33 results on '"Acuna-Hidalgo R"'
Search Results
2. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies
- Author
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van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), Hoischen, A. (Alex), van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), and Hoischen, A. (Alex)
- Abstract
Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.
- Published
- 2020
- Full Text
- View/download PDF
3. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies
- Author
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van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, Hoischen, A, van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, and Hoischen, A
- Published
- 2020
4. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
- Author
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Putte, R. van de, Wijers, C.H.W., Reutter, H., Vermeulen, S.H., Marcelis, C.L.M., Brosens, E., Broens, P., Homberg, M., Ludwig, M., Jenetzky, E., Zwink, N., Sloots, C.E.J., Klein, A. de, Brooks, A.S., Hofstra, R.M.W., Holsink, S.A.C., Zanden, L.F.M. van der, Galesloot, T.E., Tam, P.K.H, Steehouwer, M., Acuna-Hidalgo, R., Vorst, J.M. van de, Kiemeney, L.A.L.M., Garcia- Barcelo, M.M., Blaauw, I. de, Brunner, H.G., Roeleveld, N., Rooij, I.A.L.M. van, Putte, R. van de, Wijers, C.H.W., Reutter, H., Vermeulen, S.H., Marcelis, C.L.M., Brosens, E., Broens, P., Homberg, M., Ludwig, M., Jenetzky, E., Zwink, N., Sloots, C.E.J., Klein, A. de, Brooks, A.S., Hofstra, R.M.W., Holsink, S.A.C., Zanden, L.F.M. van der, Galesloot, T.E., Tam, P.K.H, Steehouwer, M., Acuna-Hidalgo, R., Vorst, J.M. van de, Kiemeney, L.A.L.M., Garcia- Barcelo, M.M., Blaauw, I. de, Brunner, H.G., Roeleveld, N., and Rooij, I.A.L.M. van
- Abstract
Contains fulltext : 205341.pdf (publisher's version ) (Open Access)
- Published
- 2019
5. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
- Author
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van de Putte, R., Wijers, C.H.W. (Charlotte), Reutter, H. (Heiko), Vermeulen, SH, Marcelis, CLM, Brosens, E. (Erwin), Broens, P.M.A. (Paul), Homberg, M., Ludwig, M. (Michael), Jenetzky, E. (Ekkehart), Zwink, N. (Nadine), Sloots, C.E.J. (Pim), Klein, J.E.M.M. (Annelies) de, Brooke, A.S., Hofstra, R.M.W. (Robert), Holsink, S.A.C., Zanden, L.F.M. (Loes) van der, Galesloot, TE, Tam, P.K.H. (Paul), Steehouwer, M., Acuna-Hidalgo, R., van de Vorst, M., Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, H.G., Roeleveld, N. (Nel), de Rooij, I, van de Putte, R., Wijers, C.H.W. (Charlotte), Reutter, H. (Heiko), Vermeulen, SH, Marcelis, CLM, Brosens, E. (Erwin), Broens, P.M.A. (Paul), Homberg, M., Ludwig, M. (Michael), Jenetzky, E. (Ekkehart), Zwink, N. (Nadine), Sloots, C.E.J. (Pim), Klein, J.E.M.M. (Annelies) de, Brooke, A.S., Hofstra, R.M.W. (Robert), Holsink, S.A.C., Zanden, L.F.M. (Loes) van der, Galesloot, TE, Tam, P.K.H. (Paul), Steehouwer, M., Acuna-Hidalgo, R., van de Vorst, M., Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, H.G., Roeleveld, N. (Nel), and de Rooij, I
- Abstract
Introduction Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, as
- Published
- 2019
- Full Text
- View/download PDF
6. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
- Author
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van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, de Rooij, I, van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, and de Rooij, I
- Published
- 2019
7. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease
- Author
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Nicolas, Gael, Acuna Hidalgo, R., Keogh, Michael J., Quenez, Olivier, Steehouwer, M., Lelieveld, S.H., Oud, M.S., Gilissen, C., Veltman, J.A., Hoischen, A., Nicolas, Gael, Acuna Hidalgo, R., Keogh, Michael J., Quenez, Olivier, Steehouwer, M., Lelieveld, S.H., Oud, M.S., Gilissen, C., Veltman, J.A., and Hoischen, A.
