Locus FRA12A DIP2B

FRA12A is a rare, folate-sensitive chromosomal fragile site on chromosome 12 associated with intellectual developmental disorder, FRA12A type. Impaired intellectual development with or without other anomalies has been described in patients with over 40% of cells expressing FRA12A¹. The DIP2B CGG repeat expansion causes this folate-sensitive site and is associated with a broad phenotypic range, including intellectual disability, ataxia/movement disorder, and epilepsy^2,3,4; cardiovascular associations have also been reported⁵.

Prevalence

Appears to occur in those of European ancestry/ethnicity¹.

Age of Onset

Typical: 0-1 (small sample size)⁶. Range: 0-3⁷.

HPO Terms

–

Association

Mendelian

Locus

hg19 chr12:50898784-50898807

hg38 chr12:50505001-50505024

t2t chr12:50468095-50468118

Details

Repeat ranges reflect affected and unaffected individuals from a cohort study of 70 controls (6-23 repeats), unaffected carriers representing the intermediate alleles (139-206), and affected individuals (273-306)³. It has been hypothesized that unmethylated expansions may correspond to movement-related phenotypes (chorea, dystonia, and ataxia)².

Mechanism

LoF

Hypermethylation leading to decreased expression, although unmethylated expansion leads to increased expression^1,8.

Detection

Short-read sequencing can underestimate expansion size. RP-PCR and Southern blotting detect expansions [@pmid:17236128], while long-read sequencing has been reported to accurately size them [@pmid:39854091].

Year

2007³

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

GGC

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GGC

Pathogenic (gene)

CGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

References

Direct supporting references for info on this page.

1omim:136630

Disco-Interacting Protein 2 Homolog B CGG Repeat Expansion in Siblings with Neurodevelopmental Disability and Progressive Movement Disorder.

Emilie T,Théberge, Kate,Durbano, Diane,Demailly, Sophie,Huby, Aleksandra,Mitina, Yue,Yin, Arezoo,Mohajeri, Clara,van Karnebeek, Gabriella A,Horvath, Ryan K C,Yuen, Karen,Usdin, Anna,Lehman, Laura,Cif, Phillip A,Richmond

Movement disorders : official journal of the Movement Disorder Society · 2025-01-24

pmid:39854091

CGG-repeat expansion in the DIP2B gene is associated with the fragile site FRA12A on chromosome 12q13.1.

Birgitta,Winnepenninckx, Kim,Debacker, Jacqueline,Ramsay, Dominique,Smeets, Arie,Smits, David R,FitzPatrick, R Frank,Kooy

American journal of human genetics · 2006-12-12

pmid:17236128

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome.

Farah,Qaiser, Tara,Sadoway, Yue,Yin, Quratulain,Zulfiqar Ali, Charlotte M,Nguyen, Natalie,Shum, Ian,Backstrom, Paula T,Marques, Sepideh,Tabarestani, Renato P,Munhoz, Timo,Krings, Christopher E,Pearson, Ryan K C,Yuen, Danielle M,Andrade

Brain communications · 2021-09-14

pmid:34622207

Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy.

Aleksandra,Mitina, Mahreen,Khan, Robert,Lesurf, Yue,Yin, Worrawat,Engchuan, Omar,Hamdan, Giovanna,Pellecchia, Brett,Trost, Ian,Backstrom, Keyi,Guo, Linda M,Pallotto, Phoenix Hoi,Lam Doong, Zhuozhi,Wang, Thomas,Nalpathamkalam, Bhooma,Thiruvahindrapuram, Tanya,Papaz, Christopher E,Pearson, Jiannis,Ragoussis, Padmaja,Subbarao, Meghan B,Azad, Stuart E,Turvey, Piushkumar,Mandhane, Theo J,Moraes, Elinor,Simons, Stephen W,Scherer, Jane,Lougheed, Tapas,Mondal, John,Smythe, Luis,Altamirano-Diaz, Erwin,Oechslin, Seema,Mital, Ryan K C,Yuen

EBioMedicine · 2024-02-27

pmid:38418263

A family with craniofrontonasal dysplasia, and fragile site 12q13 segregating independently.

D,Kumar, J W,Clark, C E,Blank, M A,Patton

Clinical genetics · 1986-06-01

pmid:3742859

Heritable fragility at 11q13 and 12q13.

D F,Smeets, J M,Scheres, T W,Hustinx

Clinical genetics · 1985-08-01

pmid:4042396

Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.

Warren A,Cheung, Adam F,Johnson, William J,Rowell, Emily,Farrow, Richard,Hall, Ana S A,Cohen, John C,Means, Tricia N,Zion, Daniel M,Portik, Christopher T,Saunders, Boryana,Koseva, Chengpeng,Bi, Tina K,Truong, Carl,Schwendinger-Schreck, Byunggil,Yoo, Jeffrey J,Johnston, Margaret,Gibson, Gilad,Evrony, William B,Rizzo, Isabelle,Thiffault, Scott T,Younger, Tom,Curran, Aaron M,Wenger, Elin,Grundberg, Tomi,Pastinen

Nature communications · 2023-05-29

pmid:37248219

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

No Evidence for an Association Between DIP2B Repeat Expansion and Neurological Disease.

Chia-Ying,Ko, Leon,Schütz, Thomas,Braun, Elena,Buena-Atienza, Nicolas,Casadei, Danique,Beijer, Ludger,Schöls, Tobias B,Haack, Stephan,Ossowski, Holger,Hengel

Movement disorders : official journal of the Movement Disorder Society · 2026-05-28

pmid:42205056

Transcriptome and Genome Analysis Uncovers a

Chiara,Folland, Vijay,Ganesh, Ben,Weisburd, Catriona,McLean, Andrew J,Kornberg, Anne,O'Donnell-Luria, Heidi L,Rehm, Igor,Stevanovski, Sanjog R,Chintalaphani, Paul,Kennedy, Ira W,Deveson, Gianina,Ravenscroft

Neurology. Genetics · 2023-03-14

pmid:37090938