A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma.

The identification of 9 susceptibility genes for paraganglioma/pheochromocytoma between 2001 and 2010 has led to the development of routine genetic tests. To study the evolution in genetic screening for paraganglioma/pheochromocytoma over the past decade, we carried out a retrospective study on the tests performed in our laboratory from January 2001 to December 2010. A genetic test for paraganglioma/pheochromocytoma was assessed for 2 499 subjects, 1 620 index cases, and 879 presymptomatic familial genetic tests. A germline mutation in a PGL/PCC susceptibility gene was identified in 363 index cases (22.4%): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. A presymptomatic paraganglioma/pheochromocytoma test was positive in 427 subjects. Advances in molecular screening techniques led to an increase in the total number of mutation-carriers diagnosed each year. Overall, during the last decade, our laboratory identified a germline mutation in 44.7% of patients with a suspect hereditary PGL/PCC and in 8% of patients with an apparently sporadic PGL/PCC. During the past decade, the discoveries of new paraganglioma/pheochromocytoma susceptibility genes and the subsequent progress of molecular screening techniques have enabled us to diagnose a hereditary paraganglioma/pheochromocytoma in about 22% of patients tested in routine practice. This genetic testing is of major importance for the follow-up of affected patients and for the genetic counselling of their families.

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4alpha) and hepatocyte nuclear factor 1 alpha (HNF-1alpha) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers for MODY3 for mutations in the HNF-1alpha gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.

Diabetes complications in NIDDM kindreds linked to the MODY3 locus on chromosome 12q.

OBJECTIVE: To assess the prevalence of diabetes complications and the severity of diabetes in kindreds with NIDDM linked to the MODY3 locus (chromosome 12q) and to compare these parameters with data obtained in glucokinase (GCK)-deficient and other-MODY (unlinked to any of the three known loci) families, as well as with data from families with a late age of onset of NIDDM. RESEARCH DESIGN AND METHODS: Clinical and biological data were obtained from 667 affected members of 7 MODY3, 25 GCK-deficient, 6 other-MODY, and 81 NIDDM families. Severity of diabetes (glucose tolerance status and insulin secretion) was assessed by an oral glucose tolerance test. Neurological examination and eye fundus examination were performed in 349 and 251 subjects, respectively, and proteinuria was tested with strips in 282 family members. RESULTS: A higher prevalence of proliferative retinopathy was observed in MODY3 (21%) and NIDDM subjects (23%) than in GCK-deficient (3%) and other-MODY subjects (8%; P = 0.004). Proteinuria was detected in 19, 7, 5, and 0% (P = 0.07) of subjects, respectively. Prevalence of neuropathy was higher in NIDDM (17%; P = 0.005) than in MODY3 (4%), GCK-deficient (5%) and other-MODY (0%) subjects. MODY3 and NIDDM subjects had significantly higher fasting glucose levels than subjects in the other groups. Glucose levels after 2 h were significantly higher, and the ratios of insulin to glucose levels were significantly lower in MODY3 subjects than in the other three groups. CONCLUSIONS: The MODY3 subtype of NIDDM is characterized by a severe insulin secretory defect and by major hyperglycemia that progresses rapidly to overt diabetes. Microvascular complications of diabetes were frequently observed in the MODY3 subjects and the subjects with a late age of onset of NIDDM in this cohort. Both the duration and the severity of diabetes were independently associated with these complications.

A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q.

Maturity-onset diabetes of the young (MODY) is a subtype of non-insulin dependent diabetes mellitus, with early age of onset. MODY is genetically heterogeneous, associated with glucokinase mutations and a locus on chromosome 20q; in about 50% of cases, its genetic background is unknown. We have studied 12 families in which MODY is unlinked to either glucokinase or chromosome 20q markers, and find significant evidence for linkage with microsatellite markers on chromosome 12q, most likely within a 7 centimogran interval bracketed by D12S86 and D12S342. The disease was estimated to be linked to this chromosome region in approximately 50% of families in a heterogeneity analysis. These MODY patients exhibit major hyperglycaemia with a severe insulin secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function.