- Abstract
Item does not contain fulltext
- Published
- 2018
8. Timing of de novo mutations - relevance to health and disease
- Author
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Acuna Hidalgo, R., Veltman, J.A., Hoischen, A., Gilissen, C.F.H.A., and Radboud University Nijmegen
- Subjects
Radboud Institute for Molecular Life Sciences ,Neurodevelopmental disorders [Radboudumc 7] ,Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7] - Abstract
Contains fulltext : 173265.pdf (Publisher’s version ) (Open Access) The work presented in this thesis shows that mutations arise constantly, between one generation and the next but also throughout life. This continuous occurrence of mutations leads to extraordinary genetic diversity between individuals but is also at the origin of the existence of genetically different populations of cells within a single human being. While the occurrence of novel mutations represents an important biological phenomenon in humans with a role on prenatal development, physiology and evolution, novel mutations also contribute to different forms of human disease ranging from rare and severe developmental disorders to adult-onset diseases such as cancer. The work in this thesis supports that in addition to the detection of mutations, NGS can be used as a tool to identify the timing of mutations in order to include the dimension of time in the interpretation of mutations and their possible consequences. De novo mutations have different recurrence risks depending on the exact timing at which they occurred, which can be determined by meticulous analysis with NGS methods. Indeed, genetic mosaicism resulting from mutations occurring during embryogenesis is common and, depending on their timing, postzygotic mutations can be transmitted to the next generation. Additionally, somatic mutations arise in stem cells throughout life and can be detected using highly sensitive sequencing methods. Furthermore, the timing of a mutation can also shape the resulting phenotype, as the same mutation can be involved in different disorders depending on its timing. For instance, overlapping germline and somatic mutations in SETBP1, leading to Schinzel-Giedion syndrome and to myeloid leukemia, respectively. Future work focusing on the role of timing of somatic and germline mutations will provide us with a better understanding of the effect of the expression of a mutation in the dynamic context of a cell, a tissue and a whole organism. Radboud University, 08 juni 2017 Promotor : Veltman, J.A. Co-promotores : Hoischen, A., Gilissen, C.F.H.A.
- Published
- 2017
9. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
- Author
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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
10. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies
- Author
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Shen, W., Heeley, J.M., Carlston, C.M., Acuna Hidalgo, R., Nillesen, W.M., Dent, K.M., Douglas, G.V., Levine, K.L., Bayrak-Toydemir, P., Marcelis, C.L., Shinawi, M., Carey, J.C., Shen, W., Heeley, J.M., Carlston, C.M., Acuna Hidalgo, R., Nillesen, W.M., Dent, K.M., Douglas, G.V., Levine, K.L., Bayrak-Toydemir, P., Marcelis, C.L., Shinawi, M., and Carey, J.C.
- Abstract
Item does not contain fulltext, De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.
- Published
- 2017
11. Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life
- Author
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Acuna Hidalgo, R., Sengul, H., Steehouwer, M., Vorst, M. van de, Vermeulen, S.H., Kiemeney, B., Veltman, J.A., Gilissen, C.F., Hoischen, A., Acuna Hidalgo, R., Sengul, H., Steehouwer, M., Vorst, M. van de, Vermeulen, S.H., Kiemeney, B., Veltman, J.A., Gilissen, C.F., and Hoischen, A.
- Abstract
Contains fulltext : 177281.pdf (publisher's version ) (Closed access), Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals >/=65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.
