Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients.
BACKGROUND
Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma patients.


METHODS
Mutational screening was performed by Sanger sequencing or next-generation sequencing. The frequencies of variants of unknown clinical significance, e.g. intronic, missense, and synonymous variants, were determined using the Exome Aggregation Consortium database, while the significance of missense mutations was predicted by in silico and loss of heterozygosity analysis when possible.


RESULTS
We report 18 germline variants; nine in SDHB, six in SDHC, and three in SDHD. Of these 18 variants, eight are novel. We classify 12 variants as likely pathogenic/pathogenic, one as likely benign, and five as variants of unknown clinical significance.


CONCLUSIONS
Identifying and classifying SDHB, SDHC, and SDHD variants present in the Danish population will augment the growing knowledge on variants in these genes and may support future clinical risk assessments.
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Marc
M
Bennedbæk
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Maria
M
Rossing
Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Åse K
ÅK
Rasmussen
Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Anne-Marie
AM
Gerdes
Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21 C, Aarhus N, 8200 Denmark.
Anne-Bine
AB
Skytte
Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21 C, Aarhus N, 8200 Denmark.
Uffe B
UB
Jensen
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Finn C
FC
Nielsen
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Thomas V O
TVO
Hansen
Classification; Germline; Mutation; Paraganglioma; Pheochromocytoma; SDHB; SDHC; SDHD