Genetic anticipation

Introduction: To identify HCM at the earliest time possible, estimating the onset of disease based on diagnostic criteria is vital in timing the initiation of screening and interventions. Hypothesis: Clinic observations indicate an early diagnose of HCM in second generation of most affected families. From the pedigrees with or without mutations in beta-myosin heavy chain gene (MYH7) affected in two or more generations with hypertrophic cardiomyopathy (HCM), ages and maximal wall thickness (MWT) of left ventricles at diagnosis were evaluated to investigate the potential genetic anticipation in patients with familiar HCM (FHCM). Methods: 56 individuals from 25 families were analyzed. Linear mixed effects models were adopted to prevent misinterpretation resulting from the cohort effect. Published data containing 9 sarcomere mutations (181 individuals in 52 families) also were extracted. Results: MYH7 mutations were detected in 9 of the 25 probands, The median age of HCM diagnosis was 24 in the younger generation and 55 in the older (p < 0.001). In the parametric model, the estimated change in the expected age at diagnosis for the entire cohort was 25.8 years (p <0.001). Statistically significant earlier ages at diagnoses were also observed within subgroups of MYH7+ and MYH7- mutations, and probands older and younger than 30 years old. Although the estimated change in MWT at diagnosis for the entire cohort was only 2.161 mm (p =0.212), the subgroup of probands in the younger generation aged less than 30 years had 10.393 mm (p=0.018) thicker MWT and showed a significant reverse correlation with age. Analysis of published data also supports these findings. Conclusions: Genetic anticipation was observed in patients with FHCM. FHCM is prone to be diagnosed at an earlier age in younger generations. Patients who are younger with relatives affected by HCM, especially those who are diagnosed before 30 years of age, should continue to be tracked to offer appropriate screening modalities as earlier as possible.

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Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa257 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2491-e2500

Author(s):

Medard F M van den Broek ◽

Bernadette P M van Nesselrooij ◽

Carolina R C Pieterman ◽

Annemarie A Verrijn Stuart ◽

Annenienke C van de Ven ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Multiple Endocrine Neoplasia ◽

Molecular Mechanisms ◽

Multiple Endocrine Neoplasia Type ◽

Genetic Anticipation ◽

Screening Programs ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Successive Generations

Abstract Context Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. Conclusions These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

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