- Published
- 2017
12. Timing of de novo mutations - relevance to health and disease
- Author
-
Veltman, J.A., Hoischen, A., Gilissen, C.F.H.A., Acuna Hidalgo, R., Veltman, J.A., Hoischen, A., Gilissen, C.F.H.A., and Acuna Hidalgo, R.
- Abstract
Radboud University, 8 juni 2017, Promotor : Veltman, J.A. Co-promotores : Hoischen, A., Gilissen, C.F.H.A., Contains fulltext : 173265.pdf (publisher's version ) (Open Access), The work presented in this thesis shows that mutations arise constantly, between one generation and the next but also throughout life. This continuous occurrence of mutations leads to extraordinary genetic diversity between individuals but is also at the origin of the existence of genetically different populations of cells within a single human being. While the occurrence of novel mutations represents an important biological phenomenon in humans with a role on prenatal development, physiology and evolution, novel mutations also contribute to different forms of human disease ranging from rare and severe developmental disorders to adult-onset diseases such as cancer. The work in this thesis supports that in addition to the detection of mutations, NGS can be used as a tool to identify the timing of mutations in order to include the dimension of time in the interpretation of mutations and their possible consequences. De novo mutations have different recurrence risks depending on the exact timing at which they occurred, which can be determined by meticulous analysis with NGS methods. Indeed, genetic mosaicism resulting from mutations occurring during embryogenesis is common and, depending on their timing, postzygotic mutations can be transmitted to the next generation. Additionally, somatic mutations arise in stem cells throughout life and can be detected using highly sensitive sequencing methods. Furthermore, the timing of a mutation can also shape the resulting phenotype, as the same mutation can be involved in different disorders depending on its timing. For instance, overlapping germline and somatic mutations in SETBP1, leading to Schinzel-Giedion syndrome and to myeloid leukemia, respectively. Future work focusing on the role of timing of somatic and germline mutations will provide us with a better understanding of the effect of the expression of a mutation in the dynamic context of a cell, a tissue and a whole organism.
- Published
- 2017
13. 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
- View/download PDF
14. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
- Author
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Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, van Bon, BW, Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, and van Bon, BW
- Published
- 2017
15. New insights into the generation and role of de novo mutations in health and disease
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Acuna Hidalgo, R., Veltman, J.A., Hoischen, A., Acuna Hidalgo, R., Veltman, J.A., and Hoischen, A.
- Abstract
Contains fulltext : 165722.pdf (publisher's version ) (Open Access), Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent-offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.
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- 2016
16. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (THRA)
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Tylki-Szymanska, A., Acuna Hidalgo, R., Krajewska-Walasek, M., Lecka-Ambroziak, A., Steehouwer, M., Gilissen, C.F., Brunner, H.G., Jurecka, A., Rozdzynska-Swiatkowska, A., Hoischen, A., Chrzanowska, K.H., Tylki-Szymanska, A., Acuna Hidalgo, R., Krajewska-Walasek, M., Lecka-Ambroziak, A., Steehouwer, M., Gilissen, C.F., Brunner, H.G., Jurecka, A., Rozdzynska-Swiatkowska, A., Hoischen, A., and Chrzanowska, K.H.
- Abstract
Item does not contain fulltext, BACKGROUND: Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor beta (TRbeta), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor alpha gene (THRA) defects. METHODS: We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families. FINDINGS: Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations. INTERPRETATION: THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.
- Published
- 2015
17. Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation
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Acuna Hidalgo, R., Bo, T., Kwint, M.P., Vorst, M. van de, Pinelli, M., Veltman, J.A., Hoischen, A., Vissers, L.E.L.M., Gilissen, C., Acuna Hidalgo, R., Bo, T., Kwint, M.P., Vorst, M. van de, Pinelli, M., Veltman, J.A., Hoischen, A., Vissers, L.E.L.M., and Gilissen, C.
- Abstract
Item does not contain fulltext, De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of "de novo" variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.
- Published
- 2015
18. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway
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Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., Zenker, M., Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., and Zenker, M.
