Spinocerebellar ataxia type 4 (SCA4) is a very rare progressive subtype of type I autosomal dominant cerebellar ataxia (ADCA type I) characterized by ataxia with sensory neuropathy (adapted from Mondo)¹.

Prevalence

Observed in 20 families, all with a Swedish founder background^2,3,4. A common ancestral allele has been identified⁵.

Age of Onset

Typical: 37 - 56; Range: 12 - 65^6,7.

Association

Mendelian

Locus

hg19chr16:72821593-72821657

hg38chr16:72787694-72787758

t2tchr16:78605502-78605569

Details

Disease-causing expansions range from 46 repeats⁷to 74 repeats⁸. Possible anticipation in disease^9,8; intermediate alleles may correspond to premutations⁷. Most unaffected individuals had 21 motifs, but benign alleles range from 14-26 repeats⁸. Normal alleles are interrupted. In ~3,200 European alleles, nearly all carried ≥1 synonymous GGT, and most also carried a missense interruption of AGT, AGC, GAC or AAT¹⁰. pathogenicity depends on length (>41) and an uninterrupted GGC tract¹⁰.

Mechanism

GoF?

Polyglycine protein gain of function mechanism theorized¹¹.

Detection

Year

2023⁸

Location in Gene

Coding, Last Exon (exon number is transcript dependent)

Gene Strand

Alleles

Ref. Motif

CCG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CCG

Pathogen. (gene)

CGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0010847

2omim:600223

Frequency of ZFHX3-Mediated Spinocerebellar Ataxia 4 in a US Undiagnosed Ataxia Cohort.

Annie,Chen, Udbhav,Avadhani, Kathie,Ngo, Rosario I,Corona, George de V Carvalho,Neto, Karla P,Figueroa, Susan,Perlman, Stefan M,Pulst, Stanley F,Nelson, Darice,Wong, Brent L,Fogel

Movement disorders : official journal of the Movement Disorder Society · 2026-06-03

pmid:42236257

Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients.

Paula,Saffie-Awad, Abraham,Moller, Kensuke,Daida, Pilar,Alvarez Jerez, Zhongbo,Chen, Zachary B,Anderson, Mariam,Isayan, Kimberly,Paquette, Sophia B,Gibson, Madison,Fulcher, Abigail,Miano-Burkhardt, Laksh,Malik, Breeana,Baker, Paige,Jarreau, Henry,Houlden, Mina,Ryten, Bida,Gu, Mark J P,Chaisson, Danny E,Miller, Pedro,Chaná-Cuevas, Cornelis,Blauwendraat, Andrew B,Singleton, Kimberley J,Billingsley

Movement disorders : official journal of the Movement Disorder Society · 2025-06-03

pmid:40459184

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.

Zhongbo,Chen, Pilar,Alvarez Jerez, Claire,Anderson, Martin,Paucar, Jasmaine,Lee, Daniel,Nilsson, Hannah,Macpherson, Annarita,Scardamaglia, Kylie,Montgomery, John,Hardy, Andrew B,Singleton, Arianna,Tucci, Katherine D,Mathews, Ying-Hui,Fu, Martin,Engvall, José,Laffita-Mesa, Inger,Nennesmo, Anna,Wedell, Louis J,Ptáček, Cornelis,Blauwendraat, Emil K,Gustavsson, Per,Svenningsson, Mina,Ryten, Henry,Houlden

Movement disorders : official journal of the Movement Disorder Society · 2024-12-05

pmid:39635987

6pmid:39666847

Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.

Martin,Paucar, Daniel,Nilsson, Martin,Engvall, José,Laffita-Mesa, Cilla,Söderhäll, Mikael,Skorpil, Christer,Halldin, Patrik,Fazio, Kristina,Lagerstedt-Robinson, Göran,Solders, Maria,Angeria, Andrea,Varrone, Mårten,Risling, Hong,Jiao, Inger,Nennesmo, Anna,Wedell, Per,Svenningsson

Journal of internal medicine · 2024-07-07

pmid:38973251

Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.

