Locus FRAXG BCLAF3

Reported in a cohort of five males to date: intellectual disability was present in all, with epilepsy in at least 3/5 and autism spectrum disorder in at least 2/5¹. Of the three males with long-read sequencing and DNA methylation validation, two carried an independent primary diagnosis (Williams syndrome or Fragile X syndrome) in which the BCLAF3 expansion was invoked to explain features more severe than expected, so the phenotype of the expansion in isolation is not yet fully defined. This fragile site has also been implicated as a contributor to short stature².

Prevalence

Age of Onset

Onset of intellectual disability and developmental delay is early childhood and not precisely datable. Range refers to seizure onset, which ranged from 2.9-6 years¹.

HPO Terms

–

Association

Mendelian

Locus

hg19 chrX:20009040-20009091

hg38 chrX:19990922-19990973

t2t chrX:19573823-19573871

Details

The lower-bound of the pathogenic allele size range is based on the TRGT consensus, with the upper bound determined by the maximum mosaic size observed in the cohort¹. ONT reads in affected individuals exhibited evidence of mosaicism from 280 up to 1238 motifs. Repeat purity is relevant to phenotype and CCA interruptions may reduce transcriptional silencing: a male with 360-1,089 repeats carrying somatically mosaic CCA interruptions showed only partial hypermethylation and reduced rather than absent expression. In LaFlamme et al.¹the unaffected carrier mothers indicated X-linked recessive (XR) inheritance, but all three had X-inactivation skewed against the expanded allele, so no carrier has been observed under random X-linked inactivation. Three female probands with possible expansions have neurological phenotypes of unknown significance, and the authors suggest that a female without X-inactivation skewing could be affected, so XR inheritance is provisional¹. This individual was originally identified via outlier DNA methylation array analysis in a cohort of individuals with unsolved developmental and epileptic encephalopathy, with targeted EM-seq (enzymatic methylation sequencing, a bisulfite-free method for detecting 5-methylcytosine) validating hypermethylation and ONT long-read sequencing confirming the expansion³.

Mechanism

LoF

Expansion of the 5'UTR CCG repeat drives hypermethylation of the repeat and the surrounding CpG island and shore, coupled with a shift of the locus from open euchromatin (BRD4-positive) to closed heterochromatin (HP1a-positive) and loss of BCLAF3 RNA and protein. The expanded locus constitutes a folate-sensitive fragile site. Effects extend beyond the gene itself, with MAP7D2 (~125 kb away) significantly downregulated despite no change in its promoter methylation¹.

Detection

Short-read sequencing with ExpansionHunter has detected expansion carriers as clear outliers but underestimates the true allele size roughly 5-15 fold and may miss CCA interruptions. Long-read sequencing can size expansions and resolve methylation status. Genome-wide DNA methylation arrays have accurately detected the 5'UTR differentially methylated region as a rare outlier in males as a viable screening approach¹. Targeted EM-seq (enzymatic methylation sequencing) has also been used to validate hypermethylation at this locus³.

Year

2026¹

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

CCG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CCG

Pathogen. (gene)

CGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

CCA

Interrup. (gene)

TGG

References

Direct supporting references for info on this page.

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, 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

Genome medicine · 2026-07-22

pmid:42482100

Positional cloning of a novel heritable, rare, folate-sensitive fragile site (FRAXG) in Xp22.1 associated with short stature in a Finnish kindred and cloning of an associated candidate gene (FXGAG)

Shanxiang,Zhang

2002

url:https://api.semanticscholar.org/CorpusID:89799045

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Christy W,LaFlamme, Cassandra,Rastin, Soham,Sengupta, Helen E,Pennington, Sophie J,Russ-Hall, Amy L,Schneider, Emily S,Bonkowski, Edith P,Almanza Fuerte, Talia J,Allan, Miranda Perez-Galey,Zalusky, Joy,Goffena, Sophia B,Gibson, Denis M,Nyaga, Nico,Lieffering, Malavika,Hebbar, Emily V,Walker, Daniel,Darnell, Scott R,Olsen, Pandurang,Kolekar, Mohamed Nadhir,Djekidel, Wojciech,Rosikiewicz, Haley,McConkey, Jennifer,Kerkhof, Michael A,Levy, Raissa,Relator, Dorit,Lev, Tally,Lerman-Sagie, Kristen L,Park, Marielle,Alders, Gerarda,Cappuccio, Nicolas,Chatron, Leigh,Demain, David,Genevieve, Gaetan,Lesca, Tony,Roscioli, Damien,Sanlaville, Matthew L,Tedder, Sachin,Gupta, Elizabeth A,Jones, Monika,Weisz-Hubshman, Shamika,Ketkar, Hongzheng,Dai, Kim C,Worley, Jill A,Rosenfeld, Hsiao-Tuan,Chao, Geoffrey,Neale, Gemma L,Carvill, Zhaoming,Wang, Samuel F,Berkovic, Lynette G,Sadleir, Danny E,Miller, Ingrid E,Scheffer, Bekim,Sadikovic, Heather C,Mefford

Nature communications · 2024-08-06

pmid:39107278

Additional Literature

Additional literature related to this locus.