Single-strand conformation polymorphism analysis of the &lt;i&gt;FMR1&lt;/i&gt; gene in autistic and mentally retarded children in Japan

Shinahara, Kumi; Saijo, Takahiko; Mori, Koichi; Kuroda, Yasuhiro

doi:10.2152/jmi.51.52

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…Therefore, FMR1 sequencing is rarely performed in the clinical setting, due to the expectation of a low diagnostic yield. Also, methodological constraints have previously prevented a thorough assessment of FMR1 sequence variation in a large number of patients, leaving the true significance of pathogenic sequence variants in FMR1 unknown [Castellvi-Bel et al, 1999; Chiurazzi et al, 1994; Collins et al, 2010; Gronskov et al, 1998; Reyniers et al, 1996; Shinahara et al, 2004; Vincent et al, 1996; Wang et al, 1997]. …”

Section: Introductionmentioning

confidence: 99%

Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males

Collins

Bray

Suhl

et al. 2010

American J of Med Genetics Pt A

104

106

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Fragile X syndrome (FXS), the most common inherited form of developmental delay, is typically caused by CGG-repeat expansion in FMR1. However, little attention has been paid to sequence variants in FMR1. Through the use of pooled-template massively parallel sequencing, we identified 130 novel FMR1 sequence variants in a population of 963 developmentally delayed males without CGG-repeat expansion mutations. Among these, we identified a novel missense change, p.R138Q, which alters a conserved residue in the nuclear localization signal of FMRP. We have also identified three promoter mutations in this population, all of which significantly reduce in vitro levels of FMR1 transcription. Additionally, we identified 10 noncoding variants of possible functional significance in the introns and 3'-untranslated region of FMR1, including two predicted splice site mutations. These findings greatly expand the catalogue of known FMR1 sequence variants and suggest that FMR1 sequence variants may represent an important cause of developmental delay.

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Section: Introductionmentioning

confidence: 99%

Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males

Collins

Bray

Suhl

et al. 2010

American J of Med Genetics Pt A

104

106

View full text Add to dashboard Cite

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“…The variant c.879A>C in exon 9 was previously detected in a female patient who presented with severe intellectual impairment and moderate autistic features; this silent mutation has been reported to alter the splicing of exon 9, causing a premature termination of protein synthesis lacking the second KH domain and RGG box. 8 We identified the same variant in a 3-year-old boy who presented severe mental retardation and developmental delay, as well as in his healthy mother ( Figure 1A). However, amplification encompassing the exon junction from the reverse-transcribed cDNA showed the same-length product (476 bp) in the patient as in the control ( Figure 1B).…”

Section: Resultsmentioning

confidence: 72%

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects

et al. 2014

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CGG repeat expansion is the most common cause of fragile X syndrome. Numerous efforts have been made to identify novel mutations in patients with intellectual disability, developmental delay, and/or autism. To evaluate the mutational spectrum in the at-risk Chinese population, 60 pediatric patients presenting fragile X traits but normal-sized CGG repeats were sequenced for all 17 exons and regulatory regions in FMR1. A c.879A>C mutation, reported to alter a neighboring splicing, was detected in a severely retarded male and his normal mother. However, the exon junction appears unaffected. A 237-kb deletion covering the entire FMR1 was identified to cause moderate intellectual disability and marked hyperactivity in an 8-year-old boy. The 5' and 3' breakpoints were buried in the surrounding long interspersed and short interspersed elements, respectively. In general, missense mutations do not commonly cause fragile X syndrome, whereas deletions should be considered with caution in patient referrals presenting with developmental delay and/or ordinary retardation.

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“…Similarly, a FMR1 missense mutation could selectively alter the function of only one domain of FMRP, thereby causing a specific FXS-like symptom, such as connective tissue defects or macro-orchidism, in the absence of an overall FXS-like phenotype. Given the already high level of genetic heterogeneity among patients with developmental disability [12], [18], [19], this heterogeneity may be further compounded by any of these possibilities. Perhaps accepting the unavoidable heterogeneity and sampling a much larger cohort with minimal clinical criteria (i.e.…”

Section: Discussionmentioning

confidence: 99%

Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype

et al. 2010

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BackgroundFragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract.Methodology/Principal FindingsTo more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations.Conclusions/SignificanceThese data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

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Single-strand conformation polymorphism analysis of the <i>FMR1</i> gene in autistic and mentally retarded children in Japan

Cited by 11 publications

References 30 publications

Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males

Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects

Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype

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