- Abstract
Contains fulltext : 136372.pdf (Publisher’s version ) (Closed access), Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.
- Published
- 2014
19. GENE-15. TARGETING OF EPENDYMOMA AS INFORMED BY ONCOGENIC 3D GENOME ORGANIZATION
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Okonechnikov K, Hübner J, Chapman O, Chakraborty A, Bump R, Chandran S, Kraft K, Acuna Hidalgo R, Mundlos S, Coufal N, Levy M, Crawford J, Ferhat Ay, and Chavez L
20. Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.
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Jain S, Trinidad M, Nguyen TB, Jones K, Neto SD, Ge F, Glagovsky A, Jones C, Moran G, Wang B, Rahimi K, Çalıcı SZ, Cedillo LR, Berardelli S, Özden B, Chen K, Katsonis P, Williams A, Lichtarge O, Rana S, Pradhan S, Srinivasan R, Sajeed R, Joshi D, Faraggi E, Jernigan R, Kloczkowski A, Xu J, Song Z, Özkan S, Padilla N, de la Cruz X, Acuna-Hidalgo R, Grafmüller A, Jiménez Barrón LT, Manfredi M, Savojardo C, Babbi G, Martelli PL, Casadio R, Sun Y, Zhu S, Shen Y, Pucci F, Rooman M, Cia G, Raimondi D, Hermans P, Kwee S, Chen E, Astore C, Kamandula A, Pejaver V, Ramola R, Velyunskiy M, Zeiberg D, Mishra R, Sterling T, Goldstein JL, Lugo-Martinez J, Kazi S, Li S, Long K, Brenner SE, Bakolitsa C, Radivojac P, Suhr D, Suhr T, and Clark WT
- Abstract
Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A ( ARSA ) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research., Competing Interests: Declarations Conflict of interest/Competing interests Wyatt T. Clark, Marena Trinidad, Courtney Astore, Teague Sterling, and Sufyan Kazi are former employees and potential shareholders of BioMarin Pharmaceutical. Rocio Acuna-Hidalgo is a current employee and shareholder of Nostos Genomics GmbH. Andrea Grafmüller and Laura T. Jiménez Barrón are former employees of Nostos Genomics GmbH.
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- 2024
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21. 3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.
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Okonechnikov K, Camgöz A, Chapman O, Wani S, Park DE, Hübner JM, Chakraborty A, Pagadala M, Bump R, Chandran S, Kraft K, Acuna-Hidalgo R, Reid D, Sikkink K, Mauermann M, Juarez EF, Jenseit A, Robinson JT, Pajtler KW, Milde T, Jäger N, Fiesel P, Morgan L, Sridhar S, Coufal NG, Levy M, Malicki D, Hobbs C, Kingsmore S, Nahas S, Snuderl M, Crawford J, Wechsler-Reya RJ, Davidson TB, Cotter J, Michaiel G, Fleischhack G, Mundlos S, Schmitt A, Carter H, Michealraj KA, Kumar SA, Taylor MD, Rich J, Buchholz F, Mesirov JP, Pfister SM, Ay F, Dixon JR, Kool M, and Chavez L
- Subjects
- Child, Humans, Child, Preschool, Chromosomes, Chromosome Mapping, Genome, Chromatin genetics, Neoplasm Recurrence, Local genetics, Ependymoma genetics, Ependymoma pathology
- Abstract
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations., (© 2023. The Author(s).)
- Published
- 2023
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22. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies.
