Genetics in medicine : official journal of the American College of Medical Genetics · 2022
Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Meester Josephina A N, Peeters Silke, Van Den Heuvel Lotte, Vandeweyer Geert, Fransen Erik, Cappella Elizabeth, Dietz Harry C, Forbus Geoffrey, Gelb Bruce D, Goldmuntz Elizabeth, Hoskoppal Arvind, Landstrom Andrew P, Lee Teresa, Mital Seema, Morris Shaine, Olson Aaron K, Renard Marjolijn, Roden Dan M, Singh Michael N, Selamet Tierney Elif Seda, Tretter Justin T, Van Driest Sara L, Willing Marcia, Verstraeten Aline, Van Laer Lut, Lacro Ronald V, Loeys Bart L
Аннотация
PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm.
METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed.
RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes.
CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.
METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed.
RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes.
CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.