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Interindividual gene copy-number variation (CNV) of complement component C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to different susceptibilities to autoimmune disease. We investigated the C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, two copies of C4A, and two copies of C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long C4 genes were strongly correlated with C4A ( R= 0.695; P<.0001). Short C4 genes were correlated with C4B (R = 0.437; P < .0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only two copies of total C4 (patients 9.3%; unrelated controls 1.5%; odds ratio [OR] = 6.514; P = .00002) but decreased in those with ⩾5 copies of C4 (patients 5.79%; controls P = .00002 12%; OR = 0.466; P =0.16). Both zero copies (OR = 5.267 ;P = .0001) and one copy (OR = 1.613; P = .002) of C4A were risk factors for SLE, whereas 3 copies of C4A appeared to be protective (OR = 0.574; P = 012). Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based review of treatment for MPS II demonstrated insufficient strength in all data analyzed to create a definitive practice guideline based solely on published evidence. The American College of Medical Genetics and Genomics (ACMG) Therapeutics Committee conducted a Delphi study to generate an MPS II clinical practice resource of the treatment for these individuals for the genetics community, based on the evidence-based review and subsequent literature. This report describes the process, including consensus development and areas where consensus could not be obtained due to lack of quality evidence. Recommendations from the Delphi process were generated, and areas were highlighted that need further study to help guide clinical care of these individuals.

Purpose: The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life., Methods: A writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document., Results: A genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted., Conclusion: Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant condition with an increased risk of sudden cardiac death. Although clinical genetic testing can be used for confirmation of a clinical diagnosis as well as a predictive test, based on our clinical experience it is underutilized. Therefore, we developed and administered a questionnaire to assess potential determinants of parental interest in this testing. Of the 30 adult caregivers who participated, 80% had heard of genetic testing, whereas only 30% knew about genetic testing specifically for HCM. Once informed of the availability, 62% said they would consider testing in the future and 28% would consider it in the next year. Participants' younger age, higher education level, knowledge of carrier testing, and positive view of genetic testing were significantly associated with the participant considering HCM genetic testing for their child (p