<scp>Non‐GAA</scp>Repeat Expansions in<scp>FGF14</scp>Are Likely Not Pathogenic—Reply to: “Shaking Up Ataxia:<scp>FGF14</scp>and<scp>RFC1</scp>Repeat Expansions in Affected and Unaffected Members of a Chilean Family”

Pellerin, David; Iruzubieta, Pablo; Tekgül, Şeyma; Danzi, Matt C.; Ashton, Catherine; Dicaire, Marie‐Josée; Wandzel, Marion; Roth, Virginie; Lamont, Phillipa; Bonnet, Céline; Renaud, Mathilde; Synofzik, Matthis; Züchner, Stephan; Brais, Bernard; Başak, A. Nazlı; Houlden, Henry

doi:10.1002/mds.29552

Cited by 9 publications

(7 citation statements)

References 10 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B). The AAGGAG expansion segregated in two affected individuals from a Spanish family but was present in only the index case but not the affected parent of a German family and was further considered as non-pathogenic, as already reported 6,7,17,18 .…”

Section: Resultsmentioning

confidence: 71%

“…So far, at least 40 different SCA subtypes, classified according to their underlying locus/genetic cause, have been reported 2 . This list includes repeat expansions of CAG trinucleotides encoding polyglutamine (PolyQ) repeats (SCA1, 2,3,6,7,12,17) as well as noncoding repeat expansions of penta-or hexanucleotides (SCA10, 12,31,36,37). Furthermore, point variants have been described in at least 28 distinct genes 1,2 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

Mohren,

Erdlenbruch,

Leitão

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Repeat expansions in theFGF14gene have recently been identified as a frequent cause of autosomal dominant late-onset cerebellar ataxia (SCA27B). The threshold for pathogenicity was estimated to range from 250 (incomplete penetrance) to 300 AAG repeats (full penetrance) based on expansion sizes observed in patients and controls. However, the full sequences of pathogenic and non-pathogenic alleles remain largely unknown. In this study, we used STRling and ExpansionHunter/STRipy to detect short tandem repeat expansions in short-read genome data of 80 patients with unsolved neurological disorders, including 48 patients from 39 unrelated families with cerebellar ataxia. Significant outlier values indicating a possibleFGF14repeat expansion were detected in 49% of families with ataxia. We used long-range PCR and repeat-primed PCR to confirm repeat motifs and number, and to further screen forFGF14repeat expansions in 106 additional patients. The distribution ofFGF14alleles was also analyzed in 802 control individuals. Long-range PCR amplicons from affected and control subjects with at least one expanded allele were sequenced by nanopore sequencing. Altogether, we report a total of 38 individuals from 31 families with a pure AAG expansion ≥250 repeats inFGF14(range: 254-937) out of 134 families with unsolved ataxia (23%). Four families had biallelic expansions. One individual showed mosaicism of the expansion, with two distinct large alleles detected. The overall distribution ofFGF14alleles significantly differs in patients and control subjects with pure expansions from 180 repeats being enriched in patients while AAGGAG and interrupted alleles were more frequent in controls. Expanded and non-expandedFGF14alleles were associated with different 5'-flanking regions correlating with repeat stability. Episodic symptoms of ataxia and downbeat nystagmus were frequent in patients with SCA27B independently of the repeat number. A family with a novel nonsense variant (NM_175929.3: c.239T > G; p.Leu80*; SCA27A) exhibited similar symptoms but earlier age at onset than patients with pathogenic expansions (SCA27B). In conclusion, this study reveals the complete sequence of pathogenic and non-pathogenicFGF14expansions. We suggest that pure AAG expansions are pathogenic from a lower threshold than previously reported, comprised between 180 and 220 pure AAG repeats, while full penetrance would be above 320-335 repeats. Interrupted expansions and expansions composed of other hexanucleotide repeats motifs are non-pathogenic. Diagnostic tests should thus include a complete sequencing of the expansion in addition to repeat number assessment. Finally, we provide mechanistic insights into how pure AAG repeat expansions could lead to adult-onset cerebellar ataxia.

show abstract

Section: Resultsmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

Mohren,

Erdlenbruch,

Leitão

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In fact, 88.9% of alleles longer than 250 repeat units in controls subjected to long‐read sequencing were identified to be GAA‐impure (Figure 1B). 32 To our knowledge, no studies have yet shown segregation of non‐GAA repeats with SCA27B 21,23,33,34 …”

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

“…As of today, since short‐read sequencing cannot accurately size FGF14 GAA expansions, 22 molecular testing for SCA27B relies on a bespoke targeted PCR‐based gene analysis to determine the length and purity of FGF14 GAA repeats 41 . With accumulating evidence suggesting that non‐GAA‐pure repeat expansions are likely non‐pathogenic for ataxia, 21,23,34 it becomes imperative to adopt standardised diagnostic strategies to diagnose SCA27B. One such strategy, which was found to compare favourably to long‐read sequencing and subsequently validated in a French cohort, relies on the combination of fragment length analysis of fluorescent long‐range PCR amplification products, bidirectional repeat‐primed PCRs, and, in some cases, agarose gel electrophoresis of long‐range PCR amplification products and/or Sanger sequencing 41 .…”

Section: Molecular Diagnosismentioning

confidence: 99%

Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

Pellerin,

Danzi,

Renaud

et al. 2024

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease‐modifying gene‐stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long‐read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)•(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult‐onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9–61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late‐onset slowly progressive pan‐cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4‐aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B.

show abstract

“…FGF14 repeat expansions were considered disease related with a repeat number > 250 [ 5 ]. Of note, patients with interrupted GAA repeat expansions/non-GAA repeat expansions were excluded [ 11 , 12 ].…”

mentioning

confidence: 99%

Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B

Borsche,

Thomsen,

Szmulewicz

et al. 2023

J Neurol

View full text Add to dashboard Cite

Non‐GAARepeat Expansions inFGF14Are Likely Not Pathogenic—Reply to: “Shaking Up Ataxia:FGF14andRFC1Repeat Expansions in Affected and Unaffected Members of a Chilean Family”

Cited by 9 publications

References 10 publications

Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B

Contact Info

Product

Resources

About