Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1

Pęczkowska, Mariola; Erlic, Zoran; Hoffmann, Michael M.; Furmanek, Mariusz; Ćwikła, Jarosław B.; Kubaszek, Agata; Prejbisz, Aleksander; Szutkowski, Z.; Kawecki, Andrzej; Chojnowski, Krzysztof; Lewczuk, Anna; Litwin, Mieczysław; Szyfter, Witold; Walter, Martin A.; Sullivan, Maren; Eng, Charis; Januszewicz, Andrzej; Neumann, Hartmut P. H.

doi:10.1210/jc.2008-1290

Cited by 28 publications

(22 citation statements)

References 34 publications

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“…Currently, there is no international consensus regarding intervals and specific programs. Our consortium sites suggest conventional multisection imaging by magnetic resonance imaging of the skull-base and neck, the thorax, the abdomen, and the pelvis to detect unrecognized paraganglial tumors in time (35)(36)(37). This type of surveillance will detect incidental ''other'' tumors including those of the kidneys, thyroid, and gastrointestinal stromal tumors (19,22).…”

Section: Discussionmentioning

confidence: 99%

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Neumann

Erlic

Boedeker³

et al. 2009

Cancer Research

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Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs fUS$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for

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Section: Discussionmentioning

confidence: 99%

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Neumann

Erlic

Boedeker³

et al. 2009

Cancer Research

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171

177

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“…For example, 40% of all unselected male breast cancers and 10% of all female breast cancers diagnosed in Iceland are accounted for by a single mutation in BRCA2, 999del5 (28,29). Similarly, several mutations in the SDHB, SDHD, and VHL genes have been observed to occur in higher frequencies in some restricted geographic areas and most likely represent founder mutations (14,(30)(31)(32)(33)(34). For patients coming from these areas, genetic testing for the region-specific founder mutation should be offered first in the absence of obvious syndromic features.…”

Section: Discussionmentioning

confidence: 99%

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

Erlic

Rybicki

Pęczkowska³

et al. 2009

Clinical Cancer Research

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Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼$3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378-85)

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“…We have described a founder deletion of exon 3 of the SDHB gene in nine patients of this same group of point mutation-negative patients (Bayley et al 2009). While founder mutations are common in the Dutch population , Zeegers et al 2004, as once again shown by the identification of the SDHB exon 3 deletion, other populations also show founder effects (Cascon et al 2008, Peczkowska et al 2008b, Opocher et al 2009), indicating that while the general frequency of SDH deletions across all paraganglioma patient populations cannot yet be established, the proportion of deletions found in the Dutch population may have wider relevance.…”

Section: Discussionmentioning

confidence: 96%

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Bayley

Weiss

Grimbergen

et al. 2009

Endocrine-Related Cancer

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A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg-AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb-Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.

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Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1

Abstract: The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.

Cited by 28 publications

References 34 publications

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

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