A common flanking variant is associated with enhanced meiotic stability of the<i>FGF14</i>-SCA27B locus

Pellerin, David; Gobbo, Giulia; Couse, Madeline; Dolzhenko, Egor; Dicaire, Marie‐Josée; Rebelo, Adriana P.; Roth, Virginie; Wandzel, Marion; Bonnet, Céline; Ashton, Catherine; Lamont, Phillipa; Laing, Nigel G.; Renaud, Mathilde; Ravenscroft, Gianina; Houlden, Henry; Synofzik, Matthis; Eberle, Michael A.; Boycott, Kym M.; Pastinen, Tomi; Brais, Bernard; Züchner, Stephan; Danzi, Matt C.

doi:10.1101/2023.05.11.540430

Cited by 6 publications

(14 citation statements)

References 9 publications

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“…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%

“…(A) Diagram of the FGF14 gene, isoform 1b showing the location of the (GAA) n •(TTC) n repeat locus in the first intron (GRCh38, chr13:102,161,575‐102,161,726) with representation of the normal alleles, alleles of uncertain pathogenicity, incompletely penetrant alleles, pathogenic alleles and likely non‐pathogenic non‐GAA‐pure alleles, such as (GAAGGA)n n and [(GAA) n (GCA) m ] z . (B) Swarm plot showing the allele distribution of the FGF14 repeat locus in 2191 non‐ataxic controls (4382 chromosomes) as assessed by PacBio HiFi long‐read sequencing 32 . The colour of the data points is a function of the GAA repeat motif purity, with dark blue indicating pure and lighter blue impure/interrupted motif (a hue scale is shown on the right y axis).…”

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

“…The high degree of motif variation observed at this locus further complicates efforts to identify the pathogenic threshold. Long‐read sequencing of close to 2200 controls has revealed a wide variety of alternative motifs present at the SCA27B locus, particularly at longer allele lengths 32 . Many of these alternative motifs have GAA interleaved with other triplets at regular intervals, such as [(GAA) 4 (GCA) 1 ] n .…”

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

“…The SCA27B locus also exhibits high levels of intergenerational instability, dependent on the length and GAA purity of the tandem repeat 21,32 . GAA‐pure tracts longer than 75 repeat units most often expand upon maternal transmission and contract upon paternal transmission, with the degree of instability increasing proportional to GAA tract length 21,32 . The significant instability of the FGF14 GAA repeat locus upon intergenerational transmission likely explains in part the high incidence of sporadic cases of SCA27B, varying between 15 and 50% 21,30,35 .…”

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

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

Pellerin,

Danzi,

Renaud

et al. 2024

Clinical & Translational Med

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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.

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Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

See 3 more Smart Citations

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

Pellerin,

Danzi,

Renaud

et al. 2024

Clinical & Translational Med

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

et al. 2023

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Challenges facing repeat expansion identification, characterisation, and the pathway to discovery

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Davies,

Thompson

et al. 2023

Emerging Topics in Life Sciences

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Tandem repeat DNA sequences constitute a significant proportion of the human genome. While previously considered to be functionally inert, these sequences are now broadly accepted as important contributors to genetic diversity. However, the polymorphic nature of these sequences can lead to expansion beyond a gene-specific threshold, causing disease. More than 50 pathogenic repeat expansions have been identified to date, many of which have been discovered in the last decade as a result of advances in sequencing technologies and associated bioinformatic tools. Commonly utilised diagnostic platforms including Sanger sequencing, capillary array electrophoresis, and Southern blot are generally low throughput and are often unable to accurately determine repeat size, composition, and epigenetic signature, which are important when characterising repeat expansions. The rapid advances in bioinformatic tools designed specifically to interrogate short-read sequencing and the development of long-read single molecule sequencing is enabling a new generation of high throughput testing for repeat expansion disorders. In this review, we discuss some of the challenges surrounding the identification and characterisation of disease-causing repeat expansions and the technological advances that are poised to translate the promise of genomic medicine to individuals and families affected by these disorders.

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A common flanking variant is associated with enhanced meiotic stability of theFGF14-SCA27B locus

Cited by 6 publications

References 9 publications

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

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

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

Challenges facing repeat expansion identification, characterisation, and the pathway to discovery

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