Christopher A. Friedrich

Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication

BackgroundInterstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported.ResultsIn this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities.ConclusionOur report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.

Ideal Cardiovascular Health is Inversely Associated with Incident Cancer: The Atherosclerosis Risk in Communities Study

Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant ( P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics ( P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence. # Clinical Perspective {#article-title-29}Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.

Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13‐year‐old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non‐classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3‐year follow‐up, he had stable disease. Pediatr Blood Cancer 2010;54:473–475.

Novel COL4A3 Mutations in African American Siblings With Autosomal Recessive Alport Syndrome

We describe a novel mutational study in 2 African American siblings with autosomal recessive Alport syndrome. Both siblings were compound heterozygotes for 2 abnormal DNA sequences in exon 49 of the COL4A3 gene, p.Arg1496X (CGA-->TGA) and p.Arg1516X (CGA-->TGA). These are nonsense mutations in the noncollagenous domain resulting in premature termination codons and have not been previously reported. In an African American population in which autosomal recessive Alport syndrome is rarely seen, complete sequencing of the COL4A3 and COL4A4 genes may be necessary to identify the underlying mutation and confirm the diagnosis.

The Role of DNA Testing in Breast, Ovarian, and Colon Cancers

A proportion of cases of breast and colon cancers are caused by inherited mutations that confer a greatly increased susceptibility to malignancy. Certain clinical features may help distinguish patients with a genetic cause for their cancer from the larger number of patients with sporadic tumors. A thorough family medical history is also necessary to identify those at high risk for developing cancer. Many of the normal functions of these genes are understood, and mutation analysis for patients and their families is now available as a clinical service. Presymptomatic detection of mutations allows the patient to pursue preventive measures to reduce the probability of developing a malignancy. Evidence is now available that some prophylactic measures do reduce the incidence of cancer and reduce mortality in mutation carriers, and the standard of care is evolving rapidly. The essential elements necessary to provide accurate interpretations of molecular genetics test results to patients are described.

Ideal Cardiovascular Health Is Inversely Associated With Incident CancerClinical Perspective: The Atherosclerosis Risk in Communities Study

Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant ( P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics ( P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence. # Clinical Perspective {#article-title-29}Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.

An Internist’s Update on Cholesterol Management

&NA; Coronary heart disease (CHD) remains the leading cause of death in the United States. It is now well established that cholesterol is an important, reversible risk factor for CHD. This article provides a brief background on classification of the dyslipidemias, then discusses current recommendations for the evaluation and treatment of hyperlipidemia. Other risk factors currently being investigated as they relate to the development of CHD are discussed.

Genetic Risks of Ovarian Cancer

Although most cases of ovarian cancer occur sporadically, some families carry germline mutations that can increase the risk for developing ovarian and other cancers substantially. Practitioners need to recognize characteristics of an individual patient or family to identify those who are more likely to carry one of these mutations and who might benefit from genetic testing. There is not a known gene that increases the risk only for ovarian cancer. Mutations in two well-established genes, BRCA1 and BRCA2, increase the risk substantially for both breast cancer and ovarian cancer. Mutations in other more recently discovered and less common cancer susceptibility syndrome genes increase the risk for ovarian cancer, along with increasing the risk for several other cancers specific to each syndrome. A thorough family medical history can identify relatives whose medical history may be related to the current patient’s situation. It is also necessary to understand the strategies to follow in identifying which family member is most informative for initial testing, how to interpret the test results, and what to recommend regarding testing for relatives. For patients at increased risk of developing ovarian cancer due to germline mutations, guidelines have been published with the goal of reducing morbidity and mortality among those at highest risk.

Ideal Cardiovascular Health Is Inversely Associated With Incident CancerClinical Perspective

Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant ( P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics ( P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence. # Clinical Perspective {#article-title-29}Background— The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. Methods and Results— After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (P trend =0.03). Conclusions— Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.

Genomics 101: What the practicing physician needs to know about the genetics revolution

This meeting brought together a wide range of speakers from industry, academic health centers, patient advocacy groups and nongovernmental organizations. The audience included physicians (both generalists and specialists), genetic counsellors, researchers from private industry and administrators from healthcare plans. The speakers covered a range of topics, but this report focuses on four talks describing: • How large-scale association studies are being used to identify susceptibility genes for common conditions (e.g., asthma)