PMID- 38130397
OWN - NLM
STAT- MEDLINE
DCOM- 20231225
LR  - 20240228
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 14
DP  - 2023
TI  - GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial 
      isolated hyperparathyroidism.
PG  - 1254156
LID - 10.3389/fendo.2023.1254156 [doi]
LID - 1254156
AB  - CONTEXT: A germline mutation can be identified in up to 10% of patients with 
      primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 
      004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT 
      Ashkenazi Jews (AJ). OBJECTIVE: To evaluate the presence of the GCM2 p.Tyr394Ser 
      variant in Israeli patients addressed for genetic evaluation to characterize 
      their phenotype and clinical management. METHOD: Patients with PHPT who underwent 
      addressed for genetic screening for suspected familial hypocalciuric 
      hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or 
      failed parathyroidectomy with persistent PHPT were recruited. Those with normal 
      initial selected gene sequencing or hyperparathyroid genetic panel completed the 
      GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated 
      using our local genomic database. RESULTS: A total of 42 single individuals from 
      unrelated kindreds were evaluated. A disease-causing mutation was found in 11 
      (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 
      mutations), and one patient had a CKN2B mutation. In 28 of the remaining 
      patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all 
      were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 
      (20%), and of those, two had a history of familial isolated hyperparathyroidism. 
      Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these 
      patients. No clinical or laboratory findings could discriminate patients with the 
      GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium 
      levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 
      tests in our local genomic database was 0.98%. CONCLUSION: In contrast to 
      previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be 
      mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, 
      surgeons should be aware of the possibility of multiple gland diseases in these 
      patients. The clinical spectrum and clinical utility of screening for this 
      variant warrant further investigation.
CI  - Copyright (c) 2023 Szalat, Shpitzen, Pollack, Mazeh, Durst and Meiner.
FAU - Szalat, Auryan
AU  - Szalat A
AD  - Endocrinology and Metabolism Service, Department of Internal Medicine, 
      Osteoporosis Center, Hadassah-Hebrew University Medical Center, Jerusalem, 
      Israel.
FAU - Shpitzen, Shoshana
AU  - Shpitzen S
AD  - Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Pollack, Rena
AU  - Pollack R
AD  - Endocrinology and Metabolism Service, Department of Internal Medicine, 
      Osteoporosis Center, Hadassah-Hebrew University Medical Center, Jerusalem, 
      Israel.
FAU - Mazeh, Haggi
AU  - Mazeh H
AD  - Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 
      Israel.
FAU - Durst, Ronen
AU  - Durst R
AD  - Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Meiner, Vardiella
AU  - Meiner V
AD  - Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, 
      Israel.
LA  - eng
PT  - Journal Article
DEP - 20231207
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 0 (Parathyroid Hormone)
RN  - 0 (GCM2 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - Hyperparathyroidism 1
RN  - Hypocalciuric hypercalcemia, familial, type 1
SB  - IM
MH  - Humans
MH  - *Hyperparathyroidism, Primary/diagnosis/genetics
MH  - Israel/epidemiology
MH  - Parathyroid Hormone/genetics
MH  - Mutation
MH  - Nuclear Proteins/genetics
MH  - Transcription Factors/genetics
PMC - PMC10733520
OTO - NOTNLM
OT  - AP2S1
OT  - calcium-sensing receptor
OT  - familial hypocalciuric hypercalcemia
OT  - gcm2
OT  - hypercalcemia
OT  - parathyroid
OT  - primary hyperparathyroidism
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/12/22 06:42
MHDA- 2023/12/25 06:42
PMCR- 2023/01/01
CRDT- 2023/12/22 03:48
PHST- 2023/07/06 00:00 [received]
PHST- 2023/11/20 00:00 [accepted]
PHST- 2023/12/25 06:42 [medline]
PHST- 2023/12/22 06:42 [pubmed]
PHST- 2023/12/22 03:48 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2023.1254156 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2023 Dec 7;14:1254156. doi: 
      10.3389/fendo.2023.1254156. eCollection 2023.