Joel,Wallenius, Efthymia,Kafantari, Emma,Jhaveri, Sorina,Gorcenco, Adam,Ameur, Christin,Karremo, Sigurd,Dobloug, Kristina,Karrman, Tom,de Koning, Andreea,Ilinca, Maria,Landqvist Waldö, Andreas,Arvidsson, Staffan,Persson, Elisabet,Englund, Hans,Ehrencrona, Andreas,Puschmann

American journal of human genetics · 2023-11-29

pmid:38035881

Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.

Zhongbo,Chen, Emil K,Gustavsson, Hannah,Macpherson, Claire,Anderson, Chris,Clarkson, Clarissa,Rocca, Eleanor,Self, Pilar,Alvarez Jerez, Annarita,Scardamaglia, David,Pellerin, Kylie,Montgomery, Jasmaine,Lee, Delia,Gagliardi, Huihui,Luo, John,Hardy, James,Polke, Andrew B,Singleton, Cornelis,Blauwendraat, Katherine D,Mathews, Arianna,Tucci, Ying-Hui,Fu, Henry,Houlden, Mina,Ryten, Louis J,Ptáček

Movement disorders : official journal of the Movement Disorder Society · 2024-01-10

pmid:38197134

Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.

Zoe N,Zussa, Andrew N,Smith, Joke J F A,van Vugt, Daniel S,O'Shaughnessy, Natalie,Grima, Sandrine,Chan Moi Fat, Ian P,Blair, Dominic B,Rowe, Roger,Pamphlett, Garth A,Nicholson, Matthew C,Kiernan, Wouter,van Rheenen, Jan,Veldink, Kelly L,Williams, Lyndal,Henden

Journal of human genetics · 2026-09-15

pmid:42736322

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Karla P,Figueroa, Caspar,Gross, Elena,Buena-Atienza, Sharan,Paul, Mandi,Gandelman, Naseebullah,Kakar, Marc,Sturm, Nicolas,Casadei, Jakob,Admard, Joohyun,Park, Christine,Zühlke, Yorck,Hellenbroich, Jelena,Pozojevic, Saranya,Balachandran, Kristian,Händler, Simone,Zittel, Dagmar,Timmann, Friedrich,Erdlenbruch, Laura,Herrmann, Thomas,Feindt, Martin,Zenker, Thomas,Klopstock, Claudia,Dufke, Daniel R,Scoles, Arnulf,Koeppen, Malte,Spielmann, Olaf,Riess, Stephan,Ossowski, Tobias B,Haack, Stefan M,Pulst

Nature genetics · 2024-04-29

pmid:38684900

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)

Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic strategy.

Jin-Yang,Yu, Yi-Min,Sun, Yi,Dong, Jian-Jun,Wu, Chen-Hao,Zhu, Yi-Chu,Du, Yi-Xin,Zhang, Yue,Zhang, Sheng-Mei,Zou, Yin,Ma, Hai-Lin,Dong, Zhi-Ying,Wu

Translational neurodegeneration · 2026-09-29

pmid:42806408

Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.

Journal of human genetics · 2026-09-15

pmid:42736322

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.

