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Smith H.,University of Birmingham | Smith H.,University College London | Galmes R.,University Utrecht | Gogolina E.,University College London | And 23 more authors.
Human Mutation | Year: 2012

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apical-basolateral polarity regulator (VIPAR). Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients with ARC do not survive past the first year of life. We report two patients presenting with a mild ARC phenotype, now 5.5 and 3.5 years old. Both patients were compound heterozygotes with the novel VPS33B donor splice-site mutation c.1225+5G>C in common. Immunoblotting and complementary DNA analysis suggest expression of a shorter VPS33B transcript, and cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function). This study provides the first evidence of genotype-phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype. We have established an interactive online database for ARC (https://grenada.lumc.nl/LOVD2/ARC) comprising all known variants in VPS33B and VIPAR. Also included in the database are 15 novel pathogenic variants in VPS33B and five in VIPAR. © 2012 Wiley Periodicals, Inc. Source

Nishimura G.,Tokyo Metropolitan Kiyose Childrens Hospital | Dai J.,RIKEN | Dai J.,Nanjing University | Lausch E.,University Hospital Freiburg | And 14 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

Recent discoveries have established the existence of a family of skeletal dysplasias caused by dominant mutations in TRPV4. This family comprises, in order of increasing severity, dominant brachyolmia, spondylo-metaphyseal dysplasia Kozlowski type, and metatropic dysplasia.Wetested the hypothesis that a further condition, Spondylo-epiphyseal dysplasia (SED), Maroteaux type (MIM 184095; also known as pseudo-Morquio syndrome type 2), could be caused by TRPV4 mutations. We analyzed six individuals with Maroteaux type SED, including three who had previously been reported. All six patients were found to have heterozygous TRPV4 mutations; three patients had unreported mutations, while three patients had mutations previously described in association with metatropic dysplasia. In addition, we tested one individual with a distinct rare disorder, parastremmatic dysplasia (MIM 168400). This patient had a common, recurrent mutation seen in several patients with Kozlowski type spondylo-metaphyseal dysplasia. We conclude that SED Maroteaux type and parastremmatic dysplasia are part of the TRPV4 dysplasia family and that TRPV4 mutations show considerable variability in phenotypic expression resulting in distinct clinical radiographic phenotypes. © 2010 Wiley-Liss, Inc. Source

Varga R.-E.,Jena University Hospital | Schule R.,Hertie Institute for Clinical Brain Research and Center for Neurology | Schule R.,University of Miami | Fadel H.,Al Kortobi Hospital | And 13 more authors.
Human Mutation | Year: 2013

The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex-dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders. © 2013 Wiley Periodicals, Inc. Source

Malagoli C.,University of Modena and Reggio Emilia | Crespi C.M.,University of California at Los Angeles | Rodolfi R.,Local Health Unit of Reggio Emilia | Signorelli C.,University of Parma | And 9 more authors.
Bioelectromagnetics | Year: 2012

The issue of adverse human health effects due to exposure to electromagnetic fields is still unclear, and congenital anomalies are among the outcomes that have been inconsistently associated with such exposure. We conducted a population-based, case-control study to examine the risk of congenital anomalies associated with maternal exposure to magnetic fields (MF) from high-voltage power lines during pregnancy in a community in northern Italy. We identified 228 cases of congenital malformations diagnosed in live births, stillbirths, and induced abortions among women living in the municipality of Reggio Emilia during the period 1998-2006, and a reference group of healthy newborns was matched for year of birth, maternal age, and hospital of birth. We identified maternal residence during early pregnancy and used Geographic Information System to determine whether the residences were within geocoded corridors with MF ≥0.1μT near high-voltage power lines, then calculated the relative risk (RR) of congenital anomalies associated with maternal exposure. One case and 5 control mothers were classified as exposed, and the RR associated with MF ≥0.1μT was 0.2 (95% CI: 0.0-2.0) after adjusting for maternal education. While small or moderate effects may have gone undetected due to low statistical power, the results of this study overall do not provide support for major effects of a teratogenic risk due to exposure to MF during early pregnancy. © 2011 Wiley Periodicals, Inc. Source

Huber C.,University of Paris Descartes | Wu S.,University of California at Los Angeles | Kim A.S.,University of California at Los Angeles | Sigaudy S.,Clinical Genetic Unit | And 12 more authors.
American Journal of Human Genetics | Year: 2013

Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-kB activation pathway is involved in the pathogenesis of the skeletal ciliopathies. © 2013 by The American Society of Human Genetics. All rights reserved. Source

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