524 results on '"Venselaar H"'
Search Results
2. De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders
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Wiel, L., Hampstead, J.E., Venselaar, H., Vissers, L.E.L.M., Brunner, H.G., Pfundt, R.P., Vriend, Gerrit, Veltman, J.A., Gilissen, C., Wiel, L., Hampstead, J.E., Venselaar, H., Vissers, L.E.L.M., Brunner, H.G., Pfundt, R.P., Vriend, Gerrit, Veltman, J.A., and Gilissen, C.
- Abstract
Item does not contain fulltext
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- 2023
3. A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder
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Snijders Blok, L., Verseput, Jolijn, Rots, D., Venselaar, H., Micheil Innes, A., Stumpel, Connie, Hoed, J. den, Brunner, H.G., Kleefstra, T., Snijders Blok, L., Verseput, Jolijn, Rots, D., Venselaar, H., Micheil Innes, A., Stumpel, Connie, Hoed, J. den, Brunner, H.G., and Kleefstra, T.
- Abstract
Contains fulltext : 287435.pdf (Publisher’s version ) (Open Access)
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- 2023
4. A protein domain-oriented approach to expand the opportunities of therapeutic exon skipping for USH2A-associated retinitis pigmentosa.
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Schellens, R.T.W., Broekman, S., Peters, Theo, Graave, Pam, Malinar, Lucija, Venselaar, H., Kremer, H., Vrieze, E. de, WIjk, E. van, Schellens, R.T.W., Broekman, S., Peters, Theo, Graave, Pam, Malinar, Lucija, Venselaar, H., Kremer, H., Vrieze, E. de, and WIjk, E. van
- Abstract
Contains fulltext : 293756.pdf (Publisher’s version ) (Open Access), Loss-of-function mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). We previously presented skipping of USH2A exon 13 as a promising treatment paradigm for USH2A-associated RP. However, RP-associated mutations are often private, and evenly distributed along the USH2A gene. In order to broaden the group of patients that could benefit from therapeutic exon skipping strategies, we expanded our approach to other USH2A exons in which unique loss-of-function mutations have been reported by implementing a protein domain-oriented dual exon skipping strategy. We first generated zebrafish mutants carrying a genomic deletion of the orthologous exons of the frequently mutated human USH2A exons 30-31 or 39-40 using CRISPR-Cas9. Excision of these in-frame combinations of exons restored usherin expression in the zebrafish retina and rescued the photopigment mislocalization typically observed in ush2a mutants. To translate these findings into a future treatment in humans, we employed in vitro assays to identify and validate antisense oligonucleotides (ASOs) with a high potency for sequence-specific dual exon skipping. Together, the in vitro and in vivo data demonstrate protein domain-oriented ASO-induced dual exon skipping to be a highly promising treatment option for RP caused by mutations in USH2A.
