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Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton Deleted their review
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton Deleted their comment
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton changed review comment from: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion.
Ronco et al., 2023 PMID: 36289003
7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings.
Weber et al., 2023 PMID: 36478048
2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Benkirane et al. 2022 PMID: 35883251
2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Arteche-López et al., 2023 PMID:36250766
2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
King et al., 2022 PMID: 36524104
1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS.

Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.; to: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion.
Ronco et al., 2023 PMID: 36289003
7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings.
Weber et al., 2023 PMID: 36478048
2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Benkirane et al. 2022 PMID: 35883251
2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Arteche-López et al., 2023 PMID:36250766
2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
King et al., 2022 PMID: 36524104
1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS.

Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36289003, 36478048, 35883251, 36250766, 36524104; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM: 614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v7.19 RFC1_AAGGG Sarah Leigh Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Hereditary ataxia with onset in adulthood v7.18 RFC1_AAGGG Sarah Leigh edited their review of STR: RFC1_AAGGG: Added comment: Pathogenicity at the RFC1_AAGGG repeat locus can result from the biallelic replacement of the benign AAAAG repeat with a variable number of AAGGG repeats (PMID: 30926972; 32040566). Furthermore, biallelic expansions of (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp were not pathogenic, therefore, it is the biallelic expansions of AAGGG that is pathogenic (PMID: 30926972). An additional pathogenic biallelic expansion :RFC1_ACAGG, was seen in was seen in two Asia-Pacific CANVAS families and a Japanese case (PMID: 33103729, 35355059).; Changed publications to: 30926972, 35883251, 36250766, 36289003, 36524104, 36478048, 32040566, 33103729, 35355059
Hereditary ataxia with onset in adulthood v7.18 RFC1_AAGGG Sarah Leigh STR: RFC1_AAGGG was added
STR: RFC1_AAGGG was added to Hereditary ataxia with onset in adulthood. Sources: Literature
STR, NGS Not Validated tags were added to STR: RFC1_AAGGG.
Mode of inheritance for STR: RFC1_AAGGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Phenotypes for STR: RFC1_AAGGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM: 614575
Review for STR: RFC1_AAGGG was set to GREEN
Added comment: RFC1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

RFC1_AAGGG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

RFC1_AAGGG is on https://stripy.org/database

RFC1_AARRG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02 and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
The coordinates of the sequence repeats from https://stripy.org/database were 4:39348424-39348485 (hg38)
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
And https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary ataxia with onset in adulthood v4.22 RFC1 Sarah Leigh Deleted their comment
Hereditary ataxia with onset in adulthood v4.11 RFC1 Sarah Leigh commented on gene: RFC1: Five recent papers (PMID: 35883251; 36250766; 36289003; 36524104; 36478048) report nine RFC1 pathogenic variants in trans with the RFC1_AAGGG expansion variant in at least nine unrelated cases. To date such variants have not been detected in the absence of the RFC1_AAGGG, which is why this gene is rated as Red in PanelApp. Detection of the RFC1_AAGGG expansion variant must be validated within the Genomics England pipeline and will be added to PanelApp in due course.
Hereditary ataxia with onset in adulthood v4.11 RFC1 Sarah Leigh reviewed gene: RFC1: Rating: RED; Mode of pathogenicity: None; Publications: 35883251, 36250766, 36289003, 36524104, 36478048; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia with onset in adulthood v4.11 RFC1 Sarah Leigh Phenotypes for gene: RFC1 were changed from Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335 to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome, MONDO:0044720
Hereditary ataxia with onset in adulthood v4.10 RFC1 Sarah Leigh Publications for gene: RFC1 were set to 30926972; 31824583; 32851396; 32582864; 33969391
Hereditary ataxia with onset in adulthood v4.9 RFC1 Joseph Shaw reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 35883251, 36250766, 36289003, 36524104, 36478048; Phenotypes: Ataxia, Neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Classified gene: RFC1 as Red List (low evidence)
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Added comment: Comment on list classification: Changing the rating from amber to red so that it is clear that this gene should not be added to the panel as it is an STR within an intron of this gene that is associated with the neuropathy phenotype.
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Gene: rfc1 has been classified as Red List (Low Evidence).
Hereditary ataxia with onset in adulthood v2.133 RFC1 Dmitrijs Rots changed review comment from: Only STR in this gene is associated with CANVAS / ataxia. Addition of this gene to the panel will result only in unnecessary load of RFC1 SNV/indel/CNV analysis, which are not related to human disorder.; to: Only STR in this gene is associated with CANVAS / ataxia. Addition of this gene to the panel will result only in unnecessary load of RFC1 SNV/indel/CNV analysis, which are not related to human disorder.
Additionallly, RFC1 repeat expansion, is commonly associated with sensory neuropathy (at the moment of presentation usually without clinically prominent ataxia) ,so the STR should be added to the neuropathy panel as well, not just ataxia (PMID: 33969391).
Hereditary ataxia with onset in adulthood v2.133 RFC1 Dmitrijs Rots reviewed gene: RFC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Classified gene: RFC1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but noting that it is repeat expansions within an intron that is associated with the CANVAS phenotype, not SNVs within the protein coding region. Added to the list of STRs to be added.
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Gene: rfc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.132 RFC1 Eleanor Williams Phenotypes for gene: RFC1 were changed from Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575 to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335
Hereditary ataxia with onset in adulthood v2.131 RFC1 Eleanor Williams Publications for gene: RFC1 were set to 30926972
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams Tag STR tag was added to gene: RFC1.
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams changed review comment from: The gene is associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) #614575 (AR) with two repeat expansions cited as the allelic variants.

