Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Inactivating 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. Methods: The 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. Results: A 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. Conclusions: A 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.

Original languageEnglish
Article number83
JournalBMC Medical Genetics
Volume18
Issue number1
DOIs
Publication statusPublished - Aug 3 2017

Fingerprint

Hyperparathyroidism
Exons
Parathyroid Neoplasms
Jaw
Nuclear Family
5' Untranslated Regions
Mutation
Neoplasms
Molecular Pathology
Primary Hyperparathyroidism
Sequence Deletion
Leiomyoma
Fathers
Biochemistry
Siblings
Ultrasonography
Leukocytes
Hyperparathyroidism 2
Genome
DNA

Keywords

  • CDC73
  • Germline
  • HPT-JT syndrome
  • Parathyroid carcinoma

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family. / Guarnieri, Vito; Seaberg, Raewyn M.; Kelly, Catherine; Jean Davidson, M.; Raphael, Simon; Shuen, Andrew Y.; Baorda, Filomena; Palumbo, Orazio; Scillitani, Alfredo; Hendy, Geoffrey N.; Cole, David E.C.

In: BMC Medical Genetics, Vol. 18, No. 1, 83, 03.08.2017.

Research output: Contribution to journalArticle

Guarnieri, Vito ; Seaberg, Raewyn M. ; Kelly, Catherine ; Jean Davidson, M. ; Raphael, Simon ; Shuen, Andrew Y. ; Baorda, Filomena ; Palumbo, Orazio ; Scillitani, Alfredo ; Hendy, Geoffrey N. ; Cole, David E.C. / Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family. In: BMC Medical Genetics. 2017 ; Vol. 18, No. 1.
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abstract = "Background: Inactivating 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. Methods: The 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. Results: A 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. Conclusions: A 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.",
keywords = "CDC73, Germline, HPT-JT syndrome, Parathyroid carcinoma",
author = "Vito Guarnieri and Seaberg, {Raewyn M.} and Catherine Kelly and {Jean Davidson}, M. and Simon Raphael and Shuen, {Andrew Y.} and Filomena Baorda and Orazio Palumbo and Alfredo Scillitani and Hendy, {Geoffrey N.} and Cole, {David E.C.}",
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T1 - Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family

AU - Guarnieri, Vito

AU - Seaberg, Raewyn M.

AU - Kelly, Catherine

AU - Jean Davidson, M.

AU - Raphael, Simon

AU - Shuen, Andrew Y.

AU - Baorda, Filomena

AU - Palumbo, Orazio

AU - Scillitani, Alfredo

AU - Hendy, Geoffrey N.

AU - Cole, David E.C.

PY - 2017/8/3

Y1 - 2017/8/3

N2 - Background: Inactivating 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. Methods: The 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. Results: A 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. Conclusions: A 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.

AB - Background: Inactivating 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. Methods: The 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. Results: A 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. Conclusions: A 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.

KW - CDC73

KW - Germline

KW - HPT-JT syndrome

KW - Parathyroid carcinoma

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