Name Fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency FXPOI/POF1

Inheritance

X-linked dominant

Description

A genetic syndrome caused by mutations in the FMR1 gene which is responsible for the expression of the fragile X messenger ribonucleoprotein 1 (FMR1) protein. This protein participates in neural development. This syndrome is manifested with mental, emotional, behavioral, physical, and learning disabilities. Any primary ovarian failure in which the cause of the disease is a mutation in the FMR1 gene. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia^1,2,3.

Prevalence

14 100,000

Incidence of full mutation in males 19/100,000; prevalence 14/100,000⁴. Female prevalence 9/100,000⁵. Known carrier frequency is approximately 300-500/100,000 but detected was 11/100,000⁶. FXS prevalence 1:7000 males, 1:11,000 females; FX premutation carriers 1:290-855 males, 1:148-300 females⁷. Found worldwide⁴. In Thailand, 1 in 600 women carry a premutation, and 1 in 400 carry a 'gray zone' allele⁸.

Age of Onset

Typical: FXS 1 to 'first several years of life', FXTAS 60-65⁴; Range: 0⁹- 78¹⁰; detailed description of typical symptom onset and diagnosis available from Arnold et al⁷.

HPO Terms

HP:0000020 Urinary incontinence HP:0000053 Macroorchidism HP:0000246 Sinusitis HP:0000256 Macrocephaly HP:0000275 Narrow face HP:0000276 Long face HP:0000280 Coarse facial features HP:0000298 Mask-like facies HP:0000303 Mandibular prognathia HP:0000365 Hearing impairment HP:0000388 Otitis media HP:0000389 Chronic otitis media HP:0000400 Macrotia HP:0000411 Protruding ear HP:0000486 Strabismus HP:0000639 Nystagmus HP:0000713 Agitation HP:0000716 Depression HP:0000717 Autism HP:0000722 Compulsive behaviors HP:0000726 Dementia HP:0000734 Disinhibition HP:0000737 Irritability HP:0000739 Anxiety HP:0000750 Delayed speech and language development HP:0000752 Hyperactivity HP:0000767 Pectus excavatum HP:0000802 Impotence HP:0000817 Reduced eye contact HP:0000821 Hypothyroidism HP:0000822 Hypertension HP:0000837 Increased circulating gonadotropin level HP:0000858 Irregular menstruation HP:0001152 Saccadic smooth pursuit interruptions HP:0001250 Seizure HP:0001251 Ataxia HP:0001252 Hypotonia HP:0001260 Dysarthria HP:0001265 Hyporeflexia HP:0001268 Mental deterioration HP:0001272 Cerebellar atrophy HP:0001288 Gait disturbance HP:0001300 Parkinsonism HP:0001310 Dysmetria HP:0001324 Muscle weakness HP:0001382 Joint hypermobility HP:0001634 Mitral valve prolapse HP:0001763 Pes planus HP:0002003 Large forehead HP:0002007 Frontal bossing HP:0002015 Dysphagia HP:0002020 Gastroesophageal reflux HP:0002050 Macroorchidism, postpubertal HP:0002063 Rigidity HP:0002066 Gait ataxia HP:0002067 Bradykinesia HP:0002075 Dysdiadochokinesis HP:0002080 Intention tremor HP:0002120 Cerebral cortical atrophy HP:0002167 Abnormal speech pattern HP:0002172 Postural instability HP:0002174 Postural tremor HP:0002194 Delayed gross motor development HP:0002322 Resting tremor HP:0002342 Moderate intellectual disability HP:0002345 Action tremor HP:0002354 Memory impairment HP:0002360 Sleep disturbance HP:0002363 Abnormal brainstem morphology HP:0002457 Abnormal head movements HP:0002506 Diffuse cerebral atrophy HP:0002607 Bowel incontinence HP:0002615 Hypotension HP:0002650 Scoliosis HP:0002839 Urinary bladder sphincter dysfunction HP:0003326 Myalgia HP:0003564 Folate-dependent fragile site at Xq28 HP:0004970 Ascending tubular aorta aneurysm HP:0006099 Metacarpophalangeal joint hyperextensibility HP:0006886 Impaired distal vibration sensation HP:0007010 Poor fine motor coordination HP:0007018 Attention deficit hyperactivity disorder HP:0007165 Periventricular heterotopia HP:0007340 Lower limb muscle weakness HP:0008209 Premature ovarian insufficiency HP:0008640 Congenital macroorchidism HP:0008770 Obsessive-compulsive trait HP:0009830 Peripheral neuropathy HP:0012083 Ubiquitin-positive cerebral inclusion bodies HP:0012169 Self-biting HP:0012332 Abnormal autonomic nervous system physiology HP:0012534 Dysesthesia HP:0030216 Inertia HP:0031629 Impaired tandem gait HP:0100023 Recurrent hand flapping HP:0100275 Diffuse cerebellar atrophy HP:0100515 Pollakisuria HP:0100716 Self-injurious behavior