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- 2023
5. Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences
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Waanders, E, Scheijen, B, Jongmans, M C J, Venselaar, H, van Reijmersdal, S V, van Dijk, A H A, Pastorczak, A, Weren, R D A, van der Schoot, C E, van de Vorst, M, Sonneveld, E, Hoogerbrugge, N, van der Velden, V H J, Gruhn, B, Hoogerbrugge, P M, van Dongen, J J M, Geurts van Kessel, A, van Leeuwen, F N, and Kuiper, R P
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- 2017
- Full Text
- View/download PDF
6. Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant
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Reurink, J.A., Vrieze, E. de, Li, C.H.Z., Berkel, Emma van, Broekman, S., Aben, M.J., Peters, T.A., Oostrik, J., Neveling, K., Venselaar, H., Ramos, Mariana Guimarães, Gilissen, C.F.H.A., Astuti, G.D.N, Ockeloen, C.W., Haer-Wigman, L., Hoyng, C.B., Cremers, F.P.M., Kremer, H., Roosing, S., WIjk, E. van, Reurink, J.A., Vrieze, E. de, Li, C.H.Z., Berkel, Emma van, Broekman, S., Aben, M.J., Peters, T.A., Oostrik, J., Neveling, K., Venselaar, H., Ramos, Mariana Guimarães, Gilissen, C.F.H.A., Astuti, G.D.N, Ockeloen, C.W., Haer-Wigman, L., Hoyng, C.B., Cremers, F.P.M., Kremer, H., Roosing, S., and WIjk, E. van
- Abstract
Item does not contain fulltext
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- 2022
7. Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome
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Spek, J. van der, Hoed, J. den, Snijders Blok, L., Dingemans, A.J., Schijven, Dick, Nellaker, C., Venselaar, H., Astuti, G.D.N, Brunner, H.G., Gilissen, C., Vries, B.B.A. de, Willemsen, M.H., Francks, C., Peart-Vissers, L.E.L.M., Fisher, S.E., Kleefstra, T., Spek, J. van der, Hoed, J. den, Snijders Blok, L., Dingemans, A.J., Schijven, Dick, Nellaker, C., Venselaar, H., Astuti, G.D.N, Brunner, H.G., Gilissen, C., Vries, B.B.A. de, Willemsen, M.H., Francks, C., Peart-Vissers, L.E.L.M., Fisher, S.E., and Kleefstra, T.
- Abstract
Contains fulltext : 251115.pdf (Publisher’s version ) (Closed access)
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- 2022
8. A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene
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Bertoli-Avella, A., Hotakainen, R., Shehhi, M. Al, Urzi, A., Pareira, C., Marais, A., Shidhani, K. Al, Aloraimi, S., Morales-Torres, G., Fisher, S., Demuth, L., Selim, L.A. Moteleb, Menabawy, N. Al, Busehail, M., AlShaikh, M., Gilani, N., Chalabi, D.N., Alharbi, N.S., Alfadhel, M., Abdelrahman, M., Venselaar, H., Anjum, N., Saeed, A., Alghamdi, M.A., Aljaedi, H., Arabi, H., Karageorgou, V., Khan, S., Hajjari, Z., Radefeldt, M., Al-Ali, R., Tripolszki, K., Jamhawi, A., Paknia, O., Cozma, C., Cheema, H., Ameziane, N., Al-Muhsen, S., Bauer, P., Bertoli-Avella, A., Hotakainen, R., Shehhi, M. Al, Urzi, A., Pareira, C., Marais, A., Shidhani, K. Al, Aloraimi, S., Morales-Torres, G., Fisher, S., Demuth, L., Selim, L.A. Moteleb, Menabawy, N. Al, Busehail, M., AlShaikh, M., Gilani, N., Chalabi, D.N., Alharbi, N.S., Alfadhel, M., Abdelrahman, M., Venselaar, H., Anjum, N., Saeed, A., Alghamdi, M.A., Aljaedi, H., Arabi, H., Karageorgou, V., Khan, S., Hajjari, Z., Radefeldt, M., Al-Ali, R., Tripolszki, K., Jamhawi, A., Paknia, O., Cozma, C., Cheema, H., Ameziane, N., Al-Muhsen, S., and Bauer, P.
- Abstract
Contains fulltext : 283349.pdf (Publisher’s version ) (Open Access), PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.
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- 2022
9. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort
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Hendricks, L.A.J., Hoogerbrugge, N., Venselaar, H., Aretz, Stefan, Spier, I., Legius, Eric, Schuurs-Hoeijmakers, J.H.M., Kleefstra, T., Mensenkamp, A.R., Vos, J.R., Hendricks, L.A.J., Hoogerbrugge, N., Venselaar, H., Aretz, Stefan, Spier, I., Legius, Eric, Schuurs-Hoeijmakers, J.H.M., Kleefstra, T., Mensenkamp, A.R., and Vos, J.R.
- Abstract
Item does not contain fulltext
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- 2022
10. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort
- Author
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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.
