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An InDel in Phospholipase-C-B-1 is linked with euthyroid multinodular goiter

Bakhsh, Ameen D., Ladas, Ioannis, Hamshere, Marian L. ORCID:, Bullock, Martyn, Kirov, George ORCID:, Zhang, Lei ORCID:, Taylor, Peter N. ORCID:, Gregory, John W. ORCID:, Scott-Coombes, David, Völzke, Henry, Teumer, Alexander, Mantripragada, Kiran ORCID:, Williams, E. Dillwyn ORCID:, Clifton-Bligh, Roderick J., Williams, Nigel M. ORCID: and Ludgate, Marian E. 2018. An InDel in Phospholipase-C-B-1 is linked with euthyroid multinodular goiter. Thyroid 28 (7) , pp. 891-901. 10.1089/thy.2017.0312

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Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC). Methods: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM. Results: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ2 = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02). Conclusions: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Mary Ann Liebert
ISSN: 1050-7256
Date of First Compliant Deposit: 9 May 2018
Date of Acceptance: 3 May 2018
Last Modified: 25 Jun 2024 07:06

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