Hannes,Erdmann, Annalisa,Schaub, Morghan C,Lucas, Veronika,Scholz, Anna,Benet-Pagès, Kerstin,Becker, Christine,Dineiger, Veronika,Mayer, Inga,van Buren, Eva,Breithausen, Karl,Akbari, Isabell,Cordts, Mayra,Sauer, Christine,Schneider, Rosanna,Krakowsky, Franziska,Schnabel, Konstanze,Dunker, Lena,Fabritius, Johannes,Gerb, Denis,Grabova, Ken,Möhwald, Marius,Näher, Karoline,Steinmetz, Franziska,Thiessen, Alexander,Jäck, Christiane,Schneider-Gold, Simone,Zittel, Christina,Petersen, Isolde,Schreyer, Larissa,Mämecke, Sibylle,Wilfling, Gilbert,Wunderlich, David,Brenner, Yorck,Hellenbroich, Kirsten,Muhle, Tessa,Huchtemann, Inga,Claus, Thomas,Klopstock, Michael,Strupp, Johannes,Levin, Günter U,Höglinger, Doreen,Huppert, Sandra,Becker-Bense, Filipp,Filippopulos, Fabian,Kilpert, Elsa,Leitão, Sabine,Kaya, Christel,Depienne, Florian,Schöberl, Teresa,Neuhann, Elke,Holinski-Feder, Andreas,Zwergal, Angela,Abicht

Brain : a journal of neurology · 2026-03-05

pmid:40898875

Feasibility of long-read sequencing to identify molecular alterations in an Indonesian cohort of locally advanced to advanced nasopharyngeal cancer.

,Handoko, Marlinda,Adham, Lisnawati,Rachmadi, Demak Lumban,Tobing, ,Asmarinah, ,Fadilah, Wei,Dai, Anne Wing Mui,Lee, Soehartati A,Gondhowiardjo

Scientific reports · 2025-07-01

pmid:40594369

Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.

Wai Yan,Yau, Roisin,Sullivan, Emer,O'Connor, David,Pellerin, Michael H,Parkinson, Paola,Giunti, Marie-Josée,Dicaire, Matt C,Danzi, Stephan,Züchner, Bernard,Brais, Nicholas W,Wood, Henry,Houlden, Jana,Vandrovcova

Brain communications · 2025-05-17

pmid:40488180

Identification of GGC Repeat Expansions in

Paula,Saffie-Awad, Abraham,Moller, Kensuke,Daida, Pilar Alvarez,Jerez, Zhongbo,Chen, Zachary B,Anderson, Mariam,Isayan, Kimberly,Paquette, Sophia B,Gibson, Madison,Fulcher, Abigail,Miano-Burkhardt, Laksh,Malik, Breeana,Baker, Paige,Jarreau, Henry,Houlden, Mina,Ryten, Bida,Gu, Mark Jp,Chaisson, Danny E,Miller, Pedro,Chaná-Cuevas, Cornelis,Blauwendraat, Andrew B,Singleton, Kimberley J,Billingsley

medRxiv : the preprint server for health sciences · 2025-03-19

pmid:40166539

Repeat length in spinocerebellar ataxia type 4 (SCA4) predicts age at onset and disease severity.

Andreas,Dalski, Martje G,Pauly, Henrike,Hanssen, Johann,Hagenah, Yorck,Hellenbroich, Christian,Schmidt, Jassemien,Strohschehn, Malte,Spielmann, Christine,Zühlke, Norbert,Brüggemann

Journal of neurology · 2024-08-02

pmid:39095619

FGF14 GAA repeat expansion and ZFHX3 GGC repeat expansion in clinically diagnosed multiple system atrophy patients.

Masaaki,Matsushima, Hiroaki,Yaguchi, Eriko,Koshimizu, Akihiko,Kudo, Shinichi,Shirai, Takeshi,Matsuoka, Shigehisa,Ura, Atsushi,Kawashima, Toshiyuki,Fukazawa, Satoko,Miyatake, Naomichi,Matsumoto, Ichiro,Yabe

Journal of neurology · 2024-03-12

pmid:38472396

Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients.

Luiz Eduardo,Novis, Shahryar,Alavi, David,Pellerin, Marcus Vinicius,Della Coleta, Salmo,Raskin, Mariana,Spitz, Andrea,Cortese, Henry,Houlden, Helio Afonso,Teive

Parkinsonism & related disorders · 2023-12-20

pmid:38145611

Locus SCA4 ZFHX3

Disease

Locus

Alleles

References

Additional Literature