Evidence map›Paper›PMID 42482100›Full record

ArticleGenome medicine2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

Christy W LaFlamme, Chris Clarkson, Kristina Ibañez, Jin-Yuan Wang, Soham Sengupta, Jenny Lord, Virginia Valentine, Emily S Bonkowski, Edith P Almanza Fuerte, Athena R Olszewski and 29 more

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Article in Genome medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

39 authors.

Christy W LaFlammeDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Chris ClarksonClinical Pharmacology and Precision Medicine, School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
Kristina IbañezClinical Pharmacology and Precision Medicine, School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
Jin-Yuan WangDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Soham SenguptaDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Jenny LordSheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, UK.
Virginia ValentineCytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
Emily S BonkowskiDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Edith P Almanza FuerteDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Athena R OlszewskiDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Sourav GhoshDepartment of Pathology & Laboratory Medicine, Western University, London, ON, N5A 3K7, Canada.
Bharati JadhavDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Taralynn MackDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Jiadong LinDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Sophia B GibsonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Johanna M van HagenDepartment of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Mariëlle AldersDepartment of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, Netherlands.
Alexandra Martin-GearyBig Data Institute, University of Oxford, Oxford, UK.
Bida GuDepartment of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
Mira KharbandaUniversity Hospital Southampton NHS Foundation Trust, Southampton, UK.
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Helen M StuartManchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
Andrew R WebsterInstitute of Ophthalmology, University College London, 11-43 Bath Street, London, UK.
Akimoto HosokawaDepartment of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
Harriet DashnowDepartment of Biomedical Informatics, School of Medicine, University of Colorado Anschutz, Aurora, CO, USA.
Richa BajpaiCenter for Advanced Genome Engineering, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Shondra M Pruett-MillerCenter for Advanced Genome Engineering, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Mark J P ChaissonDepartment of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
Danny E MillerDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
Nicola WhiffinBig Data Institute, University of Oxford, Oxford, UK.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Sanjay M SisodiyaDepartment of Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
Andrew J SharpDepartment of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bekim SadikovicDepartment of Pathology & Laboratory Medicine, Western University, London, ON, N5A 3K7, Canada.
Marc ValentineCytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
Lynette G SadleirDepartment of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
Arianna TucciClinical Pharmacology and Precision Medicine, School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
Heather C MeffordDepartment of Genomic and Translational Neuroscience, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Heather.Mefford@stjude.org.

Funding

Sporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2M
NIMH NIH HHS R01 MH101221
6 · The paper itself

Abstract

backgroundTandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders.

methodsWe used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076).

resultsLong-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions.

conclusionsCCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

Indexed as

Neurodevelopmental DisordersTrinucleotide Repeat Expansion5' Untranslated RegionsDNA MethylationHumansMaleMultiomics5' Untranslated RegionsBCLAF3DNA methylationRepeat expansions

Identifiers

PMID42482100

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.