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van de Putte R, Dworschak GC, Brosens E, Reutter HM, Marcelis CLM, Acuna-Hidalgo R, Kurtas NE, Steehouwer M, Dunwoodie SL, Schmiedeke E, Märzheuser S, Schwarzer N, Brooks AS, de Klein A, Sloots CEJ, Tibboel D, Brisighelli G, Morandi A, Bedeschi MF, Bates MD, Levitt MA, Peña A, de Blaauw I, Roeleveld N, Brunner HG, van Rooij IALM, and Hoischen A
- Abstract
Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL ( n = 211), ARM ( n = 204), and EA/TEF ( n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4 , and MID1 , genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families., (Copyright © 2020 van de Putte, Dworschak, Brosens, Reutter, Marcelis, Acuna-Hidalgo, Kurtas, Steehouwer, Dunwoodie, Schmiedeke, Märzheuser, Schwarzer, Brooks, de Klein, Sloots, Tibboel, Brisighelli, Morandi, Bedeschi, Bates, Levitt, Peña, de Blaauw, Roeleveld, Brunner, van Rooij and Hoischen.)
- Published
- 2020
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23. Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases.
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Melo US, Schöpflin R, Acuna-Hidalgo R, Mensah MA, Fischer-Zirnsak B, Holtgrewe M, Klever MK, Türkmen S, Heinrich V, Pluym ID, Matoso E, Bernardo de Sousa S, Louro P, Hülsemann W, Cohen M, Dufke A, Latos-Bieleńska A, Vingron M, Kalscheuer V, Quintero-Rivera F, Spielmann M, and Mundlos S
- Subjects
- Chromatin Assembly and Disassembly genetics, Chromosome Breakpoints, Cohort Studies, Humans, SOX9 Transcription Factor genetics, Segmental Duplications, Genomic genetics, Chromosomes, Human genetics, Developmental Disabilities genetics, Genome, Human genetics, Molecular Conformation, Translocation, Genetic genetics
- Abstract
Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). Three individuals had previously been identified as harboring duplications at the SOX9 locus and six had been identified with translocations. Hi-C resolved the positions of the duplications and was instructive in interpreting their distinct pathogenic effects, including the formation of new topologically associating domains (neo-TADs). Hi-C was very sensitive in detecting translocations, and it revealed previously unrecognized complex rearrangements at the breakpoints. In several cases, we observed the formation of fused-TADs promoting ectopic enhancer-promoter interactions that were likely to be involved in the disease pathology. In summary, we show that Hi-C is a sensible method for the detection of complex SVs in a clinical setting. The results help interpret the possible pathogenic effects of the SVs in individuals with DDs., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2020
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24. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.
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van de Putte R, Wijers CHW, Reutter H, Vermeulen SH, Marcelis CLM, Brosens E, Broens PMA, Homberg M, Ludwig M, Jenetzky E, Zwink N, Sloots CEJ, de Klein A, Brooks AS, Hofstra RMW, Holsink SAC, van der Zanden LFM, Galesloot TE, Tam PK, Steehouwer M, Acuna-Hidalgo R, Vorst MV, Kiemeney LA, Garcia-Barceló MM, de Blaauw I, Brunner HG, Roeleveld N, and van Rooij IALM
- Subjects
- Adult, Female, Humans, Male, Anorectal Malformations genetics, Exome, Genetic Variation, Oligonucleotide Array Sequence Analysis
- Abstract
Introduction: Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model., Methods: We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing., Results: When we applied a MAF of ≥1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing., Conclusion: Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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25. Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations.
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Kraft K, Magg A, Heinrich V, Riemenschneider C, Schöpflin R, Markowski J, Ibrahim DM, Acuna-Hidalgo R, Despang A, Andrey G, Wittler L, Timmermann B, Vingron M, and Mundlos S
- Subjects
- Animals, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Chromosomes, Mammalian genetics, Genomics methods, Limb Buds embryology, Mice, Receptor, EphA4 genetics, Receptor, EphA4 metabolism, Chromosome Inversion, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Developmental, Limb Buds metabolism
- Abstract
Balanced chromosomal rearrangements such as inversions and translocations can cause congenital disease or cancer by inappropriately rewiring promoter-enhancer contacts
1,2 . To study the potentially pathogenic consequences of balanced chromosomal rearrangements, we generated a series of genomic inversions by placing an active limb enhancer cluster from the Epha4 regulatory domain at different positions within a neighbouring gene-dense region and investigated their effects on gene regulation in vivo in mice. Expression studies and high-throughput chromosome conformation capture from embryonic limb buds showed that the enhancer cluster activated several genes downstream that are located within asymmetric regions of contact, the so-called architectural stripes3 . The ectopic activation of genes led to a limb phenotype that could be rescued by deleting the CCCTC-binding factor (CTCF) anchor of the stripe. Architectural stripes appear to be driven by enhancer activity, because they do not form in mouse embryonic stem cells. Furthermore, we show that architectural stripes are a frequent feature of developmental three-dimensional genome architecture often associated with active enhancers. Therefore, balanced chromosomal rearrangements can induce ectopic gene expression and the formation of asymmetric chromatin contact patterns that are dependent on CTCF anchors and enhancer activity.- Published
- 2019
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26. Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype.