PMID: 30926972 - Cortese et al 2019 - found a recessive intronic AAGGG repeat expansion in the RFC1 gene as a cause of familial CANVAS in 11 families. 4 SNPs around RFC1 were shared by all individuals except in family 5, suggesting a founder haplotype. They found an additional 33 sporadic cases carrying the recessive AAGGG repeat expansion in a cohort of 150 patients diagnosed with sporadic late-onset ataxia (22%). They also note that all sporadic cases with the repeat expansion, except for one individual, shared the same haplotype as familial CANVAS cases. Although the expansion size varied across different families, ranging from around 400 to 2000 repeats, in the majority of cases approximately 1000 repeats were observed. In 304 healthy controls, 4/608 chromosomes (0.7%) chromosomes carried an AAGGG expansion in the heterozygous state. 3 other conformations were observed: (AAAAG)11 (75.5%); (AAAAG)exp(13.0%); and (AAAGG)exp (7.9%). They did not observe a reduced level of RFC1 expression at either the transcript or the protein level in CANVAS patients.

PMID: 31824583 - Akçimen et al 2019 - looked at RFC1 repeat expansions in cohort of Brazilian cases and two cohorts of Canadian cases. 1 Brazilian and 1 Canadian case were found to carry the causative biallelic AAGGG repeat expansion. Two novel repeat sequences were found in the heterozygous state; AAGAG and AGAGG.

PMID: 32851396 - Beecroft et al 2020 - describe a (AAAGG)10-25(AAGGG)exp found in New Zealand Māori and Cook Island Māori individuals which was the cause of CANVAS in all patients. Patients in 2 families also had small number of repeats of the benign variant allele (AAAGG)4-6 at the distal end of the RFC1 pathogenic expansion. The 4 patients with WGS data were found to share the same core haplotype as described in European populations in Cortese et al 2019, plus an additional region.

PMID: 32582864 - Syriani et al 2020 - 29 patients from North America were identified with biallelic repeat expansions in RFC1 (AAGGG) (3.2% of total). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%).

PMID: 33969391 - Curro et al 2021 - retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy). Patients previously diagnosed with CANVAS or with a family history of CANVAS were not included. 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.; to: The gene is associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) #614575 (AR) with two repeat expansions cited as the allelic variants.

There is data to suggest a common haplotype between most cases but this appears to be quite ancient (25000 yo) and so the cases from individuals from different countries can probably be counted as being unrelated. The mechanism of action of this intronic repeat expansion is not yet known.

