Endocrine Abstracts (2003) 5 P145

Molecular genetic diagnosis for disorders of calcium metabolism

T Cranston1, SM Huson2, A Seller1 & RV Thakker3

1Department of Genetics, Churchill Hospital, Oxford, UK; 2Clinical Genetics, Churchill Hospital, Oxford, UK; 3Molecular Endocrinology Group, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Disorders of calcium metabolism may occur as hereditary traits eg. the Multiple Endocrine Neoplasia type 1 (MEN1) or type 2 (MEN2) syndromes, Familial isolated hyperparathyroidism (FIHP), neonatal severe primary hyperparathyroidism (NSHPT), Familial benign hypocalciuric hypercalcaemia (FBHH), the autoimmune poly- endocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and DiGeorge syndromes, isolated hypoparathyroidism and the autosomal dominant hypocalcaemic hypercalciuria (ADHH) syndrome. The identification of the underlying genetic abnormality in these disorders may help in establishing the diagnosis and in facilitating decisions for patients and their relatives. We have therefore established a nationally available molecular genetic diagnostic service for such disorders. Leukocyte DNA is used for mutational analysis of the relevant genes by either direct bi-directional DNA sequencing or by dHPLC WAVE analysis with subsequent DNA sequencing of PCR products with aberrant profiles. The service has been operational for 9 months and a total of 57 samples (31 unrelated probands and 26 relatives) have been analysed. Over 70% of the requests received were for MEN1 mutational analysis, and 61% of the probands and 60% of the relatives were found to have mutations. Approximately 20% of requests received were for calcium-sensing receptor (CaSR) mutational analysis for patients and relatives with NSHPT, FBHH and ADHH, and abnormalities were identified in over 60% of these individuals. Under 10% of the requests were for MEN2 mutational analysis and no mutations were identified in these patients. The analysis was completed within a mean (plus/minus SD) of 40.6 (plus/minus 20.6) days for mutation detection in probands and 17.6 (plus/minus 5.9) days for confirmation and testing in relatives. A molecular genetic diagnostic service for disorders of calcium metabolism has been established, and this is proving useful for the clinical management and genetic counselling of patients and their families.

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