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21 results on '"Smithson, S.F."'

1. AIFM1‐associated X‐linked spondylometaphyseal dysplasia with cerebral hypomyelination

Author

Edgerley, K., Barnicoat, A., Offiah, A.C., Calder, A.D., Mankad, K., Thomas, N.S., Bunyan, D.J., Williams, M., Buxton, C., Majumdar, A., Vijayakumar, K., Hilliard, T., Turner, J., Burren, C.P., Monsell, F., and Smithson, S.F.

Abstract

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD‐H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD‐H has been associated with variants confined to a specific intra‐genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

Published
2021

2. Missense mutations in the β strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia

Author

Jackson, G.C., Barker, F.S., Jakkula, E., Czarny-Ratajczak, M., Makitie, O., Cole, W.G., Wright, M.J., Smithson, S.F., Suri, M., Rogala, P., Mortier, G.R., Baldock, C., Wallace, A., Elles, R., Ala-Kokko, L., and Briggs, M.D.

Abstract

J Med Genet 2004;41:52-59 Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia in which the hip and knee joints are most frequently affected. Both autosomal dominant [...]

Published
2004

3. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author

Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., Baralle, D., Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., and Baralle, D.

Abstract

Contains fulltext : 190731.pdf (publisher's version ) (Open Access), BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and

Published
2018

5. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Author

Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., UK10K, Knoers, N.V., Roepman, R., Mitchison, H.M., Schmidts, Miriam, Arts, Heleen H., Bongers, Ernie M. H. F., Yap, Zhimin, Oud, Machteld M., Antony, Dinu, Duijkers, Lonneke, Emes, Richard D., Stalker, Jim, Yntema, Jan-Bart L., Plagnol, Vincent, Hoischen, Alexander, Gilissen, Christian, Forsythe, Elisabeth, Lausch, Ekkehart, Veltman, Joris A., Roeleveld, Nel, Superti-Furga, Andrea, Kutkowska-Kazmierczak, Anna, Kamsteeg, Erik-Jan, Elcioglu, Nursel, van Maarle, Merel C., Graul-Neumann, Luitgard M., Devriendt, Koenraad, Smithson, Sarah F., Wellesley, Diana, Verbeek, Nienke E., Hennekam, Raoul C. M., Kayserili, Hulya, Scambler, Peter J., Beales, Philip L., Knoers, Nine V. A. M., Roepman, Ronald, Mitchison, Hannah M., Human Genetics, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and UK10K

Subjects
Exome/genetics, Cytoplasmic Dyneins, Models, Molecular, Genetics and epigenetic pathways of disease [NCMLS 6], Protein Conformation, Bioinformatics, medicine.disease_cause, 0302 clinical medicine, Models, Genetic Screening/Counselling, Missense mutation, Developmental, Exome, CRYSTAL-STRUCTURE, Diagnostics, Genetics (clinical), Exome sequencing, Renal disorder [IGMD 9], Genetics, Microscopy, 0303 health sciences, Mutation, Polydactyly, Developmental Defects, DEFECTS, Polymorphism, Single Nucleotide/genetics, 3. Good health, Gene Components, Ellis-Van Creveld Syndrome/genetics, PELVIC-PHALANGEAL DYSTROPHY, Single Nucleotide/genetics, Sequence Analysis, Mutation/genetics, Ellis-Van Creveld Syndrome, Molecular Sequence Data, IFT, Biology, DYNEIN MOTOR DOMAIN, Polymorphism, Single Nucleotide, Fluorescence, Frameshift mutation, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular Genetics, 03 medical and health sciences, Intraflagellar transport, CYTOPLASMIC DYNEIN, medicine, RETROGRADE INTRAFLAGELLAR TRANSPORT, Humans, Polymorphism, 030304 developmental biology, Clinical Genetics, Base Sequence, Genetic heterogeneity, Molecular, DNA, Sequence Analysis, DNA, Human Reproducion Genomic disorders and inherited multi-system disorders [NCEBP 12], medicine.disease, LIGHT INTERMEDIATE CHAIN, Microscopy, Fluorescence, Cytoplasmic Dyneins/chemistry, Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6], PRIMARY CILIARY DYSKINESIA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], CAENORHABDITIS-ELEGANS, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 116495.pdf (Publisher’s version ) (Open Access) BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes. 15 p.

Published
2013

6. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype

Author

Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., Mortier, G.R., Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., and Mortier, G.R.

Abstract

Item does not contain fulltext

Published
2015

7. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

Author

UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., Mitchison, H.M., UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., and Mitchison, H.M.

Abstract

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Published
2013

8. Dominant missense mutations in ABCC9 cause Cantu syndrome.

Author

Harakalova, M., Harssel, J.J. van, Terhal, P.A., Lieshout, S. van, Duran, K., Renkens, I., Amor, D.J., Wilson, L.C., Kirk, E.P., Turner, C.L., Shears, D., Garcia-Minaur, S., Lees, M.M., Ross, A., Venselaar, H., Vriend, G., Takanari, H., Rook, M.B., Heyden, M.A. van der, Asselbergs, F.W., Breur, H.M., Swinkels, M.E., Scurr, I.J., Smithson, S.F., Knoers, N.V.A.M., Smagt, J.J. van der, Nijman, IJ, Kloosterman, W.P., Haelst, M.M. van, Haaften, G. van, Cuppen, E., Harakalova, M., Harssel, J.J. van, Terhal, P.A., Lieshout, S. van, Duran, K., Renkens, I., Amor, D.J., Wilson, L.C., Kirk, E.P., Turner, C.L., Shears, D., Garcia-Minaur, S., Lees, M.M., Ross, A., Venselaar, H., Vriend, G., Takanari, H., Rook, M.B., Heyden, M.A. van der, Asselbergs, F.W., Breur, H.M., Swinkels, M.E., Scurr, I.J., Smithson, S.F., Knoers, N.V.A.M., Smagt, J.J. van der, Nijman, IJ, Kloosterman, W.P., Haelst, M.M. van, Haaften, G. van, and Cuppen, E.