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- 2022
11. Antisense oligonucleotides for dominantly inherited hearing impairment DFNA9: from cells models to humanized mice.
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Aben, F., Verdoodt, D., de Bruijn, S., Oostrik, J., Venselaar, H., Sels, L., De Backer, E., Gommeren, H., Szewczyk, K., Van Camp, G., Ponsaerts, P., Van Rompaey, V., van Wijk, E., and de Vrieze, E.
- Subjects
BIOLOGICAL models ,CONFERENCES & conventions ,NUCLEOTIDES ,MICE ,ANIMAL experimentation ,HEARING disorders ,GENETIC mutation - Abstract
The c.151C>T (p.P51S) mutation in COCH is highly prevalent in the Dutch/Belgian population and causes DFNA9 (hearing loss and vestibular dysfunction) in > 1500 individuals. The initial symptoms manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The clear non-haploinsufficiency disease mechanism indicates that blocking or reducing the p.P51S mutant cochlin protein levels may alleviate or prevent the DFNA9 phenotypes. Considering the broad expression of COCH by the fibrocytes of the inner ear, we designed "gapmer" antisense oligonucleotides (ASO) to specifically induce RNase H1-mediated degradation of COCH transcripts containing the c.151C>T mutation. We established several model systems to investigate the molecular efficacy of ASOs targeting the c. 151C>T mutation or low-frequency mutant allele-specific SNPs. Using overexpression models, we identified several ASOs that efficiently induce the degradation of mutant COCH transcripts. By introducing chemical modification to the oligonucleotide bases, we can alter the affinity and selectivity for the mutation transcript. We identified several ASOs with a strong preference for the mutant transcript in overexpression models. To investigate allele-specificity under physiological expression levels, we exposed patient-derived otic progenitor cells (iPCS-OPCs) to different ASOs for 8 days. In parallel, we developed a genetically humanized mouse model for DFNA9 in which human sequence-specific therapeutic strategies can be evaluated. Phenotypic follow-up of mice of all genotypes indicate that the genetic humanization has no adverse effects, and removal of the Cdh23ahl allele is mandatory to observe the late-onset auditory phenotype: the first signs of high-frequency hearing loss emerged at 12 months of age. Studies in iPSC-OPCs indicated that the ASOs identified in overexpression studies also effectively reduce mutant COCH transcript levels in patient-derived cells with physiological expression levels. Unfortunately, variation between replicate wells of OPC differentiation is relatively high, making it difficult to draw conclusions on allele-specificity. We selected a candidate ASO, directed against a rare mutant allele-spe-cific intronic SNP, for subsequent studies in our humanized mouse model. First intracochlear injections will be conducted in May 2024, after which we can collect the first in vivo data on gapmer ASO uptake and efficacy in fibrocytes of the mammalian inner ear. [ABSTRACT FROM AUTHOR]
- Published
- 2024
12. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype
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Roifman, M., Marcelis, C. L.M., Paton, T., Marshall, C., Silver, R., Lohr, J. L., Yntema, H. G., Venselaar, H., Kayserili, H., van Bon, B., Seaward, G., Brunner, H. G., and Chitayat, D.
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- 2015
- Full Text
- View/download PDF
13. Bifunctional protein PCBD2 operates as a co-factor for hepatocyte nuclear factor 1β and modulates gene transcription.