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Bruel AL, Bigoni S, Kennedy J, Whiteford M, Buxton C, Parmeggiani G, Wherlock M, Woodward G, Greenslade M, Williams M, St-Onge J, Ferlini A, Garani G, Ballardini E, van Bon BW, Acuna-Hidalgo R, Bohring A, Deleuze JF, Boland A, Meyer V, Olaso R, Ginglinger E, Study D, Rivière JB, Brunner HG, Hoischen A, Newbury-Ecob R, Faivre L, Thauvin-Robinet C, and Thevenon J
- Subjects
- Brain abnormalities, Brain diagnostic imaging, Child, Preschool, Facies, Female, Genetic Association Studies, Humans, Infant, Magnetic Resonance Imaging, Male, Young Adult, Autoantigens genetics, Craniosynostoses diagnosis, Craniosynostoses genetics, Genes, Recessive, Intellectual Disability diagnosis, Intellectual Disability genetics, Mutation, Phenotype
- Abstract
Background: Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical 'BOS' posture. BOS is caused by sporadic mutations of ASXL1 . However, several typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity., Objectives: To expand the phenotypical spectrum of autosomal recessive variants of KLHL7 , reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome., Methods: We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients., Results: Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the KLHL7 gene. KLHL7 encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the KLHL7 gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients., Conclusion: We have expanded the clinical spectrum of KLHL7 autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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27. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.
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Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, Douglas GV, Levine KL, Bayrak-Toydemir P, Marcelis CL, Shinawi M, and Carey JC
- Subjects
- Codon, DNA Methyltransferase 3A, Female, Genetic Predisposition to Disease, Germ-Line Mutation genetics, Hematologic Neoplasms pathology, Humans, Intellectual Disability pathology, Male, Mutation, Phenotype, DNA (Cytosine-5-)-Methyltransferases genetics, Face physiopathology, Hematologic Neoplasms genetics, Intellectual Disability genetics
- Abstract
De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies., (© 2017 Wiley Periodicals, Inc.)
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- 2017
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28. Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life.
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Acuna-Hidalgo R, Sengul H, Steehouwer M, van de Vorst M, Vermeulen SH, Kiemeney LALM, Veltman JA, Gilissen C, and Hoischen A
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- Adult, Aged, Base Sequence, Clone Cells, Genetic Loci, Humans, Middle Aged, Molecular Probes metabolism, Open Reading Frames genetics, Reproducibility of Results, Restriction Mapping, Young Adult, DNA Mutational Analysis methods, Hematopoiesis genetics, Mutation genetics
- Abstract
Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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29. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.
