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1. A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry

Author

Cortese, A, Beecroft, SJ, Facchini, S, Curro, R, Cabrera-Serrano, M, Stevanovski, I, Chintalaphani, SR, Gamaarachchi, H, Weisburd, B, Folland, C, Monahan, G, Scriba, CK, Dofash, L, Johari, M, Grosz, BR, Ellis, M, Fearnley, LG, Tankard, R, Read, J, Merve, A, Dominik, N, Vegezzi, E, Schnekenberg, RP, Fernandez-Eulate, G, Masingue, M, Giovannini, D, Delatycki, MB, Storey, E, Gardner, M, Amor, DJ, Nicholson, G, Vucic, S, Henderson, RD, Robertson, T, Dyke, J, Fabian, V, Mastaglia, F, Davis, MR, Kennerson, M, Quinlivan, R, Hammans, S, Tucci, A, Bahlo, M, McLean, CA, Laing, NG, Stojkovic, T, Houlden, H, Hanna, MG, Deveson, IW, Lockhart, PJ, Lamont, PJ, Fahey, MC, Bugiardini, E, Ravenscroft, G, Oflazer, P, Basak, NA, Kayserili, H, Yesil, G, Malfatti, E, Lilliker, JB, Wicklund, M, Pitceathly, RDS, Brady, S, Brais, B, Pellerin, D, Zuchner, S, Danzi, MC, Grandis, M, Comi, GP, Corti, SP, Abati, E, Toscano, A, Manini, A, Ghia, A, Tassorelli, C, Quartesan, I, Simone, R, Rossor, AM, Reilly, MM, Carroll, L, Straub, V, Udd, B, Chen, Z, Bonne, G, Cortese, A, Beecroft, SJ, Facchini, S, Curro, R, Cabrera-Serrano, M, Stevanovski, I, Chintalaphani, SR, Gamaarachchi, H, Weisburd, B, Folland, C, Monahan, G, Scriba, CK, Dofash, L, Johari, M, Grosz, BR, Ellis, M, Fearnley, LG, Tankard, R, Read, J, Merve, A, Dominik, N, Vegezzi, E, Schnekenberg, RP, Fernandez-Eulate, G, Masingue, M, Giovannini, D, Delatycki, MB, Storey, E, Gardner, M, Amor, DJ, Nicholson, G, Vucic, S, Henderson, RD, Robertson, T, Dyke, J, Fabian, V, Mastaglia, F, Davis, MR, Kennerson, M, Quinlivan, R, Hammans, S, Tucci, A, Bahlo, M, McLean, CA, Laing, NG, Stojkovic, T, Houlden, H, Hanna, MG, Deveson, IW, Lockhart, PJ, Lamont, PJ, Fahey, MC, Bugiardini, E, Ravenscroft, G, Oflazer, P, Basak, NA, Kayserili, H, Yesil, G, Malfatti, E, Lilliker, JB, Wicklund, M, Pitceathly, RDS, Brady, S, Brais, B, Pellerin, D, Zuchner, S, Danzi, MC, Grandis, M, Comi, GP, Corti, SP, Abati, E, Toscano, A, Manini, A, Ghia, A, Tassorelli, C, Quartesan, I, Simone, R, Rossor, AM, Reilly, MM, Carroll, L, Straub, V, Udd, B, Chen, Z, and Bonne, G

Abstract

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

Published
2024

2. Array-comparative genomic hybridization results in clinically affected cases with apparently balanced chromosomal rearrangements

Author

Satkin NB, Karaman B, Ergin S, Kayserili H, Kalelioglu IH, Has R, Yuksel A, and Basaran S

Subjects
apparently balanced structural chromosomal abnormalities (abcrs), array-comparative genomic hybridization (acgh), chromosomal microarray (cma), cryptic genomic imbalances, fetal ultrasound findings, Genetics, QH426-470
Abstract