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Tholen, L.E., Bos, C., Jansen, P.W.T.C., Venselaar, H., Vermeulen, M., Hoenderop, J.G.J., Baaij, J.H.F. de, Tholen, L.E., Bos, C., Jansen, P.W.T.C., Venselaar, H., Vermeulen, M., Hoenderop, J.G.J., and Baaij, J.H.F. de
- Abstract
01 april 2021, Contains fulltext : 232382.pdf (Publisher’s version ) (Open Access), Hepatocyte nuclear factor 1β (HNF1β) is an essential transcription factor in development of the kidney, liver, and pancreas. HNF1β-mediated transcription of target genes is dependent on the cell type and the development stage. Nevertheless, the regulation of HNF1β function by enhancers and co-factors that allow this cell-specific transcription is largely unknown. To map the HNF1β interactome we performed mass spectrometry in a mouse kidney inner medullary collecting duct cell line. Pterin-4a-carbinolamine dehydratase 2 (PCBD2) was identified as a novel interaction partner of HNF1β. PCBD2 and its close homolog PCBD1 shuttle between the cytoplasm and nucleus to exert their enzymatic and transcriptional activities. Although both PCBD proteins share high sequence identity (48% and 88% in HNF1 recognition helix), their tissue expression patterns are unique. PCBD1 is most abundant in kidney and liver while PCBD2 is also abundant in lung, spleen, and adipose tissue. Using immunolocalization studies and biochemical analysis we show that in presence of HNF1β the nuclear localization of PCBD1 and PCBD2 increases significantly. Promoter luciferase assays demonstrate that co-factors PCBD1 and PCBD2 differentially regulate the ability of HNF1β to activate the promoters of transcriptional targets important in renal electrolyte homeostasis. Deleting the N-terminal sequence of PCBD2, not found in PCBD1, diminished the differential effects of the co-factors on HNF1β activity. All together these results indicate that PCBD1 and PCBD2 can exert different effects on HNF1β-mediated transcription. Future studies should confirm whether these unique co-factor activities also apply to HNF1β-target genes involved in additional processes besides ion transport in the kidney.
- Published
- 2021
14. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder
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Polla, D.L., Farazi Fard, M.A., Tabatabaei, Z., Habibzadeh, P., Levchenko, O.A., Nikuei, P., Makrythanasis, P., Hussain, Mureed, Schuurs-Hoeijmakers, J.H.M., Venselaar, H., Linda, K., Nadif Kasri, N., Faghihi, M., Bokhoven, H. van, Polla, D.L., Farazi Fard, M.A., Tabatabaei, Z., Habibzadeh, P., Levchenko, O.A., Nikuei, P., Makrythanasis, P., Hussain, Mureed, Schuurs-Hoeijmakers, J.H.M., Venselaar, H., Linda, K., Nadif Kasri, N., Faghihi, M., and Bokhoven, H. van
- Abstract
Item does not contain fulltext
- Published
- 2021
15. Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations
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Dulla, Kalyan, Slijkerman, R.W., Diepen, Hester C. van, Albert, S., Dona, M.A., Beumer, W., Venselaar, H., Peters, T.A., Broekman, S., Pennings, R.J., Kremer, H., Vrieze, E. de, WIjk, E. van, Dulla, Kalyan, Slijkerman, R.W., Diepen, Hester C. van, Albert, S., Dona, M.A., Beumer, W., Venselaar, H., Peters, T.A., Broekman, S., Pennings, R.J., Kremer, H., Vrieze, E. de, and WIjk, E. van
- Abstract
Item does not contain fulltext
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- 2021
16. Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases
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Reurink, J.A., Dockery, A., Oziębło, D., Farrar, G.J., Ołdak, M., Brink, J.B. ten, Bergen, A.A., Rinne, T.K., Yntema, H.G., Pennings, R.J.E., Born, L.I. van den, Aben, M.J., Oostrik, J., Venselaar, H., Plomp, A.S., Khan, M.I., WIjk, E. van, Cremers, F.P.M., Roosing, S., Kremer, H., Reurink, J.A., Dockery, A., Oziębło, D., Farrar, G.J., Ołdak, M., Brink, J.B. ten, Bergen, A.A., Rinne, T.K., Yntema, H.G., Pennings, R.J.E., Born, L.I. van den, Aben, M.J., Oostrik, J., Venselaar, H., Plomp, A.S., Khan, M.I., WIjk, E. van, Cremers, F.P.M., Roosing, S., and Kremer, H.