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Acuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LM, Borges Ferreira V, Horovitz DD, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenço C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BB, Schinzel A, Fisher SE, Hoischen A, and van Bon BW
- Subjects
- Abnormalities, Multiple metabolism, Abnormalities, Multiple pathology, Blotting, Western, Carrier Proteins metabolism, Cell Line, Cell Proliferation genetics, Cell Transformation, Neoplastic genetics, Child, Child, Preschool, Craniofacial Abnormalities metabolism, Craniofacial Abnormalities pathology, Female, Gene Expression Profiling, Genetic Association Studies, Germ-Line Mutation, HEK293 Cells, Hand Deformities, Congenital metabolism, Hand Deformities, Congenital pathology, Hematologic Neoplasms metabolism, Hematologic Neoplasms pathology, Humans, Infant, Infant, Newborn, Intellectual Disability metabolism, Intellectual Disability pathology, Male, Nails, Malformed metabolism, Nails, Malformed pathology, Nuclear Proteins metabolism, Phenotype, Abnormalities, Multiple genetics, Carrier Proteins genetics, Craniofacial Abnormalities genetics, Genetic Predisposition to Disease genetics, Hand Deformities, Congenital genetics, Hematologic Neoplasms genetics, Intellectual Disability genetics, Mutation, Nails, Malformed genetics, Nuclear Proteins genetics
- 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
- View/download PDF
30. New insights into the generation and role of de novo mutations in health and disease.
- Author
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Acuna-Hidalgo R, Veltman JA, and Hoischen A
- Subjects
- Autism Spectrum Disorder pathology, Exome genetics, Gametogenesis genetics, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability pathology, Autism Spectrum Disorder genetics, Intellectual Disability genetics, Mutation genetics, Sequence Analysis, DNA
- Abstract
Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent-offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.
- Published
- 2016
- Full Text
- View/download PDF
31. Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation.
- Author
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Acuna-Hidalgo R, Bo T, Kwint MP, van de Vorst M, Pinelli M, Veltman JA, Hoischen A, Vissers LE, and Gilissen C
- Subjects
- High-Throughput Nucleotide Sequencing methods, Humans, Models, Genetic, Polymerase Chain Reaction, Embryo, Mammalian, Genetic Variation genetics, Genome genetics, Mosaicism embryology, Point Mutation genetics
- Abstract
De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of "de novo" variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
32. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA).
- Author
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Tylki-Szymańska A, Acuna-Hidalgo R, Krajewska-Walasek M, Lecka-Ambroziak A, Steehouwer M, Gilissen C, Brunner HG, Jurecka A, Różdżyńska-Świątkowska A, Hoischen A, and Chrzanowska KH
- Subjects
- Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, Facies, Female, Genotype, Humans, Male, Phenotype, Thyroid Hormone Resistance Syndrome diagnosis, Thyroid Hormone Resistance Syndrome drug therapy, Thyroxine, Treatment Failure, Young Adult, Genetic Association Studies, Mutation, Thyroid Hormone Receptors alpha genetics, Thyroid Hormone Resistance Syndrome genetics
- Abstract
Background: Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor β (TRβ), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor α gene (THRA) defects., Methods: We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families., Findings: Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations., Interpretation: THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
- Full Text
- View/download PDF
33. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
- Author
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Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, and Zenker M
- Subjects
- Abnormalities, Multiple metabolism, Amino Acid Sequence, Brain Diseases metabolism, Consanguinity, Family, Female, Fetal Growth Retardation metabolism, Homozygote, Humans, Ichthyosis metabolism, Limb Deformities, Congenital metabolism, Male, Microcephaly metabolism, Molecular Sequence Data, Phosphoglycerate Dehydrogenase chemistry, Phosphoglycerate Dehydrogenase deficiency, Phosphoric Monoester Hydrolases chemistry, Phosphoric Monoester Hydrolases deficiency, Protein Conformation, Sequence Homology, Amino Acid, Serine chemistry, Transaminases chemistry, Transaminases deficiency, Abnormalities, Multiple genetics, Brain Diseases genetics, Fetal Growth Retardation genetics, Ichthyosis genetics, Limb Deformities, Congenital genetics, Microcephaly genetics, Mutation genetics, Phosphoglycerate Dehydrogenase genetics, Phosphoric Monoester Hydrolases genetics, Serine biosynthesis, Transaminases genetics
- Abstract
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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