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1. Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

Author

Joustra, S.D. (Sjoerd), Kamp, G.A., Stalman, S.E. (Susanne E.), Donze, S.H. (Stephanie), Losekoot, M. (Monique), Kant, S.G. (Sarina), Bruin, C. (Christiaan) de, Oostdijk, W. (Wilma), Wit, J.M. (Jan), Joustra, S.D. (Sjoerd), Kamp, G.A., Stalman, S.E. (Susanne E.), Donze, S.H. (Stephanie), Losekoot, M. (Monique), Kant, S.G. (Sarina), Bruin, C. (Christiaan) de, Oostdijk, W. (Wilma), and Wit, J.M. (Jan)

Abstract

Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsufficiency. Methods: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. Results: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. Conclusion: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.

Published
2020
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2. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., Santen, G.W.E. (Gijs), van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., and Santen, G.W.E. (Gijs)

Abstract

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Published
2018
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3. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), Kremer, H. (Hannie), Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), and Kremer, H. (Hannie)

Abstract

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

Published
2018
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4. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands

Author

Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), Yntema, H.G., Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), and Yntema, H.G.

Abstract

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Published
2017
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5. Successful growth hormone therapy in Cornelia de Lange syndrome

Author

de Graaf, M. (Michael), Kant, S.G. (Sarina), Wit, J.M. (Jan), Redeker, E.J.W. (Egbert), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Losekoot, M. (Monique), Oostdijk, W. (Wilma), de Graaf, M. (Michael), Kant, S.G. (Sarina), Wit, J.M. (Jan), Redeker, E.J.W. (Egbert), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Losekoot, M. (Monique), and Oostdijk, W. (Wilma)

Abstract

Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.

Published
2017
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6. Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Author

Hannema, S.E. (Sabine), Wit, J.M. (Jan M.), Houdijk, E.C.A.M. (Mieke), Haeringen, A. (Arie) van, Bik, E.C. (Elsa), Verkerk, A., Uitterlinden, A.G. (André), Kant, S.G. (Sarina), Oostdijk, W. (Wilma), Bakker, E. (Egbert), Delemarre-van de Waal, H.A. (Henriette), Losekoot, M. (Monique), Hannema, S.E. (Sabine), Wit, J.M. (Jan M.), Houdijk, E.C.A.M. (Mieke), Haeringen, A. (Arie) van, Bik, E.C. (Elsa), Verkerk, A., Uitterlinden, A.G. (André), Kant, S.G. (Sarina), Oostdijk, W. (Wilma), Bakker, E. (Egbert), Delemarre-van de Waal, H.A. (Henriette), and Losekoot, M. (Monique)

Abstract

Background: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. Methods: Whole-exome sequencing and targeted sequencing were used to detect the LEPR mutations. RNA analysis was performed to assess the effect of splice-site mutations. Results: In 2 unrelated girls with severe obesity, three novel LEPR mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. Conclusion: The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology.

Published
2016
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7. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

Author

Ockeloen, C. (Charlotte), Willemsen, M.H. (Marjolein), Munnik, S.A. (Sonja) de, Bon, B. (Bregje) van, Leeuw, N. (Nicole) de, Verrips, A. (Aad), Kant, S.G. (Sarina), Jones, E.A. (Elizabeth A.), Brunner, H.G., Van Loon, R.L.E. (Rosa), Smeets, E.E.J. (Eric E.J.), Haelst, M.M. (Mieke) van, Haaften, G. (Gijs) van, Nordgren, A. (Ann), Malmgren, H. (Helena), Grigelioniene, G. (Giedre), Vermeer, S.E. (Sarah), Louro, P. (Pedro), Ramos, L. (Lina), Maal, T.J.J. (Thomas J.J.), Heumen, C.C.M. (Céleste) van, Yntema, H.G., Carels, C.E.L. (Carine), Kleefstra, T. (Tjitske), Ockeloen, C. (Charlotte), Willemsen, M.H. (Marjolein), Munnik, S.A. (Sonja) de, Bon, B. (Bregje) van, Leeuw, N. (Nicole) de, Verrips, A. (Aad), Kant, S.G. (Sarina), Jones, E.A. (Elizabeth A.), Brunner, H.G., Van Loon, R.L.E. (Rosa), Smeets, E.E.J. (Eric E.J.), Haelst, M.M. (Mieke) van, Haaften, G. (Gijs) van, Nordgren, A. (Ann), Malmgren, H. (Helena), Grigelioniene, G. (Giedre), Vermeer, S.E. (Sarah), Louro, P. (Pedro), Ramos, L. (Lina), Maal, T.J.J. (Thomas J.J.), Heumen, C.C.M. (Céleste) van, Yntema, H.G., Carels, C.E.L. (Carine), and Kleefstra, T. (Tjitske)

