| Title: | Comprehensive Assessment of the KDM2B-Associated Neurodevelopmental Disorder and the 12q24.31 Microdeletion Syndrome |
| Journal: | Clinical Genetics |
| Published: | 9 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41954311/ |
| DOI: | https://doi.org/10.1111/cge.70169 |
Publication 18048
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Abstract
The recently delineated KDM2B-associated neurodevelopmental disorder (NDD) is characterized by developmental delay and variable co-morbidity. Genotype-phenotype correlations are emerging, in particular a distinct clinical presentation caused by CxxC domain variants. We report here a novel intragenic deletion which leads to in vitro expression of a shortened KDM2B protein lacking the complete CxxC domain. In addition, we present data on 12 other individuals; two with larger 12q24.31 microdeletions, one with a frameshift variant, and nine with missense variants. We analyzed genotype-phenotype correlations of this cohort combined with previously reported individuals (n = 68) and classify 37 variants in 47 individuals as pathogenic or likely pathogenic. We observe a highly penetrant CxxC-related phenotype with distinct facial features supported by GestaltMatcher. In contrast, our findings point to variable expressivity and incomplete penetrance of loss-of-function variants and JmjC domain variants complicating variant classification and genetic counseling. We identify KDM2B as a strong contributor to the 12q24.31 microdeletion syndrome, while also addressing the role of additional genes in the region. Thus, our study defines the KDM2B-NDD's clinical spectrum and highlights the importance of integrating molecular, (epi)genetic, and phenotypic data in NDD diagnostics.</p>
31 Authors
- Amber S. E. van Oirsouw
- Tzung-Chien Hsieh
- Martijn Koetsier
- Abdulrazak Alali
- Fatimah Albuainain
- Elena Bacchelli
- Tahsin Stefan Barakat
- Yline Capri
- Sandra Chantot-Bastaraud
- Valeria Capra
- Deanna Alexis Carere
- Emma Clement
- Nour Elkhateeb
- Madeleine Franchi
- Jing-Mei Li
- Nicole Matthews
- Vanda McNiven
- Sarju G. Mehta
- Masayuki Nakamura
- Chanika Phornphutkul
- Nicole Revencu
- Marcello Scala
- Natalie Shallow
- Jennifer Stefanich
- Marta Viggiano
- Paola Visconti
- Susan Walker
- Federico Zara
- Mariëlle Alders
- Bobby P. C. Koeleman
- Renske Oegema
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health