- Abstract
Contains fulltext : 235033.pdf (Publisher’s version ) (Open Access)
- Published
- 2021
17. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
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Wortmann, S.B., Ziętkiewicz, S., Guerrero-Castillo, S., Feichtinger, R.G., Wagner, M., Russell, J., Ellaway, C., Mróz, D., Wyszkowski, H., Weis, D., Hannibal, I., Stülpnagel, C. von, Cabrera-Orefice, A., Lichter-Konecki, U., Gaesser, J., Windreich, R., Myers, K.C., Lorsbach, R., Dale, R.C., Gersting, S., Prada, C.E., Christodoulou, J., Wolf, N.I., Venselaar, H., Mayr, J.A., Wevers, R.A., Wortmann, S.B., Ziętkiewicz, S., Guerrero-Castillo, S., Feichtinger, R.G., Wagner, M., Russell, J., Ellaway, C., Mróz, D., Wyszkowski, H., Weis, D., Hannibal, I., Stülpnagel, C. von, Cabrera-Orefice, A., Lichter-Konecki, U., Gaesser, J., Windreich, R., Myers, K.C., Lorsbach, R., Dale, R.C., Gersting, S., Prada, C.E., Christodoulou, J., Wolf, N.I., Venselaar, H., Mayr, J.A., and Wevers, R.A.
- Abstract
Contains fulltext : 238254.pdf (Publisher’s version ) (Closed access), PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
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- 2021
18. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
- Author
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Wortmann, SB, Zietkiewicz, S, Guerrero-Castillo, S, Feichtinger, RG, Wagner, M, Russell, J, Ellaway, C, Mroz, D, Wyszkowski, H, Weis, D, Hannibal, I, von Stuelpnagel, C, Cabrera-Orefice, A, Lichter-Konecki, U, Gaesser, J, Windreich, R, Myers, KC, Lorsbach, R, Dale, RC, Gersting, S, Prada, CE, Christodoulou, J, Wolf, NI, Venselaar, H, Mayr, JA, Wevers, RA, Wortmann, SB, Zietkiewicz, S, Guerrero-Castillo, S, Feichtinger, RG, Wagner, M, Russell, J, Ellaway, C, Mroz, D, Wyszkowski, H, Weis, D, Hannibal, I, von Stuelpnagel, C, Cabrera-Orefice, A, Lichter-Konecki, U, Gaesser, J, Windreich, R, Myers, KC, Lorsbach, R, Dale, RC, Gersting, S, Prada, CE, Christodoulou, J, Wolf, NI, Venselaar, H, Mayr, JA, and Wevers, RA
- Abstract
PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
- Published
- 2021
19. De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders
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Nabais Sá, M.J., Tekle, Geniver El, Brouwer, A.P.M. de, Sawyer, Sarah L., Gaudio, Daniela del, Parker, Michael J., Boogaard, Marie-Jose H. van den, Wiel, L.J.M. van de, Gilissen, C.F., Venselaar, H., Pfundt, R.P., Vissers, L.E.L.M., Theurillat, Jean-Philippe P., Vries, B.B.A. de, Nabais Sá, M.J., Tekle, Geniver El, Brouwer, A.P.M. de, Sawyer, Sarah L., Gaudio, Daniela del, Parker, Michael J., Boogaard, Marie-Jose H. van den, Wiel, L.J.M. van de, Gilissen, C.F., Venselaar, H., Pfundt, R.P., Vissers, L.E.L.M., Theurillat, Jean-Philippe P., and Vries, B.B.A. de
- Abstract
Contains fulltext : 217324.pdf (Publisher’s version ) (Closed access)
- Published
- 2020
20. Novel GANAB variants associated with polycystic liver disease
- Author
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Laarschot, L.F.M. van de, Morsche, R.H.M. te, Hoischen, A., Venselaar, H., Roelofs, H.M.J., Cnossen, W.R., Roepman, R., Drenth, J.P.H., Laarschot, L.F.M. van de, Morsche, R.H.M. te, Hoischen, A., Venselaar, H., Roelofs, H.M.J., Cnossen, W.R., Roepman, R., and Drenth, J.P.H.
