4 research outputs found
Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations
International audienceContexte : L' hypercholestĂ©rolĂ©mie familiale (HF) est la maladie gĂ©nĂ©tique la plus courante associĂ©e Ă un risque Ă©levĂ© de maladie cardiovasculaire athĂ©rosclĂ©reuse prĂ©maturĂ©e attribuable Ă l'augmentation des taux de cholestĂ©rol LDL (LDL-C) dĂšs la naissance. L'HF est Ă la fois sous-diagnostiquĂ©e et sous-traitĂ©e.Objectif : Nous dĂ©crivons les caractĂ©ristiques cliniques, biologiques et gĂ©nĂ©tiques de 147 patients en France atteints d'HF clinique (dont un groupe de 26 sujets ĂągĂ©s de < 20 ans) ; nous explorons la meilleure façon de dĂ©tecter les patients atteints d'HF monogĂ©nique.MĂ©thodes : Nous avons examinĂ© rĂ©trospectivement toutes les donnĂ©es disponibles sur les patients subissant des tests gĂ©nĂ©tiques pour l'HF de 2009 Ă 2019. Les diagnostics d'HF Ă©taient basĂ©s sur les scores des adultes du Dutch Lipid Clinics Network (DLCN) et sur les taux Ă©levĂ©s de LDL-C chez les sujets de moins de 20 ans. . Nous avons Ă©valuĂ© le statut LDLR, APOB et PCSK9.RĂ©sultats : Les mutations des adultes (chez 25,6 % de tous les adultes) Ă©taient associĂ©es Ă des scores DLCN indiquant "FH possible", "FH probable et "FH dĂ©finitive" Ă des taux de 4 %, 16 % et 53 %, respectivement. les aires sous les courbes ROC du score DLCN et du taux maximal de LDL-C ne diffĂ©raient pas (p = 0,32).Nous avons constatĂ© que le groupe pĂ©diatrique prĂ©sentait davantage d'Ă©tiologies monogĂ©niques (77 %, augmentant Ă 91 % lorsqu'un taux Ă©levĂ© de LDL-C Ă©tait associĂ©e Ă des antĂ©cĂ©dents familiaux d'hypercholestĂ©rolĂ©mie et/ou de maladie coronarienne prĂ©maturĂ©e).Conclusion : Le diagnostic de l'HF monogĂ©nique peut ĂȘtre optimisĂ© par le dĂ©pistage des enfants en fonction de leur taux de LDL-C, associĂ© Ă un dĂ©pistage en cascade inverse des proches lorsque les enfants servent de cas index
New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-HĂŒnermann-Happle Syndrome.
International audienceX-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-HĂŒnermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301â+â5âGâ>âC in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues
Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France
International audienceAutosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function