Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening

Handt, Maximilian; Epplen, A.; Hoffjan, Sabine; Mese, Kemal; Epplen, Jörg T.; Dekomien, Gabriele

doi:10.1016/j.mcp.2014.08.003

Cited by 42 publications

(44 citation statements)

References 54 publications

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“…4 CGG-repeat expansion in the FMR1 promoter is the most frequent cause of FXS, but deletions of the entire FMR1 gene [10][11][12] or of the 5′UTR have also been reported in FXS. 9 Rare intragenic non-synonymous variations have also been identified within the FMR1 locus [16][17][18][19][20]22,23,35,41,42 but after reanalysis in the light of new public sequencing data, prediction tools and functional evidence, we showed that only six could be reclassified as convincing.…”

Section: Discussionmentioning

confidence: 88%

“…The second category of studies analyzed FMR1 coding sequences in male ID patients, with no specific clinical orientation, using high-resolution melting, Sanger or HTS). [21][22][23] The third one included large-scale studies in which FMR1 was sequenced together with other genes in unspecific ID (large panels, X-exome, exome, genome). 33 …”

Section: Literature and Database Review Of Fmr1 Variationsmentioning

confidence: 99%

“…Two other studies were conducted on unspecific ID patients. 21,22 This lack of FMR1 sequence screening has led to a marked deficit in the description of small exonic deletions or SNVs.…”

Section: Introductionmentioning

confidence: 99%

“…9 Deletions of the entire gene or of its first exon, 10-12 associated or not with full FMR1 CGG expansion in the mother, [13][14][15] have been found by conventional CGG expansion testing or by microarray analysis. Since 1992, screening for variations in the FMR1 coding sequence, performed in Fragile-X-evocative or nonspecific ID patients without expanded CGG-repeats and subsequent methylation, [16][17][18][19][20]22,23 has led to the identification of several rare intragenic non-synonymous variations within the FMR1 locus (Table 3 and Supplementary Table S2). We have also compiled the rare non-synonymous variants identified in FMR1 during large-scale studies (large panel, X-exome or wholeexome sequencing) performed on ID patients by other teams: only missense variants but no truncating variants were identified in the 3180 individuals tested.…”

Section: Identification Of Two Novel Intronic Variants Affecting Fmr1mentioning

confidence: 99%

“…[16][17][18][19] For the other missense variants reported, some are predicted to be damaging (SIFT, Polyphen2), but neither the amino acid changes by themselves nor the phenotypes of patients make it possible to draw any clear conclusions about their pathogenicity and we thus considered them 'variants of uncertain significance' (VUS). 11,[20][21][22] Some missense variants were even classified as 'likely benign'. One of them, p.Asp438Asn, located in the nuclear localization signal of FMR1, was identified by targeted HTS of 217 ID genes in two brothers with no morphological symptoms of FXS but with FXS neurodevelopmental phenotype: further familial segregation analysis showed that one unaffected half-brother also carries this variation too thus suggesting that it is a benign variant.…”

Section: Identification Of Two Novel Intronic Variants Affecting Fmr1mentioning

confidence: 99%

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Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Quartier¹,

Poquet²,

Gilbert‐Dussardier³

et al. 2017

Eur J Hum Genet

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Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G4A (family 2) and a maternally inherited c.420-8A4G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores = 15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.

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Section: Discussionmentioning

confidence: 88%

Section: Literature and Database Review Of Fmr1 Variationsmentioning

confidence: 99%

“…Two other studies were conducted on unspecific ID patients. 21,22 This lack of FMR1 sequence screening has led to a marked deficit in the description of small exonic deletions or SNVs.…”

Section: Introductionmentioning

confidence: 99%

Section: Identification Of Two Novel Intronic Variants Affecting Fmr1mentioning

confidence: 99%

Section: Identification Of Two Novel Intronic Variants Affecting Fmr1mentioning

confidence: 99%

See 3 more Smart Citations

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Quartier¹,

Poquet²,

Gilbert‐Dussardier³

et al. 2017

Eur J Hum Genet

View full text Add to dashboard Cite

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Rare FMR1 gene mutations causing fragile X syndrome: A review

Sitzmann

Hagelstrom

Tassone

et al. 2017

American J of Med Genetics Pt A

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Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG-repeat expansion. He had more features of FXS than the previously reported patient with the same mutation.Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual disability. Four of the 20 individuals had a mutation within exon 15, three within exon 5, and two within exon 2. The FMR1 missense mutation (c.413G>A) is the same as in a previously reported male where it was shown that there was preservation of the post-synaptic function of the fragile X mental retardation protein (FMRP), the encoded protein of the FMR1 gene was preserved. Both patients with this missense mutation had physical, cognitive, and behavioral features similarly seen in FXS. K E Y W O R D S

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Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2‐Methyl‐6‐(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia

Folsom

Higgins

Markowski

et al. 2018

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The fragile X mental retardation 1 knockout (Fmr1 KO) mouse replicates behavioral deficits associated with autism, fragile X syndrome, and schizophrenia. Less is known whether protein expression changes are consistent with findings in subjects with schizophrenia. In the current study, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics to determine the protein expression of four subcellular fractions in the forebrains of Fmr1 KO mice vs. C57BL/6 J mice and the effect of a negative allosteric modulator of mGluR5-2-Methyl-6-(phenylethynyl)pyridine (MPEP)-on protein expression. Strain- and treatment-specific differential expression of proteins was observed, many of which have previously been observed in the brains of subjects with schizophrenia. Western blotting verified the direction and magnitude of change for several proteins in different subcellular fractions as follows: neurofilament light protein (NEFL) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) in the total homogenate; heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC) and heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) in the nuclear fraction; excitatory amino acid transporter 2 (EAAT2) and ras-related protein rab 3a (RAB3A) in the synaptic fraction; and ras-related protein rab 35 (RAB35) and neuromodulin (GAP43) in the rough endoplasmic reticulum fraction. Individuals with FXS do not display symptoms of schizophrenia. However, the biomarkers that have been identified suggest that the Fmr1 KO model could potentially be useful in the study of schizophrenia.

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Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening

Cited by 42 publications

References 54 publications

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Rare FMR1 gene mutations causing fragile X syndrome: A review

Quantitative proteomics of forebrain subcellular fractions in fragile X mental retardation 1 knockout mice following acute treatment with 2‐Methyl‐6‐(phenylethynyl)pyridine: Relevance to developmental study of schizophrenia

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