Clinical expression of Menkes disease in females with normal karyotype

<p>Abstract</p> <p>Background</p> <p>Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the <it>ATP7A </it>gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.</p> <p>Methods</p> <p>We investigated at-risk females for mutations in the <it>ATP7A </it>gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (<it>HUMAR</it>).</p> <p>Results</p> <p>The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.</p> <p>Conclusion</p> <p>The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.</p

Abstract 15628: HeartCare: Improving Clinical Practice Through Comprehensive Cardiovascular Genetic Testing

Introduction:Cardiovascular disease (CVD) is the leading cause of mortality in the United States, leading to one in four deaths. The role of inherited susceptibility to CVD is well established, from rare monogenic disorders to polygenic traits. For many of these conditions, guidelines exist for medical interventions and other preventative care that can improve outcomes and quality of life.Methods:We developed a comprehensive genetic screen, "HeartCare", consisting of a 158 gene panel evaluating 1) Mendelian conditions including cardiomyopathies, aortopathies, arrhythmias, and dyslipidemias, 2) a coronary artery disease polygenic risk score (PRS), 3) variants in the LPA gene encoding Lipoprotein(a) that are an independent risk factor for atherosclerotic CVD events, and 4) pharmacogenetic (PGx) variants contributing to simvastatin-induced myopathy and warfarin metabolism. After sequencing in a CAP/CLIA certified laboratory, results were returned to the ordering physician after a multi-disciplinary sign-out conference and uploaded to the EMR.Results:As of June 2020, 678 individuals had completed testing with a 31% overall positive rate for Mendelian genes, elevated polygenic risk, and LPA risk alleles (excluding PGx). Of these, 8.1% had a positive finding for a Mendelian condition, the majority (60%) being dyslipidemias (e.g., FH), followed by 25% cardiomyopathies (e.g., HCM, DCM, ARVC) and 6% aortopathies (e.g., Marfan, Loeys-Dietz). Approximately 20% of individuals carried an LPA risk allele, and 9.3% belonged to the high-risk group according to their PRS. Approximately half had a PGx finding related to simvastatin and/or warfarin metabolism. Nearly one in five individuals had a finding with direct clinical care impact, including referral to specialists, imaging, laboratory studies, therapies/procedures (e.g., PCSK9i, ICD).Conclusions:To our knowledge, this is the first test of its kind assaying four distinct categories of genetic variation related to cardiovascular health. Our results demonstrate that comprehensive testing can be routinely used to identify individuals who may benefit from interventions to improve survival, reduce morbidity, and enhance quality of life

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications

Purpose Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted. Methods We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record. Results Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort. Conclusion Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research