- Abstract
Contains fulltext : 226792.pdf (publisher's version ) (Open Access)
- Published
- 2020
21. Novel defect in phosphatidylinositol 4-kinase type 2-alpha (PI4K2A) at the membrane-enzyme interface is associated with metabolic cutis laxa
- Author
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Mohamed, M., Gardeitchik, T., Balasubramaniam, S., Guerrero Castillo, S., Dalloyaux, D., Kraaij, S.A.W. van, Venselaar, H., Hoischen, A., Brandt, U., Spelbrink, H., Morava, E., Wevers, R.A., Mohamed, M., Gardeitchik, T., Balasubramaniam, S., Guerrero Castillo, S., Dalloyaux, D., Kraaij, S.A.W. van, Venselaar, H., Hoischen, A., Brandt, U., Spelbrink, H., Morava, E., and Wevers, R.A.
- Abstract
Contains fulltext : 228555.pdf (Publisher’s version ) (Open Access)
- Published
- 2020
22. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy
- Author
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Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, Trimouille, A., Lasseaux, E., Naudion, S., Lacombe, D., Piton, A., Vincent-Delorme, C., Zweier, C., Reis, A., Trollmann, R., Ruiz, A., Gabau, E., Vetro, A., Guerrini, R., Bakhtiari, S., Kruer, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, Koolen, D.A., Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, Trimouille, A., Lasseaux, E., Naudion, S., Lacombe, D., Piton, A., Vincent-Delorme, C., Zweier, C., Reis, A., Trollmann, R., Ruiz, A., Gabau, E., Vetro, A., Guerrini, R., Bakhtiari, S., Kruer, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, and Koolen, D.A.
- Abstract
Contains fulltext : 218155.pdf (Publisher’s version ) (Closed access), PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.
- Published
- 2020
23. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay
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Vissers, L.E.L.M., Kalvakuri, S., Boer, E. de, Geuer, S., Oud, M.M., Outersterp, I. van, Kwint, M.P., Witmond, M., Kersten, S., Polla, D.L., Weijers, D., Begtrup, A., McWalter, K., Ruiz, A., Gabau, E., Morton, J.E., Griffith, C., Weiss, K., Gamble, C., Bartley, J., Vernon, H.J., Brunet, K., Ruivenkamp, C., Kant, S.G., Kruszka, P., Larson, A., Afenjar, A., Billette de Villemeur, T., Nugent, K., Raymond, F.L., Venselaar, H., Demurger, F., Soler-Alfonso, C., Li, D., Bhoj, E., Hayes, I., Hamilton, N.P., Ahmad, A., Fisher, R., Born, M. van den, Willems, M., Sorlin, A., Delanne, J., Moutton, S., Christophe, P., Mau-Them, F.T., Vitobello, A., Goel, H., Massingham, L., Phornphutkul, C., Schwab, J., Keren, B., Charles, P., Vreeburg, M., Simone, L. De, Hoganson, G., Iascone, M., Milani, D., Evenepoel, L., Revencu, N., Ward, D.I., Burns, K., Krantz, I., Raible, S.E., Murrell, J.R., Wood, K., Cho, M.T., Bokhoven, H. van, Muenke, M., Kleefstra, T., Bodmer, R., Brouwer, A.P.M. de, Vissers, L.E.L.M., Kalvakuri, S., Boer, E. de, Geuer, S., Oud, M.M., Outersterp, I. van, Kwint, M.P., Witmond, M., Kersten, S., Polla, D.L., Weijers, D., Begtrup, A., McWalter, K., Ruiz, A., Gabau, E., Morton, J.E., Griffith, C., Weiss, K., Gamble, C., Bartley, J., Vernon, H.J., Brunet, K., Ruivenkamp, C., Kant, S.G., Kruszka, P., Larson, A., Afenjar, A., Billette de Villemeur, T., Nugent, K., Raymond, F.L., Venselaar, H., Demurger, F., Soler-Alfonso, C., Li, D., Bhoj, E., Hayes, I., Hamilton, N.P., Ahmad, A., Fisher, R., Born, M. van den, Willems, M., Sorlin, A., Delanne, J., Moutton, S., Christophe, P., Mau-Them, F.T., Vitobello, A., Goel, H., Massingham, L., Phornphutkul, C., Schwab, J., Keren, B., Charles, P., Vreeburg, M., Simone, L. De, Hoganson, G., Iascone, M., Milani, D., Evenepoel, L., Revencu, N., Ward, D.I., Burns, K., Krantz, I., Raible, S.E., Murrell, J.R., Wood, K., Cho, M.T., Bokhoven, H. van, Muenke, M., Kleefstra, T., Bodmer, R., and Brouwer, A.P.M. de
- Abstract
Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access), CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
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- 2020
24. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus
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Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., Opladen, T., Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., and Opladen, T.