Association

Mendelian

Locus

hg19 chrX:146993567-146993629

hg38 chrX:147912049-147912111

t2t chrX:146176677-146176769

Details

Intermediate or 'gray zone' alleles occur at 45-54 repeats and may be unstable enough to expand into the premutation range, as well as associate with parkinsonism^11,4. FXTAS/POI occurs at 55-200 repeats, FXS >200, late onset; AGG and CTG interruptions documented^4,12. Women with the premutation have been reported showing episodic memory deficits, similar to those seen in AD¹³. AGG interruptions are frequently reported in all associated diseases and appear to stabilize alleles; the length of the longest pure stretch predicts repeat instability¹⁴. Elevated POI risk was observed starting at 36 repeats, increasing continuously with repeat length¹⁵. In rare cases, FXS arises from mutations other than STR expansions, including gene deletions, nonsense, splicing, or frameshift mutations^16,17.

Mechanism

LoF/GoF

FXS: Loss of function via transcriptional silencing^18,19. FXTAS: RNA gain of function in FXTAS/FXPOI. RAN translation that creates the toxic protein FMRpolyG, which accumulates in ubiquitin-positive intranuclear inclusions^20,18,19. PRKGG appears to modulate neurotoxicity²¹.

Detection

Modern PCR techniques detect virtually all FMR1 expansion sizes, while RP-PCR detects AGG interspersions. Southern blotting has been used to approximate size and indicate methylation status⁴. Long-read sequencing has characterized repeat size, interruptions, methylation, and mosaicism^12,22,23.

Year

1992²⁴; causative gene discovered in 1991²⁵

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

CGG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CGG

Pathogen. (gene)

CGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

AGG, CTG

Interrup. (gene)

AGG, CTG

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0010383

Ontology Lookup Service (OLS)

mondo:0010706

Ontology Lookup Service (OLS)

mondo:0010382

FMR1 Disorders

Jessica Ezzell,Hunter, Elizabeth,Berry-Kravis, Heather,Hipp, Peter K.,Todd

GeneReviews® · 1993-01-01

genereviews:NBK1384

Epidemiology of fragile X syndrome: a systematic review and meta-analysis.

Jessica,Hunter, Oliver,Rivero-Arias, Angel,Angelov, Edward,Kim, Iain,Fotheringham, Jose,Leal

American journal of medical genetics. Part A · 2014-04-03

pmid:24700618

Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.

Haibao,Tang, Ewen F,Kirkness, Christoph,Lippert, William H,Biggs, Martin,Fabani, Ernesto,Guzman, Smriti,Ramakrishnan, Victor,Lavrenko, Boyko,Kakaradov, Claire,Hou, Barry,Hicks, David,Heckerman, Franz J,Och, C Thomas,Caskey, J Craig,Venter, Amalio,Telenti

American journal of human genetics · 2017-11-02

pmid:29100084

7isbn:978-3-031-66932-3

Population-based FMR1 carrier screening among reproductive women.

Quratul,Ain, Ye Hyun,Hwang, Daryl,Yeung, Pacharee,Panpaprai, Wiwat,Iamurairat, Wiboon,Chutimongkonkul, Objoon,Trachoo, Flora,Tassone, Poonnada,Jiraanont

Journal of assisted reproduction and genetics · 2024-09-25

pmid:39320553

UpToDate

url:https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents

CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS).