= AAGGG repeat expansion =

PMID: 30926972 - Cortese et al 2019 - found a recessive intronic AAGGG repeat expansion in the RFC1 gene as a cause of familial CANVAS in 11 families. 4 SNPs around RFC1 were shared by all individuals except in family 5, suggesting a founder haplotype. They found an additional 33 sporadic cases carrying the recessive AAGGG repeat expansion in a cohort of 150 patients diagnosed with sporadic late-onset ataxia (22%). They also note that all sporadic cases with the repeat expansion, except for one individual, shared the same haplotype as familial CANVAS cases. Although the expansion size varied across different families, ranging from around 400 to 2000 repeats, in the majority of cases approximately 1000 repeats were observed. In 304 healthy controls, 4/608 chromosomes (0.7%) chromosomes carried an AAGGG expansion in the heterozygous state. 3 other conformations were observed: (AAAAG)11 (75.5%); (AAAAG)exp(13.0%); and (AAAGG)exp (7.9%). They did not observe a reduced level of RFC1 expression at either the transcript or the protein level in CANVAS patients.

PMID: 31824583 - Akçimen et al 2019 - looked at RFC1 repeat expansions in cohort of Brazilian cases and two cohorts of Canadian cases. 1 Brazilian and 1 Canadian case were found to carry the causative biallelic AAGGG repeat expansion. Two novel repeat sequences were found in the heterozygous state; AAGAG and AGAGG.

PMID: 31230722 - Rafehi et al 2019 - bioinformatics paper looking at using Expansion Hunter de novo on WGS data but also reports RFC1 (AAGGG)exp in 18/22 CANVAS families. Also states that the core ancestral haplotype is estimated to have arisen in Europe more than twenty-five thousand years ago.

PMID: 32851396 - Beecroft et al 2020 - describe a (AAAGG)10-25(AAGGG)exp found in New Zealand Māori and Cook Island Māori individuals which was the cause of CANVAS in all patients. Patients in 2 families also had small number of repeats of the benign variant allele (AAAGG)4-6 at the distal end of the RFC1 pathogenic expansion. The 4 patients with WGS data were found to share the same core haplotype as described in European populations in Cortese et al 2019, plus an additional region.

PMID: 32582864 - Syriani et al 2020 - 29 patients from North America were identified with biallelic repeat expansions in RFC1 (AAGGG) (3.2% of total). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%).

PMID: 32694621 - Tsuchiya et al 2020 - found intronic (AAGGG) repeat expansions in RFC1 in 3 (12%) of the familial Japanese patients with CANVAS and 1 (8.5%) of the sporadic ones.

PMID: 33969391 - Curro et al 2021 - retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy). Patients previously diagnosed with CANVAS or with a family history of CANVAS were not included. 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.

= ACAGG repeat expansion =

PMID: 33103729 - Scriba et al 2020 - report 3 patients with CANVAS from 2 families (2 brothers who reside in Indonesia, but are of Chinese descent, and a isolated female proband from the island nation of Niue) , with a novel, likely pathogenic RFC1 repeat motif (ACAGG)exp. These patients show additional clinical features including fasciculations and elevated creatine kinase levels. They share the core haplotype described in Cortese et al 2019 and Beecroft et al 2020. The RFC1 (ACAGG) motif was found in 7 individuals from 26 745 samples from gnomAD v3; 2 African, 4 South Asian, 1 East Asian.

PMID: 32694621 - Tsuchiya et al 2020 - reports a RFC1 (ACAGG) exp in 1 Japanese individual with sporadic CANVAS.
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30926972, 31824583, 32851396, 32582864, 33969391; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575, cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809, chronic idiopathic axonal polyneuropathy, chronic polyneuropathy, MONDO:0003335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.126 RFC1 Michael Bonello reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32582864, 31824583, 33969391; Phenotypes: CANVAS Syndrome, Cerebellar ataxia, Idiopathic Sensory Neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia with onset in adulthood v2.17 RFC1 Zornitza Stark edited their review of gene: RFC1: Added comment: A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families reported in PMID 33103729. Both of these need to be added as STRs but I haven't quite figured out how to do it!; Changed publications: 30926972, 33103729
Hereditary ataxia with onset in adulthood v2.8 RFC1 Zornitza Stark gene: RFC1 was added
gene: RFC1 was added to Hereditary ataxia - adult onset. Sources: Expert Review
Mode of inheritance for gene: RFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC1 were set to 30926972
Phenotypes for gene: RFC1 were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575
Mode of pathogenicity for gene: RFC1 was set to Other
Review for gene: RFC1 was set to GREEN
gene: RFC1 was marked as current diagnostic
Added comment: 23 affected individuals from 11 families reported with biallelic AAGGG repeat expansion in intron 2. Expansion carrier frequency of 0.7% in Europeans.
Sources: Expert Review