Carriers of apparently balanced chromosomal rearrangements (ABCRs) have a 2-3-fold higher risk of carrying an abnormal phenotype, when compared to the average population. Apparently balanced chromosomal rearrangements can be imbalanced at the submicroscopic level, and changes in the gene structure, formation of a new chimeric gene, gain or loss of function of the genes and altered imprinting pattern may also affect the phenotype. Chromosomal microarray (CMA) is an efficient tool to detect submicroscopic imbalances at the breakpoints as well as in the whole genome. We aimed to determine the effectiveness of array-comparative genomic hybridization (aCGH) application in phenotypically affected cases with ABCRs at a single center from Turkey. Thirty-four affected cases (13 prenatal, 21 postnatal) carrying ABCRs were investigated with CMA. In postnatal series, ABCRs were familial in 7 and de novo in 14 cases. Seven de novo cases were imbalanced (in postnatal series 33.3% and in de novo cases 50.0%). Out of 13 prenatal cases, five were familial and eight were de novo in origin and two de novo cases were imbalanced (in 15.4% prenatal series and in 25.0% de novo cases). No cryptic imbalance was observed in familial cases. The anomaly rates with array studies ranged between 14.3-25.0% in familial and between 20.0-57.5% in de novo cases of postnatal series in the literature. Studies focused on prenatal ABCR cases with abnormal ultrasound findings are limited and no submicroscopic imbalance was reported in the cohorts. When de novo postnatal or prenatal results were combined, the percentage of abnormalities detected by CMA was 40.9%. Taking this contribution into consideration, all ABCRs should be investigated by CMA even if the fetal ultrasound findings are normal.

Published
2021
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3. Distinguishing the four genetic causes of Jouberts syndrome-related disorders

Author

Valente, E M, Marsh, S E, Castori, M, Dixon-Salazar, T, Bertini, E, Al-Gazali, L, Messer, J, Barbot, C, Woods, C G, Boltshauser, E, Al-Tawari, A A, Salpietro, C D, Kayserili, H, Sztriha, L, Gribaa, M, Koenig, M, Dallapiccola, B, and Gleeson, J G

Abstract

Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34-3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.

Published
2005

4. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome

Author

Lima, A.R., Ferreira, B.M., Zhang, C, Jolly, A., Du, H., White, J.J., Dawood, M., Lins, T.C., Chiabai, M.A., Beusekom, E. van, Cordoba, M.S., Rosa, E.C.C. Caldas, Kayserili, H., Kimonis, V., Wu, E., Mellado, C., Aggarwal, V., Richieri-Costa, A., Brunoni, D., Canó, T.M., Jorge, A.A.L., Kim, C.A., Honjo, R., Bertola, D.R., Dandalo-Girardi, R.M., Bayram, Y., Gezdirici, A., Yilmaz-Gulec, E., Gumus, E., Yilmaz, G.C., Okamoto, N., Ohashi, H., Coban-Akdemir, Z., Mitani, T., Jhangiani, S.N., Muzny, D.M., Regattieri, N.A.P., Pogue, R., Pereira, R.W., Otto, P.A., Gibbs, R.A., Ali, B.R., Bokhoven, H. van, Brunner, H.G., Sutton, V.R., Lupski, J.R., Vianna-Morgante, A.M., Carvalho, C.M., Mazzeu, J.F., Lima, A.R., Ferreira, B.M., Zhang, C, Jolly, A., Du, H., White, J.J., Dawood, M., Lins, T.C., Chiabai, M.A., Beusekom, E. van, Cordoba, M.S., Rosa, E.C.C. Caldas, Kayserili, H., Kimonis, V., Wu, E., Mellado, C., Aggarwal, V., Richieri-Costa, A., Brunoni, D., Canó, T.M., Jorge, A.A.L., Kim, C.A., Honjo, R., Bertola, D.R., Dandalo-Girardi, R.M., Bayram, Y., Gezdirici, A., Yilmaz-Gulec, E., Gumus, E., Yilmaz, G.C., Okamoto, N., Ohashi, H., Coban-Akdemir, Z., Mitani, T., Jhangiani, S.N., Muzny, D.M., Regattieri, N.A.P., Pogue, R., Pereira, R.W., Otto, P.A., Gibbs, R.A., Ali, B.R., Bokhoven, H. van, Brunner, H.G., Sutton, V.R., Lupski, J.R., Vianna-Morgante, A.M., Carvalho, C.M., and Mazzeu, J.F.

