Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes.MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development.ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development.DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome

Objective: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. Method: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. Results: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3–51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). Conclusion: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens. © 2020 Elsevier Lt

Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.

INTRODUCTION: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. METHODS: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. RESULTS: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development. DISCUSSION: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients

Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an intermediate signature to suggest that both variants had a pathological role in tumour development. DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients