Deep intronic<i>APC</i>mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis

Spier, Isabel; Horpaopan, Sukanya; Vogt, Stefanie; Uhlhaas, Siegfried; Morak, Monika; Stienen, Dietlinde; Draaken, Markus; Ludwig, Michael; Holinski‐Feder, Elke; Nöthen, Markus M.; Hoffmann, Per; Aretz, Stefan

doi:10.1002/humu.22082

Cited by 59 publications

(72 citation statements)

References 30 publications

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“…It was noticeable that exons pertaining to CCDS transcripts were better covered than those that did not (Table 1). Finally, mutations outside protein-coding exons, or not in exons at all, might also affect the actual exome (the parts covered or not covered by WES) because mutations in the middle of long introns might impair the normal splicing of exons (37). These mutations would be missed by WES but would be picked up by WGS (and selected as candidate mutations if the mRNAs were studied in parallel, for example by RNAseq).…”

Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants

Belkadi

Bolze

Itan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

510

318

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We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ∼3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of falsepositive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.hole-exome sequencing (WES) is routinely used and is gradually being optimized for the detection of rare and common genetic variants in humans (1-8). However, wholegenome sequencing (WGS) is becoming increasingly attractive as an alternative, due to its broader coverage and decreasing cost (9-11). It remains difficult to interpret variants lying outside the protein-coding regions of the genome. Diagnostic and research laboratories, whether public or private, therefore tend to search for coding variants, most of which can be detected by WES, first. Such variants can also be detected by WGS, and several studies previously compared WES and WGS for different types of variations and/or in different contexts (9,(11)(12)(13)(14)(15)(16), but none of them in a really comprehensive manner. Here, we compared WES and WGS, in terms of detection rates and quality, for single-nucleotide variants (SNVs), small insertions/ deletions (indels), and copy-number variants (CNVs) within the regions of the human genome covered by WES, using the most recent next-generation sequencing (NGS) technologies. We aimed to identify the most efficient and reliable approach for identifying these variants in coding regions of the genome, to define the optimal analytical filters for decreasing the frequency of false-positive variants, and to characterize the genes that were either hard to sequence by either approach or were poorly covered by WES kits. ResultsWe compared the two NGS techniques, perform...

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Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants

Belkadi

Bolze

Itan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

510

318

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“…Additional related mutations have been reported in genes involved in the base excision repair system or the Wnt pathway (31)(32)(33)(34)(35). Other mechanisms, such as mosaicism and deep intronic APC gene mutations, are also reportedly associated with attenuated polyposis, and could explain a small proportion of cases (36,37). The existence of other yet unknown genes involved in cases showing multiple colonic polyps with incomplete penetrance, as well as complex interactions between environmental factors and modifier genes might further account for the unexplained cases.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Characteristics of MUTYH-Associated Polyposis in Patients with Multiple Adenomatous and Serrated Polyps

Guarinós

Juárez

Egoavil

et al. 2014

Clinical Cancer Research

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Purpose: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients.Experimental Design: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations.Results: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients.Conclusions: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants.

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“…5,6 • In APC/MUTYH mutation-negative families, deep intronic mutations not covered by routine methods have been identified in up to 8% of unselected and up to 30% of familial cases. 7 • Post-zygotic mosaicism in 10-15% of de novo events. 8 • For the mutational spectrum, see locus-specific databases:…”

Section: Mutational Spectrummentioning

confidence: 99%

“…2 • Mutations deep within introns or in regulatory elements are missed with current standard methods, 7 and the causal relevance of some missense or intronic mutations is unclear, so far (variants of uncertain clinical significance, VUS).…”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 99%

Clinical Utility Gene Card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) - update 2014

2014

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Deep intronicAPCmutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis

Cited by 59 publications

References 30 publications

Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants

Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants

Prevalence and Characteristics of MUTYH-Associated Polyposis in Patients with Multiple Adenomatous and Serrated Polyps

Clinical Utility Gene Card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) - update 2014

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