Sex differences and survival in adults with bicuspid aortic valves : verification in 3 contemporary echocardiographic cohorts

Background-—Sex-related differences in morbidity and survival in bicuspid aortic valve (BAV) adults are fundamentally unknown. Contemporary studies portend excellent survival for BAV patients identified at early echocardiographic-clinical stages. Whether BAV adults incur a survival disadvantage throughout subsequent echocardiographic-clinical stages remains undetermined. Methods and Results-—Analysis was done of 3 different cohorts of consecutive patients with echocardiographic diagnosis of BAV identified retrospectively: (1) a community cohort of 416 patients with first BAV diagnosis (age 35 21 years, follow-up 16 7 years), (2) a tertiary clinical referral cohort of 2824 BAV adults (age 51 16 years, follow-up 9 6 years), and (3) a surgical referral cohort of 2242 BAV adults referred for aortic valve replacement (AVR) (age 62 14 years, follow-up 6 5 years). For the community cohort, 20-year risks of aortic regurgitation (AR), AVR, and infective endocarditis were higher in men (all P=0.04); for a total BAV-related morbidity risk of 52 4% vs 35 6% in women (P=0.01). The cohort’s 25-year survival was identical to that in the general population (P=0.98). AR independently predicted mortality in women (P=0.001). Baseline AR was more common in men (P=0.02) in the tertiary cohort, with 20-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.16 (95% confidence interval [CI] 1.05-1.29) for men versus 1.67 (95% CI 1.38-2.03) for women (P=0.001). AR independently predicted mortality in women (P=0.01). Baseline AR and infective endocarditis were higher in men (both =0.001) for the surgical referral cohort, with 15-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.34 (95% CI 1.22-1.47) for men versus 1.63 (95% CI 1.40-1.89) for women (P=0.026). AR and NYHA class independently predicted mortality in women (both P=0.04). Conclusions-—Within evolving echocardiographic-clinical stages, the long-term survival of adults with BAV is not benign, as both men and women incur excess mortality. Although BAV-related morbidity is higher in men in the community, and AR and infective endocarditis are more prevalent in men, women exhibit a significantly higher relative risk of death in tertiary and surgical referral cohorts, which is independently associated with A

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297