Primary brain calcification: an international study reporting novel variants and associated phenotypes.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Ramos Eliana Marisa, Carecchio Miryam, Lemos Roberta, Ferreira Joana, Legati Andrea, Sears Renee Louise, Hsu Sandy Chan, Panteghini Celeste, Magistrelli Luca, Salsano Ettore, Esposito Silvia, Taroni Franco, Richard Anne-Claire, Tranchant Christine, Anheim Mathieu, Ayrignac Xavier, Goizet Cyril, Vidailhet Marie, Maltete David, Wallon David, Frebourg Thierry, Pimentel Lylyan, Geschwind Daniel H, Vanakker Olivier, Galasko Douglas, Fogel Brent L, Innes A Micheil, Ross Alison, Dobyns William B, Alcantara Diana, O'Driscoll Mark, Hannequin Didier, Campion Dominique, French PFBC study group, Oliveira João R, Garavaglia Barbara, Coppola Giovanni, Nicolas Gaël
Аннотация
Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.