Abstract

Contains fulltext : 252015.pdf (Publisher’s version ) (Closed access), Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Published
2022

7. Correction: A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects (Advanced Science, (2021), 8, 5, (2001100), 10.1002/advs.202001100)

Author

Sahni, Geetika, Chang, Shu-Yung, Teo, Jeremy Choon Meng, Tan, Jerome Zu Yao, Fatien, Jean Jacques Clement, Bonnard, Carine, Utami, Kagistia Hana, Chan, Puck Wee, Tan, Thong Teck, Altunoglu, Umut, Kayserili, H. lya, Pouladi, Mahmoud, Reversade, Bruno, Toh, Yi-Chin, ACS - Heart failure & arrhythmias, and Amsterdam Reproduction & Development (AR&D)

Abstract

In the originally published article, the first name and family name of the third author were mixed-up. The corrected author byline is presented here.

Published
2021

11. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Author

Kargapolova, Y., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Yun, Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., Bon, B. van, Gilissen, C.F., Laugsch, M., Gusmao, E.G., Josipovic, N., Altmüller, J., Nürnberg, P., Längst, G., Kaiser, F.J., Watrin, E., Brunner, H.G., Rada-Iglesias, A., Kurian, L., Wollnik, B., Bouazoune, K., Papantonis, A., Kargapolova, Y., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Yun, Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., Bon, B. van, Gilissen, C.F., Laugsch, M., Gusmao, E.G., Josipovic, N., Altmüller, J., Nürnberg, P., Längst, G., Kaiser, F.J., Watrin, E., Brunner, H.G., Rada-Iglesias, A., Kurian, L., Wollnik, B., Bouazoune, K., and Papantonis, A.

Abstract

Contains fulltext : 235041.pdf (Publisher’s version ) (Open Access), Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

Published
2021

12. Author Correction: Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology (Nature Communications, (2020), 11, 1, (4589), 10.1038/s41467-020-18146-9)

Author

Elouej, Sahar, Harhouri, Karim, Mao, Morgane Le, Baujat, Genevieve, Nampoothiri, Sheela, Kayserili, H. lya, Menabawy, Nihal Al, Selim, Laila, Paneque, Arianne Llamos, Kubisch, Christian, Lessel, Davor, Rubinsztajn, Robert, Charar, Chayki, Bartoli, Catherine, Airault, Coraline, Deleuze, Jean-François, Rötig, Agnes, Bauer, Peter, Pereira, Catarina, Loh, Abigail, Escande-Beillard, Nathalie, Muchir, Antoine, Martino, Lisa, Gruenbaum, Yosef, Lee, Song-Hua, Manivet, Philippe, Lenaers, Guy, Reversade, Bruno, Lévy, Nicolas, de Sandre-Giovannoli, Annachiara, and ACS - Heart failure & arrhythmias

Abstract

The original version of this Article contained errors in the author affiliations. The affiliations of Nathalie Escande-Beillard and Bruno Reversade with ‘Medical Genetics Department, Koç University, School of Medicine (KUSoM), Istanbul, Turkey’ were inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

13. Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B

Author

Palencia-Campos A, Martínez-Fernández ML, Altunoglu U, Soto-Bielicka P, Torres A, Marín P, Aller E, Sentürk L, Berköz Ö, Yildiran M, Kayserili H, Gil-Camarero E, Colli-Lista G, Sanchís-Calvo A, Carretero A, ECEMC Working Group on Polydactyly, Guillén-Navarro E, López-González V, Ballesta-Martínez M, Rosell J, Aglan MS, Temtamy S, Otaify GA, Cuevas-Catalina L, Torres-Saavedra MN, Nevado J, Tenorio J, Lapunzina P, Bermejo-Sánchez E, and Ruiz-Pérez VL

Subjects
integumentary system, incomplete penetrance, GLI1, limb development, postaxial polydactyly A, GLI1, Postaxial polydactyly A/B, hedgehog signaling, incomplete penetrance, limb development, hedgehog signaling
Abstract

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, bi-allelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analysed the coding region of GLI1 in 95 independent probands with non-syndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B. This article is protected by copyright. All rights reserved.

Published
2020

14. Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2

Author

Escande-Beillard, N., Loh, A., Saleem, S.N., Kanata, K., Hashimoto, Yui, Altunoglu, U., Metoska, A., Grandjean, J., Ng, F.M., Pomp, O., Baburajendran, N., Wong, J., Hill, J., Beillard, E., Cozzone, P., Zaki, M., Kayserili, H., Hamada, H., Shiratori, H., Reversade, B., Escande-Beillard, N., Loh, A., Saleem, S.N., Kanata, K., Hashimoto, Yui, Altunoglu, U., Metoska, A., Grandjean, J., Ng, F.M., Pomp, O., Baburajendran, N., Wong, J., Hill, J., Beillard, E., Cozzone, P., Zaki, M., Kayserili, H., Hamada, H., Shiratori, H., and Reversade, B.

Abstract

Contains fulltext : 225883.pdf (Publisher’s version ) (Closed access), Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.

Published
2020

15. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death

Author

Fellmann, F., van El, C.G., Charron, P., Michaud, K., Howard, H.C., Boers, S.N., Clarke, A.J., Duguet, A.M., Forzano, F., Kauferstein, S., Kayserili, H., Lucassen, A., Mendes, Á., Patch, C., Radojkovic, D., Rial-Sebbag, E., Sheppard, M.N., Tassé, A.M., Temel, S.G., Sajantila, A., Basso, C., Wilde, AAM, Cornel, M.C., and on behalf of European Society of Human Genetics, European Council of Legal Medicine, European Society of Cardiology working group on myocardial and pericardial diseases, European Reference Network for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Association for European Cardiovascular Pathology

Subjects
Autopsy, Death, Sudden, Cardiac/epidemiology, Death, Sudden, Cardiac/pathology, Death, Sudden, Cardiac/prevention & control, European Union/organization & administration, Genetic Testing/standards, Heart Diseases/genetics, Heart Diseases/mortality, Heart Diseases/pathology, Humans, Myocardium/pathology
Abstract

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.

Published
2019

19. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency

Author

Van Kuilenburg, A. B. P., Vreken, P., Abeling, N. G. G. M., Bakker, H. D., Meinsma, R., Van Lenthe, H., De Abreu, R. A., Smeitink, J. A. M., Kayserili, H., Apak, M. Y., Christensen, E., Holopainen, I., Pulkki, K., Riva, D., Botteon, G., Holme, E., Tulinius, M., Kleijer, W. J., Beemer, F. A., Duran, M., Niezen-Koning, K. E., Smit, G. P. A., Jakobs, C., Smit, L. M. E., Moog, U., Spaapen, L. J. M., and Van Gennip, A. H.