- Abstract
Contains fulltext : 220941.pdf (Publisher’s version ) (Closed access), PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
- Published
- 2020
25. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy
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Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, Koolen, DA, Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, and Koolen, DA
- Abstract
PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.
- Published
- 2020
26. Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients
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Roscioli, T., Elakis, G., Cox, T. C., Moon, D. J., Venselaar, H., Turner, A. M., Le, T., Hackett, E., Haan, E., Colley, A., Mowat, D., Worgan, L., Kirk, E. P., Sachdev, R., Thompson, E., Gabbett, M., McGaughran, J., Gibson, K., Gattas, M., Freckmann, M-L., Dixon, J., Hoefsloot, L., Field, M., Hackett, A., Kamien, B., Edwards, M., Adès, L. C., Collins, F. A., Wilson, M. J., Savarirayan, R., Tan, T. Y., Amor, D. J., McGIllivray, G., White, S. M., Glass, I. A., David, D. J., Anderson, P. J., Gianoutsos, M., and Buckley, M. F.
- Published
- 2013
- Full Text
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27. Homozygosity mapping identifies genetic defects in four consanguineous families with retinal dystrophy from Pakistan
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Khan, M I, Ajmal, M, Micheal, S, Azam, M, Hussain, A, Shahzad, A, Venselaar, H, Bokhari, H, de Wijs, I J, Hoefsloot, L H, Waheed, N K, Collin, R WJ, den Hollander, A I, Qamar, R, and Cremers, F PM
- Published
- 2013
- Full Text
- View/download PDF
28. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63
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Waanders, E, Venselaar, H, te Morsche, R HM, de Koning, D B, Kamath, P S, Torres, V E, Somlo, S, and Drenth, J PH
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- 2010
- Full Text
- View/download PDF
29. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
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Kleefstra, T, van Zelst-Stams, W A, Nillesen, W M, Cormier-Daire, V, Houge, G, Foulds, N, van Dooren, M, Willemsen, M H, Pfundt, R, Turner, A, Wilson, M, McGaughran, J, Rauch, A, Zenker, M, Adam, M P, Innes, M, Davies, C, López, González-Meneses A, Casalone, R, Weber, A, Brueton, L A, Navarro, Delicado A, Bralo, Palomares M, Venselaar, H, Stegmann, S P A, Yntema, H G, van Bokhoven, H, and Brunner, H G
- Published
- 2009
- Full Text
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30. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder
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Snijders Blok, L., Kleefstra, T., Venselaar, H., Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., Gilissen, C., Pfundt, R.P., Brunner, H.G., Fisher, S.E., Snijders Blok, L., Kleefstra, T., Venselaar, H., Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., Gilissen, C., Pfundt, R.P., Brunner, H.G., and Fisher, S.E.
- Abstract
Contains fulltext : 206058.pdf (publisher's version ) (Open Access)
- Published
- 2019
31. Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin
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Bogaard, E.H.J. van den, Geel, M. van, Vlijmen-Willems, I.M.J.J. van, Jansen, P.A.M., Peppelman, M., Erp, P.E.J. van, Atalay, S., Venselaar, H., Simon, M.E., Joosten, M., Schalkwijk, J., Zeeuwen, P.L.J.M., Bogaard, E.H.J. van den, Geel, M. van, Vlijmen-Willems, I.M.J.J. van, Jansen, P.A.M., Peppelman, M., Erp, P.E.J. van, Atalay, S., Venselaar, H., Simon, M.E., Joosten, M., Schalkwijk, J., and Zeeuwen, P.L.J.M.
