Preprint
Characterization of CTNND2-related neurodevelopmental disease, phenotype-genotype spectrum and WNT dynamics in early neurogenesis
Research square
12/30/2025
DOI: 10.21203/rs.3.rs-8224288/v1
PMCID: PMC12772691
PMID: 41502569
Abstract
Heterozygous variants in
, encoding the brain-specific protein δ-catenin, are associated with a broad spectrum of neurodevelopmental disorders, including dyslexia, attention deficit hyperactivity disorder, intellectual disability, and autism. Despite its clinical significance, the full phenotypic spectrum of
-associated disorders and the neurodevelopmental role of δ-catenin, a key component of the cadherin-catenin cell adhesion complex, remain poorly defined.
Through international collaboration, we assembled the phenotypic and molecular information for 57 individuals, 42 previously unpublished, carrying heterozygous
variants. All individuals were evaluated by local clinicians, and the variants were identified through exome or genome sequencing, clinical microarray, or karyotyping. To investigate the effects of δ-catenin loss on early neurogenesis, we performed neural differentiation and transcriptomic profiling in three patient-derived neural stem cell lines and three CRISPR-Cas9-generated
knockout lines. In one patient-derived line, we further analyzed cerebral organoid development and performed pathway modulation to assess phenotypic rescue.
The 41
variants included 12 previously reported loss-of-function- and one missense variant, and 28 novel variants comprising 10 missense and 18 predicted loss-of-function changes. Eight of the novel variants occurred
, and 12 were inherited from a parent with a neurodevelopmental phenotype. The most common clinical features were developmental delay (90%), intellectual disability (74%), and behavioral abnormalities (79%). Functional studies revealed impaired early neurogenesis in one patient-derived line, characterized by aberrant neural rosette formation. Transcriptome analysis showed dysregulated WNT signaling, and partial rescue of these defects was achieved by modulating the WNT pathway, highlighting δ-catenin's role in early neural development.
This study defines the clinical symptoms of
-related neurodevelopmental disorders, outlining a recognizable yet variable phenotype that overlaps with other forms of intellectual disability and autism. Our findings provide preliminary evidence of genotype-phenotype correlations and highlight δ-catenin's critical role in modulating WNT signaling during early neural development. These insights advance our understanding of
-associated disorders and support the importance of mechanistic studies to inform personalized diagnostics and therapies.
Details
- Title: Subtitle
- Characterization of CTNND2-related neurodevelopmental disease, phenotype-genotype spectrum and WNT dynamics in early neurogenesis
- Creators
- Mansoureh Shahsavani - Karolinska InstitutetJosephine Wincent - Karolinska InstitutetRicarda Reiter - Johannes Kepler University of LinzAndrea Soltysova - Comenius University BratislavaJakob Schuy - Karolinska InstitutetHafdis T Helgadottir - Karolinska InstitutetJesper Eisfeldt - Karolinska University HospitalMarlene Ek - Karolinska InstitutetAndrej Ficek - Comenius University BratislavaLotta Druschke - Karolinska InstitutetKatarina Kusikova - Comenius University BratislavaTzung-Chien Hsieh - University of BonnAron Krichhoff - University Hospital BonnPeter Krawitz - University Hospital BonnJing-Mei Li - University Hospital BonnGerald Webersinke - Ordensklinikum Linz Barmherzige SchwesternSvetlana Gorokhova - Hôpital de la TimoneChantal Missirian - Hôpital de la TimoneFlorence Riccardi - Aix-Marseille UniversitéLisa Pavinato - Ospedale Regionale di Bellinzona e ValliAlfredo Brusco - University of TurinGiorgia Mandrile - University of TurinSlavica Trajkova - University of TurinFrancesco Pintus - University of TurinBiljana Gagachovska - University of Ss. Cyril and Methodius in TrnavaQuinten Waisfisz - Vrije Universiteit AmsterdamAnnet van Hagen - Amsterdam University Medical CentersEmma Bedoukian - Children's Hospital of PhiladelphiaKosuke Izumi - Children's Hospital of PhiladelphiaLeslie Granger - University Medical Center UtrechtAndrea Petersen - University Medical Center UtrechtRenske Oegema - University Medical Center UtrechtManon Huibers - University Medical Center UtrechtFlorence Demurger - Centre hospitalier Bretagne AtlantiqueElise Brischoux-Boucher - Université Marie et Louis PasteurSophie Julia - Charmo UniversityGuillaume Banneau - Charmo UniversityM Jesus Zavala - Universidad del Desarrollo del Estado de PueblaCatalina Lagos - Universidad del Desarrollo del Estado de PueblaGabriela M Repetto - Universidad del Desarrollo del Estado de PueblaGuillaume Jouret - Laboratoire National de SantéCatherine Kentros - Columbia UniversityMythily Ganapathi - Columbia University Irving Medical CenterWendy K Chung - Harvard UniversityHalie May - Columbia University Irving Medical CenterSusan M Hiatt - Huntsville HospitalWhitley V Kelley - Huntsville HospitalAlisa Förster - Medizinische Hochschule HannoverLisa Olfe - Medizinische Hochschule HannoverAmelle Shillington - University of Cincinnati Medical CenterBenjamin Dauriat - Hôpital Mère-EnfantSandra Mercier - Centre Hospitalier Universitaire de NantesBenjamin Cogné - Centre Hospitalier Universitaire de NantesCamille Engel - Université Bourgogne Franche-ComtéEric Dahlen - Centre Hospitalier Universitaire de BesançonGeorg Rosenberger - Universität HamburgThomas Sauvigny - Universität HamburgHamza Hadj Abdallah - Hôpital Necker-Enfants MaladesThomas Courtin - Hôpital Necker-Enfants MaladesAsbjørg Stray-Pedersen - Oslo University HospitalJohn A Bernat - University of IowaVitoria K Paolillo - Children's Mercy HospitalFlorencia Del Viso - Children's Mercy HospitalJoseph T Alaimo - Children's Mercy HospitalIsabelle Thiffault - Children's Mercy HospitalEmily G Farrow - Children's Mercy HospitalAna S A Cohen - Children's Mercy HospitalSerge Weis - Johannes Kepler University of LinzHans-Christoph Duba - Johannes Kepler University of LinzAnn Nordgren - Karolinska InstitutetAnna Falk - Karolinska InstitutetDenisa Weis - Johannes Kepler University of LinzAnna Lindstrand - Karolinska Institutet
- Resource Type
- Preprint
- Publication Details
- Research square
- DOI
- 10.21203/rs.3.rs-8224288/v1
- PMID
- 41502569
- PMCID
- PMC12772691
- NLM abbreviation
- Res Sq
- ISSN
- 2693-5015
- eISSN
- 2693-5015
- Language
- English
- Date posted
- 12/30/2025
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9985116811802771
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