Published
1999
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28. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

Author

Vega, H, Trainer, A H, Gordillo, M, Crosier, M, Kayserili, H, Skovby, F, Uzielli, M L, Schnur, R E, Manouvrier, S, Blair, E, Hurst, J A, Forzano, F, Meins, M, Simola, K O, Raas-Rothschild, A, Hennekam, R C, and Jabs, E Wang

Published
2010
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33. Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome (Genetics in Medicine, (2019), 21, 6, (1295-1307), 10.1038/s41436-018-0330-z)

Author

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

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

34. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome (vol 21, pg 1295, 2019)

Author

Sluijs, P.J. van der, Jansen, S., Vergano, S.A., Adachi-Fukuda, M., Alanay, Y., AlKindy, A., Baban, A., Bayat, A., Beck-Wodl, S., Berry, K., Bijlsma, E.K., Bok, L.A., Brouwer, A.F.J., Burgt, I. van der, Campeau, P.M., Canham, N., Chrzanowska, K., Chu, Y.W.Y., Chung, B.H.Y., Dahan, K., Rademaeker, M. de, Destree, A., Dudding-Byth, T., Earl, R., Elcioglu, N., Elias, E.R., Fagerberg, C., Gardham, A., Gener, B., Gerkes, E.H., Grasshoff, U., Haeringen, A. van, Heitink, K.R., Herkert, J.C., Hollander, N.S. den, Horn, D., Hunt, D., Kant, S.G., Kato, M., Kayserili, H., Kersseboom, R., Kilic, E., Krajewska-Walasek, M., Lammers, K., Laulund, L.W., Lederer, D., Lees, M., Lopez-Gonzalez, V., Maas, S., Mancini, G.M.S., Marcelis, C., Martinez, F., Maystadt, I., McGuire, M., Mckee, S., Mehta, S., Metcalfe, K., Milunsky, J., Mizuno, S., Moeschler, J.B., Netzer, C., Ockeloen, C.W., Oehl-Jaschkowitz, B., Okamoto, N., Olminkhof, S.N.M., Orellana, C., Pasquier, L., Pottinger, C., Riehmer, V., Robertson, S.P., Roifman, M., Rooryck, C., Ropers, F.G., Rosello, M., Ruivenkamp, C.A.L., Sagiroglu, M.S., Sallevelt, S.C.E.H., Calvo, A.S., Simsek-Kiper, P.O., Soares, G., Solaeche, L., Sonmez, F.M., Splitt, M., Steenbeek, D., Stegmann, A.P.A., Stumpel, C.T.R.M., Tanabe, S., Uctepe, E., Utine, G.E., Veenstra-Knol, H.E., Venkateswaran, S., Vilain, C., Vincent-Delorme, C., Vulto-van Silfhout, A.T., Wheeler, P., Wilson, G.N., Wilson, L.C., Wollnik, B., Kosho, T., Wieczorek, D., Eichler, E., Pfundt, R., Vries, B.B.A. de, Clayton-Smith, J., Santen, G.W.E., and Acibadem University Dspace

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

38. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)

Author

Rad, Abolfazl, Altunoglu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Caglayan, Ahmet Okay, Wu, K.M., Bakey, Z., Kayserili, H., Schmidts, M., Rad, Abolfazl, Altunoglu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Caglayan, Ahmet Okay, Wu, K.M., Bakey, Z., Kayserili, H., and Schmidts, M.

Abstract

Contains fulltext : 204020.pdf (publisher's version ) (Open Access)

Published
2019

43. Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome /692/699 /631/208/1516 article

Author

Kievit, Anneke, Tessadori, Federico, Douben, Hannie, Jordens, Ingrid, Maurice, Madelon, Hoogeboom, Jeannette, Hennekam, Raoul, Nampoothiri, Sheela, Kayserili, H. lya, Castori, Marco, Whiteford, Margo, Motter, Connie, Melver, Catherine, Cunningham, Michael, Hing, Anne, Kokitsu-Nakata, Nancy M., Vendramini-Pittoli, Siulan, Richieri-Costa, Antonio, Baas, Annette F., Breugem, Corstiaan C., Duran, Karen, Massink, Maarten, Derksen, Patrick W. B., van Ijcken, Wilfred F. J., van Unen, Leontine, Santos-Simarro, Fernando, Lapunzina, Pablo, Gil-da Silva Lopes, Vera L., Lustosa-Mendes, Elaine, Krall, Max, Slavotinek, Anne, Martinez-Glez, Victor, Bakkers, Jeroen, van Gassen, Koen L. I., de Klein, Annelies, van den Boogaard, Marie-José H., van Haaften, Gijs, APH - Quality of Care, and Amsterdam Reproduction & Development (AR&D)

