Log in
Back to feed

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

Marina Boon Meghan R. Mulligan Jolijn J A Verseput B. Šakić Pleuni Schreurs Mireia Coll-Tané A. Accogli Emily Alderman T. Athey Cornelius F. Boerkoel Antonella Boni R. Caumes E. Gerkes Sabine Haase S. Jaillard L. Jeffries Peter Kannu M. Konstantino Jonathan Lévy A. Lokchine Maarten P G Massink N. Samra R. Oegema Marcello Scala J. Schieving S. Schwartzmann H. Sczakiel T. Smol P. Striano A. Verloes Amber Begtrup R. Pfundt Barbara Franke Marieke Klein Annette Schenck L. Bicknell B. D. de Vries
Aug 2026 · American Journal of Human Genetics · 0 citations · 71 references
Medicine

TL;DR

An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Abstract

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

DOI PubMed Semantic Scholar
View source

Similar papers

Case report Open access Jul 2026

Intrafamilial Variability in NRXN1-Associated Neurodevelopmental Disorders: Clinical and Genetic Insights from a Family Case Study with Literature Review

The concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context is supported, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences.

N. Kastratović, Marina Gazdić Janković, Marina Miletić Kovačević et al. · 0 citations
Open access Jun 2026

Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder

Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males, and its pathogenicity was evaluated using a molecular dynamic simulation and transgenic Drosophila models.

Kazuyuki Komatsu, Atsushi Sugie, Yohei Nitta et al. · 1 citation
Jul 2026

Heterozygous RNF13 Truncating Variants Are Associated With Developmental and Epileptic Encephalopathy.

A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.

D. Latner, S. Hiatt, C. Finnila et al. · 0 citations
Review Aug 2026

Identifying the Potential Role of Missense KIRREL3 Variants in Neurodevelopmental Phenotypes: A Case Series.

Neurodevelopmental disorders encompass a large group of conditions, many of which can be explained by genetic variants. KIRREL3 has previously been associated with neurodevelopmental disorders and is expressed in the developing human basal ganglia and amygdala. Through GeneMatcher, which allows clinicians, families, and researchers to share information about novel gene variants, and the Simons Foundation Powering Autism Research (SPARK) project, we identified 26 individuals with different rare missense variants in KIRREL3, which were predicted to be damaging based on their REVEL score. All probands had neurodevelopmental diagnoses including autism spectrum disorder, global developmental delay, intellectual disability, or a learning disability. A full review of previous publications identified 10 rare KIRREL3 missense variants in 13 individuals who had at least one diagnosis of an autism spectrum disorder or intellectual disability. These findings highlight the potential role of KIRREL3 missense variants in neurodevelopmental disorders, which warrants further study.

Priyanka R Narayan, Sabah Sabir, Divya Jayvas et al. · 0 citations
Open access Aug 2026

Dominant truncating variants in KAT6A cause two neurodevelopmental disorders with opposite gene regulatory and metabolic changes.

Using patient-derived iPSCs and multi-omics profiling, it is demonstrated that early-truncating variants cause loss-of-function via nonsense-mediated decay (NMD), while late-truncating variants that escape NMD cause gain-of-function effects.

A. Nava, Y. Pérez-Rodríguez, T. Hsieh et al. · 0 citations