Flora,Tassone, John,Adams, Elizabeth M,Berry-Kravis, Susannah S,Cohen, Alfredo,Brusco, Maureen A,Leehey, Lexin,Li, Randi J,Hagerman, Paul J,Hagerman

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2007-06-05

pmid:17427188

Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death.

Deborah A,Hall, Sukriti,Nag, Bichun,Ouyang, David A,Bennett, Yuanqing,Liu, Aisha,Ali, Lili,Zhou, Elizabeth,Berry-Kravis

Movement disorders : official journal of the Movement Disorder Society · 2020-05-28

pmid:32463542

Detecting AGG Interruptions in Females With a FMR1 Premutation by Long-Read Single-Molecule Sequencing: A 1 Year Clinical Experience.

Simon,Ardui, Valerie,Race, Thomy,de Ravel, Hilde,Van Esch, Koenraad,Devriendt, Gert,Matthijs, Joris R,Vermeesch

Frontiers in genetics · 2018-05-16

pmid:29868108

Cognitive dysfunction in women with the

Jessica,Klusek, Jillian,Gierman, Amanda J,Fairchild, Andreana M,Benitez, Elizabeth,Berry-Kravis, Marsha R,Mailick

Journal of Alzheimer's disease : JAD · 2026-01-20

pmid:41555826

Length of uninterrupted CGG repeats determines instability in the FMR1 gene.

E E,Eichler, J J,Holden, B W,Popovich, A L,Reiss, K,Snow, S N,Thibodeau, C S,Richards, P A,Ward, D L,Nelson

Nature genetics · 1994-09-01

pmid:7987398

Large-scale analysis of FMR1 CGG repeat length and risk of premature ovarian insufficiency in over 92 000 women.

Emily J,Morbey, Felix R,Day, Daniel J,Wright, Jack R A,Murzynowski, Sinead M,McGlacken-Byrne, Anna,Murray, Ken K,Ong, John R B,Perry

Human reproduction (Oxford, England) · 2026-06-01

pmid:42001465

Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in

Cedrik,Tekendo-Ngongang, Angela,Grochowsky, Benjamin D,Solomon, Sho T,Yano

Genes · 2021-10-22

pmid:34828275

Two new cases of fragile X syndrome without CGG triplet expansion. Clinical-molecular characterization and review of the literature.

Giulia,Lauretti, Roberta,Pietrobono, Benedetta,Niccolini, Clarissa,Modafferi, Maria,Accadia, Ada,Piepoli, Daniela,Orteschi, Maria Grazia,Pomponi, Pietro,Chiurazzi, Maurizio,Genuardi, Giovanni,Neri, Elisabetta,Tabolacci

European journal of medical genetics · 2026-07-15

pmid:42456893

Diseases of unstable repeat expansion: mechanisms and common principles.

Jennifer R,Gatchel, Huda Y,Zoghbi

Nature reviews. Genetics · 2005-10-01

pmid:16205714

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.

Daria,Niewiadomska, Agnieszka,Piasecka, Anna,Baud, Izabela,Broniarek, Krzysztof,Sobczak

Nucleic acids research · 2026-06-08

pmid:42301916

Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome.

Yulin,Jin, Yiqu,Cao, Wenjing,Ma, Ronghua,Li, Yujing,Li, Yunhee,Kang, Jing,Huang, Michael P,Epstein, Xiangxue,Guo, Junghwa,Lim, Natalia,Rivera, Ying,Zhou, Zhexing,Wen, Emily G,Allen, Peng,Jin

Nature communications · 2026-01-08

pmid:41507195

22pmid:31740840

Establishment of a New-Generation National Reference Material System for Fragile X Syndrome Using Targeted Long-Read Sequencing.

Mi,Zhang, Wenxin,Zhang, Fei,Gao, Huiying,Fang, Li,Zhang, Yaning,Qi, Wei,Zhang, Peiwen,Xu, Jie,Li, Shoufang,Qu

Genes · 2026-06-02

pmid:42353815

Molecular studies of the fragile X syndrome.

