Papers by Olivier Vanakker
Clinical Zinc Deficiency as Early Presentation of Wilson Disease
Journal of Pediatric Gastroenterology and Nutrition, 2014
Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygo... more Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2+) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion.
SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity
Journal of Bone and Mineral Research, 2013
Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by r... more Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of "Västerbottenian osteopetrosis," named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF-κB ligand (RANKL), receptor activator of NF-κB (RANK) and osteopetrosis-associated transmembrane protein 1 (OSTM1)-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies.
Pseudoxanthome élastique (PXE) associé à un digénisme ABCC6/GCCX
Annales de Dermatologie et de Vénéréologie, 2014
The Genetics of Soft Connective Tissue Disorders
Annual Review of Genomics and Human Genetics, 2014
Over the last few years, the field of hereditary connective tissue disorders has changed tremendo... more Over the last few years, the field of hereditary connective tissue disorders has changed tremendously. This review highlights exciting insights into three prototypic disorders affecting the soft connective tissue: Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and cutis laxa. For each of these disorders, the identification and characterization of several novel but related conditions or subtypes have widened the phenotypic spectrum. In parallel, the vast underlying molecular network connecting these phenotypes is progressively being uncovered. Identification and characterization (both clinical and molecular) of new phenotypes within the connective tissue disorder spectrum are often key to further unraveling the pathways involved in connective tissue biology and delineating the clinical spectrum and pathophysiology of the disorders. Although difficult challenges remain, recent findings have expanded our pathophysiological understanding and may lead to targeted therapies in the near future. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 16 is August 31, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Cutis laxa acquise associée à une gammapathie monoclonale chez un patient porteur d’une mutation du gène de l’élastine
La Revue de Médecine Interne, 2013
European journal of human genetics : EJHG, Jan 11, 2015
Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator comp... more Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.European Journal of Human Geneti...
Molecular Genetics and Metabolism, 2014
Introduction: Stickler syndrome is caused by mutations in genes encoding type II and type XI coll... more Introduction: Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3. Methods: We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings. Results: In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques. Conclusion: We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndrome patients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.
Stroke Research and Treatment, 2011
Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multif... more Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis.
Neuromuscular Disorders, 2010
There are 14 genes known in which a variety of mutations cause autosomal recessive LGMD type 2 (L... more There are 14 genes known in which a variety of mutations cause autosomal recessive LGMD type 2 (LGMD2), but approximately 30% of LGMD patients lack a molecular diagnosis. We ascertained 13 consanguineous pedigrees informative for linkage analysis in which
Molecular Genetics and Metabolism, 2011
. Non-opacified CT-scan of the lower legs in a patient with PXE disease (male, 59 years) showing ... more . Non-opacified CT-scan of the lower legs in a patient with PXE disease (male, 59 years) showing the typical calcified proximal (blue) and distal (cyan) arteries. Note the absence of arteriomegaly.
Journal of the American Academy of Dermatology, 2011
Background-Pseudoxanthoma elasticum (PXE) is thought to be a metabolic disorder resulting from mu... more Background-Pseudoxanthoma elasticum (PXE) is thought to be a metabolic disorder resulting from mutations in the gene encoding the cellular transporter, ABCC6, which is primarily expressed in liver and kidney. We encountered three patients who developed clinical and histopathological evidence of PXE after liver transplantation, suggesting that PXE could have been acquired from the transplanted organ.
Human Mutation, 2012
Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unk... more Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra-and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major-if not only-cause of classic EDS.
European Journal of Pediatrics, 2002
The use of a patient-triggered and automatic event recorder is documented in a 17-month-old girl ... more The use of a patient-triggered and automatic event recorder is documented in a 17-month-old girl presenting with paroxysmal episodes of loss of consciousness. After pacemaker implantation, the paroxysmal attacks disappeared. Conclusion: we recommend a more frequent use of the event recorder in the investigation of syncope, especially in small children.
Cutis laxa acquise associée à une gammapathie monoclonale chez un patient porteur d’une mutation du gène de l’élastine
Annales de Dermatologie et de Vénéréologie, 2012
American Journal of Medical Genetics Part A, 2014
Journal of Medical Genetics
Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic vari... more Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were fou...
European Journal of Paediatric Neurology, 2015
Array: 112-118kb deletion of chr. 4p31.23
Nature genetics, Jan 4, 2015
Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium ph... more Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
The Journal of investigative dermatology, 2015
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissu... more The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exom...
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Papers by Olivier Vanakker