Primary brain calcification: an international study reporting novel variants and associated phenotypes.
Eur J Hum Genet. 2018-06-28; 26(10): 1462-1477
DOI: 10.1038/s41431-018-0185-4
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1. Eur J Hum Genet. 2018 Oct;26(10):1462-1477. doi: 10.1038/s41431-018-0185-4. Epub
2018 Jun 28.
Primary brain calcification: an international study reporting novel variants and
associated phenotypes.
Ramos EM(1), Carecchio M(2)(3)(4), Lemos R(5), Ferreira J(5), Legati A(1), Sears
RL(1), Hsu SC(1), Panteghini C(2), Magistrelli L(6), Salsano E(7), Esposito S(3),
Taroni F(8), Richard AC(9), Tranchant C(10)(11), Anheim M(10)(11), Ayrignac
X(12), Goizet C(13)(14), Vidailhet M(15), Maltete D(16), Wallon D(17), Frebourg
T(9), Pimentel L(5), Geschwind DH(1), Vanakker O(18), Galasko D(19), Fogel
BL(20), Innes AM(21), Ross A(22), Dobyns WB(23), Alcantara D(24), O’Driscoll
M(24), Hannequin D(25), Campion D(9)(26); French PFBC study group, Oliveira
JR(5), Garavaglia B(2), Coppola G(27), Nicolas G(28).
Author information:
(1)Department of Psychiatry, David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA.
(2)Molecular Neurogenetics Unit, Movement Disorders Section, IRCCS Foundation
Carlo Besta Neurological Institute, Via L. Temolo n. 4, Milan, 20116, Italy.
(3)Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological
Institute, Via Celoria 11, Milan, 20131, Italy.
(4)PhD Programme in Translational and Molecular Medicine, Milan Bicocca
University, Monza, Italy.
(5)Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil.
(6)Department of Neurology, University of Eastern Piedmont, C.so Mazzini 18,
Novara, 28100, Italy.
(7)Department of Clinical Neurosciences, IRCCS Foundation Carlo Besta
Neurological Institute, Via Celoria 11, Milan, 20131, Italy.
(8)IRCCS Foundation Carlo Besta Neurological Institute, Via Amadeo 42, Milan,
20133, Italy.
(9)Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital,
Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and
Personalized Medicine, Rouen, France.
(10)Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de
Hautepierre; Fédération de Médecine Translationnelle de Strasbourg (FMTS),
Université de Strasbourg, Strasbourg, France.
(11)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC),
INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Strasbourg, Illkirch, France.
(12)Department of Neurology, Montpellier University Hospital, Montpellier,
France.
(13)CHU Bordeaux, Service de Génétique Médicale, 33000, Bordeaux, France.
(14)INSERM U1211, Univ Bordeaux, Laboratoire Maladies Rares, Génétique et
Métabolisme, 33000, Bordeaux, France.
(15)Département de neurologie, Hôpital Pitié-Salpêtrière, Assistance
Publique-Hôpitaux de Paris, Paris, UPMC Univ Paris 06, Inserm U1127, CNRS UMR
7225, ICM, F-75013, Sorbonne Universites, Paris, France.
(16)Normandie Univ, UNIROUEN, Inserm U1073, Rouen University Hospital, Department
of Neurology, F 76000, Rouen, France.
(17)Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital,
Department of Neurology and CNR-MAJ, F 76000, Normandy Center for Genomic and
Personalized Medicine, Rouen, France.
(18)Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185,
B-9000, Ghent, Belgium.
(19)Veterans Affairs Medical Center, San Diego and University of California, San
Diego, USA.
(20)Departments of Neurology and Human Genetics, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA, USA.
(21)Department of Medical Genetics and Alberta Children’s Hospital Research
Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
(22)Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK.
(23)Departments of Pediatrics and Neurology, University of Washington; and Center
for Integrative Brain Research, Seattle Children’s Research Institute, Seattle,
WA, USA.
(24)Genome Damage & Stability Centre, University of Sussex, Brighton, UK.
(25)Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital,
Department of Neurology, Department of Genetics and CNR-MAJ, F 76000, Normandy
Center for Genomic and Personalized Medicine, Rouen, France.
(26)Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen,
Rouen, France.
(27)Department of Psychiatry, David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA. .
(28)Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital,
Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and
Personalized Medicine, Rouen, France. .
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.
DOI: 10.1038/s41431-018-0185-4
PMCID: PMC6138755
PMID: 29955172 [Indexed for MEDLINE]