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1. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author

Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, Genuardi M (ORCID:0000-0002-7410-8351), Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, and Genuardi M (ORCID:0000-0002-7410-8351)

Abstract

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants. Keywords: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.

Published
2022

2. Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Author

Arts, P, Simons, A, AlZahrani, MS, Yilmaz, E, AlIdrissi, E, van Aerde, KJ, Alenezi, N, AlGhamdi, HA, AlJubab, HA, Al-Hussaini, AA, AlManjomi, F, Alsaad, AB, Alsaleem, B, Andijani, AA, Asery, A, Ballourah, W, Bleeker-Rovers, CP, van Deuren, M, Flier, Michiel, Gerkes, E H, Gilissen, C, Habazi, MK, Hehir-Kwa, JY, Henriet, SS, Hoppenreijs, EP, Hortillosa, S, Kerkhofs, CH, Keski-Filppula, R, Lelieveld, SH, Lone, K, MacKenzie, MA, Mensenkamp, AR, Moilanen, J, Nelen, M, ten Oever, J, Potjewijd, J, van Paassen, P, Schuurs-Hoeijmakers, JHM, Simon, A, Stokowy, T, van de Vorst, M, Vreeburg, M, Wagner, Anja, van Well, GTJ, Zafeiropoulou, D, Zonneveld-Huijssoon, E, Veltman, JA, van Zelst-Stams, W A G, Faqeih, EA, van de Veerdonk, FL, Netea, MG, Hoischen, A, Arts, P, Simons, A, AlZahrani, MS, Yilmaz, E, AlIdrissi, E, van Aerde, KJ, Alenezi, N, AlGhamdi, HA, AlJubab, HA, Al-Hussaini, AA, AlManjomi, F, Alsaad, AB, Alsaleem, B, Andijani, AA, Asery, A, Ballourah, W, Bleeker-Rovers, CP, van Deuren, M, Flier, Michiel, Gerkes, E H, Gilissen, C, Habazi, MK, Hehir-Kwa, JY, Henriet, SS, Hoppenreijs, EP, Hortillosa, S, Kerkhofs, CH, Keski-Filppula, R, Lelieveld, SH, Lone, K, MacKenzie, MA, Mensenkamp, AR, Moilanen, J, Nelen, M, ten Oever, J, Potjewijd, J, van Paassen, P, Schuurs-Hoeijmakers, JHM, Simon, A, Stokowy, T, van de Vorst, M, Vreeburg, M, Wagner, Anja, van Well, GTJ, Zafeiropoulou, D, Zonneveld-Huijssoon, E, Veltman, JA, van Zelst-Stams, W A G, Faqeih, EA, van de Veerdonk, FL, Netea, MG, and Hoischen, A

Published
2019

3. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Author

Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, de Vries, BBA, Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, and de Vries, BBA

Abstract

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

Published
2017

4. MLL2 mutation detection in 86 patients with Kabuki syndrome: A genotype-phenotype study

Author

Makrythanasis, P, van Bon, BW, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, BM, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, EMHF, del Campo, M, Cordeiro, I, Cueto-González, AM, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, SM, Hoyer, J, Yntema, HG, Kets, CM, Koolen, DA, Marcelis, CL, Medeira, A, Micale, L, Mohammed, S, de Munnik, SA, Nordgren, A, Psoni, S, Reardon, W, Revencu, N, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, HG, Schoumans, J, Schuurs-Hoeijmakers, JHM, Silengo, MC, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, RC, Perez-Jurado, L, Dupont, J, de Vries, BBA, Brunner, HG, Veltman, JA, Merla, G, Antonarakis, SE, Hoischen, A, Makrythanasis, P, van Bon, BW, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, BM, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, EMHF, del Campo, M, Cordeiro, I, Cueto-González, AM, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, SM, Hoyer, J, Yntema, HG, Kets, CM, Koolen, DA, Marcelis, CL, Medeira, A, Micale, L, Mohammed, S, de Munnik, SA, Nordgren, A, Psoni, S, Reardon, W, Revencu, N, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, HG, Schoumans, J, Schuurs-Hoeijmakers, JHM, Silengo, MC, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, RC, Perez-Jurado, L, Dupont, J, de Vries, BBA, Brunner, HG, Veltman, JA, Merla, G, Antonarakis, SE, and Hoischen, A

Abstract

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p<0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Published
2013

5. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, Hoischen, A, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, and Hoischen, A

Abstract

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Published
2013

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