Abstract

Item does not contain fulltext, Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantu syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantu syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantu syndrome.

Published
2012

9. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Author

Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., Vries, L.B.A. de, Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., and Vries, L.B.A. de

Abstract

Item does not contain fulltext, Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

Published
2011

10. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Author

Hoornaert, K.P., Vereecke, I., Dewinter, C., Rosenberg, T., Beemer, F.A., Leroy, J.G., Bendix, L., Bjorck, E., Bonduelle, M., Boute, O., Cormier-Daire, V., Die-Smulders, C.E.M. de, Dieux-Coeslier, A., Dollfus, H., Elting, M., Green, A., Guerci, V.I., Hennekam, R.C.M., Hilhorts-Hofstee, Y., Holder, M., Hoyng, C.B., Jones, K.J., Josifova, D., Kaitila, I., Kjaergaard, S., Kroes, Y.H., Lagerstedt, K., Lees, M., Lemerrer, M., Magnani, C., Marcelis, C.L.M., Martorell, L., Mathieu, M., McEntagart, M., Mendicino, A., Morton, J., Orazio, G., Paquis, V., Reish, O., Simola, K.O., Smithson, S.F., Temple, K.I., Aken, E. Van, Bever, Y. Van, Ende, J. van den, Hagen, J.M. van, Zelante, L., Zordania, R., Paepe, A. de, Leroy, B.P., Buyzere, M. de, Coucke, P.J., Mortier, G.R., Hoornaert, K.P., Vereecke, I., Dewinter, C., Rosenberg, T., Beemer, F.A., Leroy, J.G., Bendix, L., Bjorck, E., Bonduelle, M., Boute, O., Cormier-Daire, V., Die-Smulders, C.E.M. de, Dieux-Coeslier, A., Dollfus, H., Elting, M., Green, A., Guerci, V.I., Hennekam, R.C.M., Hilhorts-Hofstee, Y., Holder, M., Hoyng, C.B., Jones, K.J., Josifova, D., Kaitila, I., Kjaergaard, S., Kroes, Y.H., Lagerstedt, K., Lees, M., Lemerrer, M., Magnani, C., Marcelis, C.L.M., Martorell, L., Mathieu, M., McEntagart, M., Mendicino, A., Morton, J., Orazio, G., Paquis, V., Reish, O., Simola, K.O., Smithson, S.F., Temple, K.I., Aken, E. Van, Bever, Y. Van, Ende, J. van den, Hagen, J.M. van, Zelante, L., Zordania, R., Paepe, A. de, Leroy, B.P., Buyzere, M. de, Coucke, P.J., and Mortier, G.R.

Abstract

1 augustus 2010, Contains fulltext : 89172.pdf (publisher's version ) (Closed access), Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

Published
2010

11. Schimke immunoosseous dysplasia: Defining skeletal features

Author

Hunter, K.B. (Kshamta), Lücke, T. (Thomas), Spranger, J. (Jürgen), Smithson, S.F. (Sarah), Alpay, H. (Harika), André, J.-L. (Jean-Luc), Asakura, Y. (Yumi), Bogdanovic, R. (Radovan), Bonneau, D. (Dominique), Cairns, R. (Robyn), Cransberg, K. (Karlien), Fründ, S. (Stefan), Fryssira, H. (Helen), Goodman, D. (David), Helmke, K. (Knut), Hinkelmann, B. (Barbara), Lama, G. (Guiliana), Lamfers, P. (Petra), Loirat, C. (Chantal), Majore, S. (Silvia), Mayfield, C. (Christy), Pontz, B.F. (Betram), Rusu, C. (Christina), Saraiva, J.M. (Jorge), Schmidt, B. (Beate), Schoemaker, L. (Lawrence), Sigaudy, S. (Sabine), Stajic, N. (Natasa), Taha, D. (Doris), Boerkoel, C.F. (Cornelius), Hunter, K.B. (Kshamta), Lücke, T. (Thomas), Spranger, J. (Jürgen), Smithson, S.F. (Sarah), Alpay, H. (Harika), André, J.-L. (Jean-Luc), Asakura, Y. (Yumi), Bogdanovic, R. (Radovan), Bonneau, D. (Dominique), Cairns, R. (Robyn), Cransberg, K. (Karlien), Fründ, S. (Stefan), Fryssira, H. (Helen), Goodman, D. (David), Helmke, K. (Knut), Hinkelmann, B. (Barbara), Lama, G. (Guiliana), Lamfers, P. (Petra), Loirat, C. (Chantal), Majore, S. (Silvia), Mayfield, C. (Christy), Pontz, B.F. (Betram), Rusu, C. (Christina), Saraiva, J.M. (Jorge), Schmidt, B. (Beate), Schoemaker, L. (Lawrence), Sigaudy, S. (Sabine), Stajic, N. (Natasa), Taha, D. (Doris), and Boerkoel, C.F. (Cornelius)

Abstract

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Published
2010
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