Abstract

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal

Published
2015
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8. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation-in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

Author

Oostdijk, W. (Wilma), Idkowiak, J. (Jan), Mueller, J.W. (Jonathan W.), House, P.J. (Philip J.), Taylor, A.E. (A.), O'Reilly, M.W. (Michael W.), Hughes, B.A. (Beverly A.), Vries, M.C. (Martine) de, Kant, S.G. (Sarina), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Wit, J.M. (Jan), Losekoot, M. (Monique), Arlt, W. (Wiebke), Oostdijk, W. (Wilma), Idkowiak, J. (Jan), Mueller, J.W. (Jonathan W.), House, P.J. (Philip J.), Taylor, A.E. (A.), O'Reilly, M.W. (Michael W.), Hughes, B.A. (Beverly A.), Vries, M.C. (Martine) de, Kant, S.G. (Sarina), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Wit, J.M. (Jan), Losekoot, M. (Monique), and Arlt, W. (Wiebke)

Abstract

Copyright

Published
2015
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9. Phenotype and genotype in 101 males with x-linked creatine transporter deficiency

Author

van de Kamp, J.M. (Jiddeke M.), Betsalel, O.T. (Ofir), Mercimek-Mahmutoglu, S. (Saadet), Abulhoul, L. (L.), Grünewald, S. (Sonja), Anselm, I. (I.), Azzouz, H. (H.), Bratkovic, D. (D.), Brouwer, A.P.M. (Arjan) de, Hamel, B.C. (Ben), Kleefstra, T. (Tjitske), Yntema, H.G., Campistol, J.M., Vilaseca, M.A. (M.), Cheillan, D. (David), D'Hooghe, M. (M.), Diogo, L. (Luisa), Garcia, P. (Paula), Valongo, C. (C.), Fonseca, M. (M.), Frints, S.G.M. (Suzanna), Wilcken, B. (Bridget), Haar, S. (Sigrun) von der, Meijers-Heijboer, E.J. (Hanne), Hofstede, F.C. (Floris), Johnson, D. (David), Kant, S.G. (Sarina), Lion-Francois, L. (Laurence), Pitelet, G. (G.), Longo, N. (N.), Maat-Kievit, A.A. (Anneke), Monteiro, J.P. (J.), Munnich, A. (Arnold), Muntau, A.C. (A.), Nassogne, M.C. (M.), Osaka, H. (H.), Õunap, K. (Katrin), Pinard, J.M. (J.), Quijano-Roy, S. (S.), Poggenburg, I. (I.), Poplawski, N. (Nicola), Abdul-Rahman, O.A. (Omar), Ribes, A. (A.), Arias Pérez, J.I. (José Ignacio), Yaplito-Lee, J. (J.), Schulze, A. (A.), Schwartz, C.E., Schwenger, S. (S.), Soares, G. (G.), Sznajer, Y. (Yves), Valayannopoulos, V. (Vassili), Esch, H. (Hilde) van, Waltz, S. (S.), Wamelink, M.M.C. (Mirjam), Pouwels, P.J.W. (Petra), Errami, A. (Abdellatif), Knaap, M.S. (Marjo) van der, Jakobs, C. (Cornelis), Mancini, G.M.S. (Grazia), Salomons, G.S. (Gajja), van de Kamp, J.M. (Jiddeke M.), Betsalel, O.T. (Ofir), Mercimek-Mahmutoglu, S. (Saadet), Abulhoul, L. (L.), Grünewald, S. (Sonja), Anselm, I. (I.), Azzouz, H. (H.), Bratkovic, D. (D.), Brouwer, A.P.M. (Arjan) de, Hamel, B.C. (Ben), Kleefstra, T. (Tjitske), Yntema, H.G., Campistol, J.M., Vilaseca, M.A. (M.), Cheillan, D. (David), D'Hooghe, M. (M.), Diogo, L. (Luisa), Garcia, P. (Paula), Valongo, C. (C.), Fonseca, M. (M.), Frints, S.G.M. (Suzanna), Wilcken, B. (Bridget), Haar, S. (Sigrun) von der, Meijers-Heijboer, E.J. (Hanne), Hofstede, F.C. (Floris), Johnson, D. (David), Kant, S.G. (Sarina), Lion-Francois, L. (Laurence), Pitelet, G. (G.), Longo, N. (N.), Maat-Kievit, A.A. (Anneke), Monteiro, J.P. (J.), Munnich, A. (Arnold), Muntau, A.C. (A.), Nassogne, M.C. (M.), Osaka, H. (H.), Õunap, K. (Katrin), Pinard, J.M. (J.), Quijano-Roy, S. (S.), Poggenburg, I. (I.), Poplawski, N. (Nicola), Abdul-Rahman, O.A. (Omar), Ribes, A. (A.), Arias Pérez, J.I. (José Ignacio), Yaplito-Lee, J. (J.), Schulze, A. (A.), Schwartz, C.E., Schwenger, S. (S.), Soares, G. (G.), Sznajer, Y. (Yves), Valayannopoulos, V. (Vassili), Esch, H. (Hilde) van, Waltz, S. (S.), Wamelink, M.M.C. (Mirjam), Pouwels, P.J.W. (Petra), Errami, A. (Abdellatif), Knaap, M.S. (Marjo) van der, Jakobs, C. (Cornelis), Mancini, G.M.S. (Grazia), and Salomons, G.S. (Gajja)

