Large intragenic deletion of CDC73 (exons 4\u201310) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family

Vito Guarnieri,M Jean Davidson,Andrew Y Shuen,Geoffrey N Hendy,David E C Cole,Catherine Kelly,Orazio Palumbo,Raewyn M Seaberg,Simon Raphael,Alfredo Scillitani,Filomena Baorda

doi:10.1186/s12881-017-0445-0

Abstract

BackgroundInactivating mutations of CDC73 cause Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), Familial Isolated Hyperparathyroidism (FIHP) and sporadic parathyroid carcinoma. We conducted CDC73 mutation analysis in an HPT-JT family and confirm carrier status of the proband’s daughter.MethodsThe proband had primary hyperparathyroidism (parathyroid carcinoma) and uterine leiomyomata. Her father and daughter had hyperparathyroidism (parathyroid adenoma) but no other manifestations of HPT-JT. CDC73 mutation analysis (sequencing of all 17 exons) and whole-genome copy number variation (CNV) analysis was done on leukocyte DNA of the three affecteds as well as the proband’s unaffected sister.ResultsA novel deletion of exons 4 to 10 of CDC73 was detected by CNV analysis in the three affecteds. A novel insertion in the 5’UTR (c.-4_-11insG) that co-segregated with the deletion was identified. By in vitro assay the 5’UTR insertion was shown to significantly impair the expression of the parafibromin protein. Screening for the mutated CDC73 confirmed carrier status in the proband’s daughter and the biochemistry and ultrasonography led to pre-emptive surgery and resolution of the hyperparathyroidism.ConclusionsA novel gross deletion mutation in CDC73 was identified in a three-generation HPT-JT family emphasizing the importance of including screening for large deletions in the molecular diagnostic protocol.

Highlights

Inactivating mutations of cell division cycle protein 73 homolog (CDC73) cause Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), Familial Isolated Hyperparathyroidism (FIHP) and sporadic parathyroid carcinoma
The HPT-JT syndrome is caused by mutations of the cell division cycle protein 73 homolog (CDC73) gene, at chromosome 1q31.2 [5]
We report here a 3-generation HPT-JT syndrome family in which initial analysis identified a variant in the 5’UTR of the mRNA no mutation was found in the protein-coding exons or exon/intron junctions

Summary

Introduction

Inactivating mutations of CDC73 cause Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), Familial Isolated Hyperparathyroidism (FIHP) and sporadic parathyroid carcinoma. Primary hyperparathyroidism (PHPT) is a common endocrine disorder affecting up to 2% of individuals over the age of 55 years [1]. It is caused by solitary benign adenoma in 80–85%, hyperplasia in 10–15%, and parathyroid carcinoma in less than 1%. The HPT-JT syndrome is caused by mutations of the cell division cycle protein 73 homolog (CDC73) gene, at chromosome 1q31.2 [5]. The 17 exons of the CDC73 tumor suppressor gene encode the predominantly nuclear, 531-amino acid protein, parafibromin [6].

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