Unusual Association of Two Germline Rearrangements in CDC73/HRPT2 Gene: Complexity of Clinical Counseling in the Age of Genomic Medicine

Background: Primary hyperparathyroidism is a phenotype shared by several hereditary endocrine and non-endocrine cancer predisposition syndromes caused by heterozygous germline mutations deactivating tumor suppressor genes including CDC73 (=HRPT2). Objectives and Results: We describe the genetic investigation of a family in which the proband was a 16- year-old male patient suffering from primary hyperparathyroidism related to a unique parathyroid adenoma. His DNA analyses revealed a CDC73 germline heterozygous deletion of exons 7 to 13 in the 1q31.2 locus of the chromosome 1. Geneticinvestigations in his parents who were both asymptomatic showed that the father was not carrying the deletion. Twochromosomal rearrangements were carried by the mother, both affecting CDC73: the deletion previously identified in her son and a 626 kb duplication encompassing 6 contiguous genes: UCHL5, TROVE2 GLRX2, CDC73, MIR1278 and B3GALT2. This duplicated segment was inserted into chromosome 20. Lack of symptoms in the proband's mother suggests that the CDC73 extra copy is able to balance the loss of function caused by the deleted allele by allowing a normal level of parafibromin expression. Conclusion: For the first time, we describe the association of two large and complex genetic events in CDC73 gene complicating genetic counseling. Literature doesn't provide much information about potential consequences of these genes deletion or duplication, thus highlighting the importance of multidisciplinarity in the practice of precision and genomic medicine. Moreover, this study demonstrates that copy number variations should be carefully investigated in routine diagnosis in order to deliver an accurate genetic counseling to those families.