Abstract

Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 30 end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Published
2013
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10. The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Author

Nikkel, S.M. (Sarah), Dauber, A. (Andrew), Munnik, S.A. (Sonja) de, Connolly, M. (Meghan), Hood, R.L. (Rebecca L), Caluseriu, O. (Oana), Hurst, J.A. (Jane), Kini, U. (Usha), Nowaczyk, M.J.M., Afenjar, A. (Alexandra), Albrecht, B., Allanson, J.E. (Judith), Balestri, P. (Paolo), Ben-Omran, T. (Tawfeg), Brancati, F. (Fred), Cordeiro, I. (Isabel), Da Cunha, B.S. (Bruna Santos), Delaney, P.F. (Peter), Destrée, A. (Anne), Fitzpatrick, D.R. (David), Forzano, F. (Francesca), Ghali, N. (Neeti), Gillies, G. (Greta), Harwood, J., Hendriks, Y., Héron, D. (Delphine), Hoischen, A. (Alex), Honey, E.M. (Engela Magdalena), Hoefsloot, E.H. (Lies), Ibrahim, J. (Jennifer), Jacob, C. (Claire), Kant, S.G. (Sarina), Kim, C.A. (Chong), Kirk, E.P. (Edwin P), Knoers, N.V.A.M. (Nine), Lacombe, D. (Denis), Lee, C.Y. (Chung-Yee), Lo, I.F.M. (Ivan F M), Lucas, L.S. (Luiza S), Mari, F. (Francesca), Mericq, V. (Veronica), Moilanen, J.S. (Jukka S), Møller, S.T. (Sanne Traasdahl), Moortgat, S. (Stephanie), Pilz, D.T. (Daniela), Pope, K. (Kate), Price, S. (Susan), Renieri, A. (Alessandra), Sá, J. (Joaquim), Schoots, J. (Jeroen), Silveira, E.L. (Elizabeth L), Simon, M.E.H. (Marleen), Slavotinek, A. (Anne), Temple, I.K., Burgt, I. (Ineke) van der, Vries, B.B.A. (Bert) de, Weisfeld-Adams, J.D. (James D), Whiteford, M.L. (Margo L), Wierczorek, D. (Dagmar), Wit, J.M. (Jan), Yee, C.F.O. (Connie Fung On), Beaulieu, P. (Patrick), White, S.M. (Sue M), Bulman, B., Bongers, E. (Ernie), Brunner, H. (Han), Feingold, M. (Murray), Boycott, K.M. (Kym), Nikkel, S.M. (Sarah), Dauber, A. (Andrew), Munnik, S.A. (Sonja) de, Connolly, M. (Meghan), Hood, R.L. (Rebecca L), Caluseriu, O. (Oana), Hurst, J.A. (Jane), Kini, U. (Usha), Nowaczyk, M.J.M., Afenjar, A. (Alexandra), Albrecht, B., Allanson, J.E. (Judith), Balestri, P. (Paolo), Ben-Omran, T. (Tawfeg), Brancati, F. (Fred), Cordeiro, I. (Isabel), Da Cunha, B.S. (Bruna Santos), Delaney, P.F. (Peter), Destrée, A. (Anne), Fitzpatrick, D.R. (David), Forzano, F. (Francesca), Ghali, N. (Neeti), Gillies, G. (Greta), Harwood, J., Hendriks, Y., Héron, D. (Delphine), Hoischen, A. (Alex), Honey, E.M. (Engela Magdalena), Hoefsloot, E.H. (Lies), Ibrahim, J. (Jennifer), Jacob, C. (Claire), Kant, S.G. (Sarina), Kim, C.A. (Chong), Kirk, E.P. (Edwin P), Knoers, N.V.A.M. (Nine), Lacombe, D. (Denis), Lee, C.Y. (Chung-Yee), Lo, I.F.M. (Ivan F M), Lucas, L.S. (Luiza S), Mari, F. (Francesca), Mericq, V. (Veronica), Moilanen, J.S. (Jukka S), Møller, S.T. (Sanne Traasdahl), Moortgat, S. (Stephanie), Pilz, D.T. (Daniela), Pope, K. (Kate), Price, S. (Susan), Renieri, A. (Alessandra), Sá, J. (Joaquim), Schoots, J. (Jeroen), Silveira, E.L. (Elizabeth L), Simon, M.E.H. (Marleen), Slavotinek, A. (Anne), Temple, I.K., Burgt, I. (Ineke) van der, Vries, B.B.A. (Bert) de, Weisfeld-Adams, J.D. (James D), Whiteford, M.L. (Margo L), Wierczorek, D. (Dagmar), Wit, J.M. (Jan), Yee, C.F.O. (Connie Fung On), Beaulieu, P. (Patrick), White, S.M. (Sue M), Bulman, B., Bongers, E. (Ernie), Brunner, H. (Han), Feingold, M. (Murray), and Boycott, K.M. (Kym)