Abstract

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Published
2018

44. Mutation spectrum of 260 dystrophinopathy patients from Turkey and important highlights for genetic counseling

Author

Toksoy, G, primary, Durmus, H, additional, Aghayev, A, additional, Bagirova, G, additional, Sevinc Rustemoglu, B, additional, Basaran, S, additional, Avci, S, additional, Karaman, B, additional, Parman, Y, additional, Altunoglu, U, additional, Yapici, Z, additional, Tekturk, P, additional, Deymeer, F, additional, Topaloglu, H, additional, Kayserili, H, additional, Oflazer-Serdaroglu, P, additional, and Uyguner, ZO, additional

Published
2019
Full Text
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45. 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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47. Responsible implementation of expanded carrier screening

Author

Henneman, L., Borry, P., Chokoshvili, D., Cornel, M. C., van El, C. G., Forzano, F., Hall, A., Howard, H. C., Janssens, S., Kayserili, H., Lakeman, P., Lucassen, A., Metcalfe, S. A., Vidmar, L., de Wert, G., Dondorp, W. J., Peterlin, B., Henneman, L., Borry, P., Chokoshvili, D., Cornel, M. C., van El, C. G., Forzano, F., Hall, A., Howard, H. C., Janssens, S., Kayserili, H., Lakeman, P., Lucassen, A., Metcalfe, S. A., Vidmar, L., de Wert, G., Dondorp, W. J., and Peterlin, B.

Abstract

This corrects the article DOI: 10.1038/ejhg.2015.271., Henneman, Lidewij Borry, Pascal Chokoshvili, Davit Cornel, Martina C van El, Carla G Forzano, Francesca Hall, Alison Howard, Heidi C Janssens, Sandra Kayserili, Hulya Lakeman, Phillis Lucassen, Anneke Metcalfe, Sylvia A Vidmar, Lovro de Wert, Guido Dondorp, Wybo J Peterlin, Borut eng Published Erratum England 2017/10/13 06:00 Eur J Hum Genet. 2017 Nov;25(11):1291. doi: 10.1038/ejhg.2017.159.

Published
2017

48. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., Bon, B.W.M. van, Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., and Bon, B.W.M. van

Abstract

Contains fulltext : 174787.pdf (publisher's version ) (Open Access), Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017

49. Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Author

Mendes, M.I., Smith, D.E., Pop, A., Lennertz, P., Fernandez Ojeda, M.R., Kanhai, W.A., Dooren, S.J. van, Anikster, Y., Baric, I., Boelen, C., Campistol, J., Boer, L. de, Kariminejad, A., Kayserili, H., Roubertie, A., Verbruggen, K.T., Vianey-Saban, C., Williams, M., Salomons, G.S., Mendes, M.I., Smith, D.E., Pop, A., Lennertz, P., Fernandez Ojeda, M.R., Kanhai, W.A., Dooren, S.J. van, Anikster, Y., Baric, I., Boelen, C., Campistol, J., Boer, L. de, Kariminejad, A., Kayserili, H., Roubertie, A., Verbruggen, K.T., Vianey-Saban, C., Williams, M., and Salomons, G.S.

Abstract

Contains fulltext : 182871.pdf (Publisher’s version ) (Open Access), We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase-the hydrolysis of N-acetyl-l-aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC-MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non-typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD.

Published
2017

50. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), Bon, B. (Bregje) van, Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), and Bon, B. (Bregje) van

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017
Full Text
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