S J,Knight, M C,Hirst, A,Roche, Z,Christodoulou, S M,Huson, R,Winter, M,Fitchett, M J,McKinley, R H,Lindenbaum, Y,Nakahori

American journal of medical genetics

pmid:1605194

Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.

A J,Verkerk, M,Pieretti, J S,Sutcliffe, Y H,Fu, D P,Kuhl, A,Pizzuti, O,Reiner, S,Richards, M F,Victoria, F P,Zhang

Cell · 1991-05-31

pmid:1710175

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)

Beyond Repeats: Intragenic Variants in FMR1 and Their Contribution to Fragile X Syndrome Pathogenesis

Abayomi,Latunji

Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria · 2026-06-30

pmid:42537027

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

DNA Methylation and Proteomic Profiling of Postmortem Brain Tissue Reveals Epigenetic Dysregulation and Neuroinflammatory in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).

Reymundo,Lozano, Xiao,Lin, Randi,Hagerman, Verónica Martínez,Cerdeño, Dalila,Pinto

bioRxiv : the preprint server for biology · 2026-07-10

pmid:42465430

Two new cases of fragile X syndrome without CGG triplet expansion. Clinical-molecular characterization and review of the literature.

European journal of medical genetics · 2026-07-15

pmid:42456893

Neonatal expression of human FMRP isoform corrects cortical deficits and improves behavior in a mouse model of fragile X syndrome.

Anna O,Norman, Courtney,Scaramella, Dominik,Biezonski, Ralph D,Hector, Alexandra,Varallo, Aarushi,Sahni, Nadia,Farooq, Suzanne R,Burstein, Juliana,Benito, Khaleel A,Razak, Jim,Selfridge, Stuart,Cobb, Iryna M,Ethell

Molecular therapy. Nucleic acids · 2026-06-12

pmid:42389555

Establishment of a New-Generation National Reference Material System for Fragile X Syndrome Using Targeted Long-Read Sequencing.

Mi,Zhang, Wenxin,Zhang, Fei,Gao, Huiying,Fang, Li,Zhang, Yaning,Qi, Wei,Zhang, Peiwen,Xu, Jie,Li, Shoufang,Qu

Genes · 2026-06-02

pmid:42353815

Intermediate FMR1 cytosine‒guanine‒guanine repeats do not impair assisted reproductive technology outcomes in a large real-world cohort.

Adi,Dayan-Schwartz, Nitzan Dana,Sela, Ido,Izhaki, Morad,Khayat, Shira,Baram, Ronit,Beck-Fruchter

Reproductive biomedicine online · 2026-05-20

pmid:42330760

Glymphatic dysfunction and neuroinflammation in FXTAS: evidence from DTI-ALPS and gene expression analysis.

Andrea,Elias-Mas, Esther Granell,Moreno, Cèlia Painous,Martí, Marta,Rubio-Roy, Jorge,Aguado-Gracia, Emma,Muñoz-Moreno, Alejandro,Hinojosa, Iñigo,Herrero, Maria Isabel,Alvarez-Mora, Randi,Hagerman, Jun Yi,Wang, Idoia,Zaro, Sofia González,Ortiz, Jerzy,Krupinski, Laia,Rodriguez-Revenga

Frontiers in molecular neuroscience · 2026-05-28

pmid:42325958

Structural Variant and Repeat Expansion Findings Identified by Optical Genome Mapping in Complex Autism Spectrum Disorder With Concomitant Neurodevelopmental Disorders.

Mehmet Burak,Mutlu, Özge Beyza Gündoğdu,Öğütlü, Özlem,Öz, Fahrettin,Duymuş, Serhat,Seyhan, Ayşe Gül Bayrak,Tokaç, Esad,Tezcan, Hakan,Öğütlü, Fatma,Demiryılmaz, Nurcan,Silahtarlıoğlu, Kader,Bilgil, Sümeyye,Elma, Murat,Erdoğan, Hakan,Gümüş, Sefer,Kumandaş, Fethiye,Kılıçaslan

Human mutation · 2026-06-11

pmid:42293335

Locus FXS FMR1

Disease

Locus

Alleles

gnomAD

References

Additional Literature