Abstract

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2

Published
2013
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11. An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities

Author

Hannema, S.E. (Sabine), Duyvenvoorde, H.A. (Hermine) van, Thomas, P. (Premsler), Yang, R.-B. (Ruey-Bing), Mueller, T.D. (Thomas), Gassner, I.J. (Ingrid), Oberwinkler, H. (Heike), Roelfsema, F. (Ferdinand), Santen, G.W.E. (Gijs), Prickett, T. (Timothy), Kant, S.G. (Sarina), Verkerk, A., Uitterlinden, A.G. (André), Espiner, E. (Eric), Ruivenkamp, C.A. (Claudia), Oostdijk, W. (Wilma), Pereira, A.M. (Alberto), Losekoot, M. (Monique), Kuhn, M. (Michael), Wit, J.M. (Jan), Hannema, S.E. (Sabine), Duyvenvoorde, H.A. (Hermine) van, Thomas, P. (Premsler), Yang, R.-B. (Ruey-Bing), Mueller, T.D. (Thomas), Gassner, I.J. (Ingrid), Oberwinkler, H. (Heike), Roelfsema, F. (Ferdinand), Santen, G.W.E. (Gijs), Prickett, T. (Timothy), Kant, S.G. (Sarina), Verkerk, A., Uitterlinden, A.G. (André), Espiner, E. (Eric), Ruivenkamp, C.A. (Claudia), Oostdijk, W. (Wilma), Pereira, A.M. (Alberto), Losekoot, M. (Monique), Kuhn, M. (Michael), and Wit, J.M. (Jan)

Abstract

Background: C-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype, and skeletal abnormalities.Asimilar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain. Case: Here we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain. Objectives: The objective of the study was to investigate the functional and structural effects of the NPR2 mutation. Methods: Guanylyl cyclase activities of wild-type vs mutant NPR2 were analyzed in transfected human embryonic kidney 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation. Results: CNP-stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected human embryonic kidney 293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilization by ATP. Coimmunoprecipitation showed that wild-type and mutant NPR2 can form stable heterodimers, suggesting a dominant-positive effect. In accordance with augmented endogenous receptor activity, plasma N-terminal pro-CNP (a marker of CNP production in tissues) was reduced in the proband. Conclusions:Wereport the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.

Published
2013
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12. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification

Author

Walenkamp, M.J.E. (Marie), Muinck Keizer-Schrama, S.M.P.F. (Sabine) de, Mos, M. (Marianne) de, Kalf, M.E. (Margot), Duyvenvoorde, H.A. (Hermine) van, Boot, A.M. (Annemieke), Kant, S.G. (Sarina), White, S.J. (Stefan), Losekoot, M. (Monique), Dunnen, J.T. (Johan) den, Karperien, M. (Marcel), Wit, J.M. (Jan), Walenkamp, M.J.E. (Marie), Muinck Keizer-Schrama, S.M.P.F. (Sabine) de, Mos, M. (Marianne) de, Kalf, M.E. (Margot), Duyvenvoorde, H.A. (Hermine) van, Boot, A.M. (Annemieke), Kant, S.G. (Sarina), White, S.J. (Stefan), Losekoot, M. (Monique), Dunnen, J.T. (Johan) den, Karperien, M. (Marcel), and Wit, J.M. (Jan)

Abstract

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height. Copyright

Published
2008
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