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Background <p>Tandem 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 <i>BCLAF3</i> in males with neurodevelopmental disorders.</p> Methods <p>We used patient-derived fibroblasts and neuronal models from a family with <i>BCLAF3</i> repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with <i>BCLAF3</i> repeat expansions, we screened methylation arrays (<i>n</i> = 12,375) and short-read genomes (<i>n</i> = 15,963) from probands with neurodevelopmental presentations. We also characterized <i>BCLAF3</i> repeat expansions in the general population using long-read sequencing data (<i>n</i> = 793) and population-level short-read sequencing data (<i>n</i> = 410,076).</p> Results <p>Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed <i>BCLAF3</i> RNA and protein expression. We show that the <i>BCLAF3</i> 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 (<i>n</i> = 2) or short-read sequencing predicted (<i>n</i> = 2) repeat expansions. In one family, the <i>BCLAF3</i> 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 <i>BCLAF3</i> repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than <i>FMR1</i> repeat expansions.</p> Conclusions <p>CCG repeat expansions in the 5’UTR of <i>BCLAF3</i> 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年7月22日

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  • 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,
  • Sourav Ghosh,
  • Bharati Jadhav,
  • Taralynn Mack,
  • Jiadong Lin,
  • Sophia B. Gibson,
  • Johanna M. van Hagen,
  • Mariëlle Alders,
  • Alexandra Martin-Geary,
  • Bida Gu,
  • Mira Kharbanda,
  • Siddharth Banka,
  • Helen M. Stuart,
  • Andrew R. Webster,
  • Akimoto Hosokawa,
  • Harriet Dashnow,
  • Richa Bajpai,
  • Shondra M. Pruett-Miller,
  • Mark J.P. Chaisson,
  • Danny E. Miller,
  • Nicola Whiffin,
  • Evan E. Eichler,
  • Sanjay M. Sisodiya,
  • Henry Houlden,
  • Andrew J. Sharp,
  • Bekim Sadikovic,
  • Marc Valentine,
  • Lynette G. Sadleir,
  • Arianna Tucci,
  • Heather C. Mefford

摘要

Background

Tandem 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.

Methods

We 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).

Results

Long-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.

Conclusions

CCG 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.