, Praveen Dhondurao Sudhindar, Robert M. Geraghty et al.
American Journal of Medical Genetics Part A
Genetic and Kidney Cyst Diseases
article

Expanding the Phenotypic Spectrum of TXNDC15 ‐Related Ciliopathies to Include Joubert Syndrome

Thomas M. Kitzler, Jennifer C. Dempsey, Praveen Dhondurao Sudhindar, Robert M. Geraghty, Fulvio D’Abrusco, Bosanka Jocić-Jakubi, John Andrew Sayer, Zachary T. Sentell, Juliana Estefania Arcila-Galvis, Miguel Barroso‐Gil, Valentina Serpieri, Dan Doherty, Gabrielle Wheway, Enza Maria Valente, Eleanor G. Seaby, Kate Chandler, Sergio Foullerat Cañada
article en

Abstract

ABSTRACT Biallelic loss‐of‐function variants in TXNDC15 are a known cause of the perinatally lethal ciliopathy Meckel syndrome (MKS). TXNDC15 encodes an endoplasmic reticulum (ER)‐resident thioredoxin‐domain protein required for ciliary transition zone integrity. Many ciliopathy genes show a spectrum of severity, producing a clinical continuum from lethal MKS to the less severe Joubert syndrome (JS). Using genome and exome sequencing analysis, we identified four unrelated children with JS who harbor rare biallelic variants in TXNDC15. In contrast to the biallelic truncating variants typical of MKS, all individuals with JS carried a missense variant in trans with a truncating variant. Three of four missense variants cluster within the functionally critical thioredoxin domain. In silico structural modeling using AlphaFold and variant effect prediction (AlphaMissense, DynaMut2) support a deleterious effect on protein stability and function for the majority of these missense variants. This work expands the phenotypic spectrum of TXNDC15 ‐related ciliopathies to include JS. All four individuals carried a missense allele in trans with a truncating allele. Our findings underscore the importance of including TXNDC15 in the genetic diagnosis of JS.

American Journal of Medical Genetics Part A
University of Washington (US), University of Pavia (IT), Dar Al-Shifa Hospital (PS), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), McGill University Health Centre (CA), Manchester University NHS Foundation Trust (GB), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), Hospital Universitario 12 De Octubre (ES), NIHR Newcastle Biomedical Research Centre (GB), University of Southampton (GB), McGill University (CA), Newcastle University (GB)
Openalex Percentile: Top 13%
Genetic and Kidney Cyst Diseases
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