Reduced penetrance of intermediate size alleles in spinocerebellar ataxia type 10

Alonso, Isabel; Jardim, Laura Bannach; Artigalás, Osvaldo Alfonso Pinto; Saraiva-Pereira, Maria Luiza; Matsuura, Tetsuya; Ashizawa, Tetsuo; Sequeiros, Jorge; Silveira, Isabel

doi:10.1212/01.wnl.0000216266.30177.bb

Cited by 39 publications

(33 citation statements)

References 6 publications

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“…From capillary electrophoresis analysis, we detected 31 (22.8%) and 70 (26.5%) homozygotes in 136 SCA patients and 264 healthy controls, respectively, which was a few more than that of the former report (Matsuura et al 2000), but was similar with that of some other reports (Matsuura et al 2000Sulek et al 2004;Alonso et al 2006).…”

Section: Discussionsupporting

confidence: 86%

“…Alleles with 280-370 ATTCT repeats may be an intermediate alleles with reduced or no penetrance. Further investigation is needed to determine whether alleles with 400 to 760 ATTCT repeats are full penetrance (Alonso et al 2006). Thus, the SCA10 repeat expansion is one of the largest known microsatellite repeat expansion existing in the human genome.…”

Section: Discussionmentioning

confidence: 99%

“…The expansion of pentanucleotide (ATTCT) repeat is located in intron 9 of the ATXN10 gene (Zu et al 1999;Matsuura et al 2000). In SCA10, normal alleles carry 10-22 ATTCT repeats, intermediate alleles with reduced or no penetrance range from 280 to 370 ATTCT repeats, and pathological alleles contain 800-4500 ATTCT repeats (Alonso et al 2006). …”

Section: Introductionmentioning

confidence: 99%

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Lack of variation of ATTCT pentanucleotide repeats at ATXN10 gene between clinically diagnosed ataxia patients and normal individuals originated from Chinese Han

Wang

Jiang

Zhang

et al. 2008

J Genet

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of variation of ATTCT pentanucleotide repeats at ATXN10 gene between clinically diagnosed ataxia patients and normal individuals originated from Chinese Han

Wang

Jiang

Zhang

et al. 2008

J Genet

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“…Notably, alleles of 280-850 units show reduced penetrance in SCA10, and alleles of 33-280 repeats have not been observed. [41][42][43] DAB1 lies within the mapped SCA37 locus in chromosomal region 1p32 in a family originating from Spain. 20 The occurrence of multiple SCA gene mutations clustered in small genomic regions is rare and has been seen only in PDYN (MIM: 131340; associated with SCA23 [MIM: 610245]), NOP56 (associated with SCA36), and TGM6 (MIM: 613900; associated with SCA35 [MIM: 613908]), which are contained in a 750 kb region on human chromosomal arm 20p.…”

Section: Discussionmentioning

confidence: 99%

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Seixas

Loureiro

Costa

et al. 2017

The American Journal of Human Genetics

118

173

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Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the noncoding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC) n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT) 7-400 ] and [(ATTTT) 60-79 (ATTTC) 31-75 (ATTTT) ], respectively. (ATTTC) n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC) n is located in 5 0 UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC) 58 insertion, but not (ATTTT) n , leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC) 58 insertion, but not (AUUUU) n , showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

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“…The ATTCT repeat can range from 9 to 32 repeats in normal individuals [2]; however, the disease allele can expand from 800 up to 4500 repeats [1] in length with intermediate allele sizes ranging from 280 to 850 repeats [3–5]. …”

Section: Introductionmentioning

confidence: 99%

Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

et al. 2013

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Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confers a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling.

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Reduced penetrance of intermediate size alleles in spinocerebellar ataxia type 10

Cited by 39 publications

References 6 publications

Lack of variation of ATTCT pentanucleotide repeats at ATXN10 gene between clinically diagnosed ataxia patients and normal individuals originated from Chinese Han

Lack of variation of ATTCT pentanucleotide repeats at ATXN10 gene between clinically diagnosed ataxia patients and normal individuals originated from Chinese Han

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

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