- Abstract
Contains fulltext : 205151.pdf (publisher's version ) (Open Access), PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin. METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes. RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant. CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.
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- 2019
32. Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans
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Cox, T.C., Lidral, A.C., McCoy, J.C., Liu, H., Cox, L.L., Zhu, Y, Anderson, R.D., Uribe, L.M. Moreno, Anand, D., Deng, M., Richter, C.T., Nidey, N.L., Standley, J.M., Blue, E.E., Chong, J.X., Smith, J.D., Kirk, E.P., Venselaar, H., Krahn, K.N., Bokhoven, H. van, Zhou, H., Cornell, R.A., Glass, I.A., Bamshad, M.J., Nickerson, D.A., Murray, J.C., Lachke, S.A., Thompson, T.B., Buckley, M.F., Roscioli, T., Cox, T.C., Lidral, A.C., McCoy, J.C., Liu, H., Cox, L.L., Zhu, Y, Anderson, R.D., Uribe, L.M. Moreno, Anand, D., Deng, M., Richter, C.T., Nidey, N.L., Standley, J.M., Blue, E.E., Chong, J.X., Smith, J.D., Kirk, E.P., Venselaar, H., Krahn, K.N., Bokhoven, H. van, Zhou, H., Cornell, R.A., Glass, I.A., Bamshad, M.J., Nickerson, D.A., Murray, J.C., Lachke, S.A., Thompson, T.B., Buckley, M.F., and Roscioli, T.
- Abstract
Contains fulltext : 208676.pdf (publisher's version ) (Closed access), Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
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- 2019
33. Investigating the active site of human trimethyllysine hydroxylase
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Wang, Yali, Reddy, Y.Vijayendar, Temimi, Abbas H.K. Al, Venselaar, H., Nelissen, F.H.T, Lenstra, D. C., Mecinovic, Jasmin, Wang, Yali, Reddy, Y.Vijayendar, Temimi, Abbas H.K. Al, Venselaar, H., Nelissen, F.H.T, Lenstra, D. C., and Mecinovic, Jasmin
- Abstract
Item does not contain fulltext
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- 2019
34. Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features
- Author
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Vlasveld, L.T., Janssen, Roel, Bardou-Jacquet, E., Venselaar, H., Hamdi-Roze, H., Drakesmith, H., Swinkels, D.W., Vlasveld, L.T., Janssen, Roel, Bardou-Jacquet, E., Venselaar, H., Hamdi-Roze, H., Drakesmith, H., and Swinkels, D.W.
- Abstract
Contains fulltext : 208591.pdf (publisher's version ) (Open Access)
- Published
- 2019
35. Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin
- Author
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van den Bogaard, EHJ, van Geel, M, van Vlijmen-Willems, I, Jansen, PAM, Peppelman, M, van Erp, PEJ, Atalay, S, Venselaar, H, Simon, MEH, Joosten, Marieke, Schalkwijk, J, Zeeuwen, P, van den Bogaard, EHJ, van Geel, M, van Vlijmen-Willems, I, Jansen, PAM, Peppelman, M, van Erp, PEJ, Atalay, S, Venselaar, H, Simon, MEH, Joosten, Marieke, Schalkwijk, J, and Zeeuwen, P
- Published
- 2019
36. 190 Deficiency of the Human Cysteine Protease Inhibitor Cystatin M/E Causes Hypotrichosis and Dry Skin
- Author
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Zeeuwen, P., primary, van den Bogaard, E., additional, van Geel, M., additional, van Vlijmen-Willems, I., additional, Jansen, P., additional, van Erp, P., additional, Venselaar, H., additional, Joosten, M., additional, and Schalkwijk, J., additional
- Published
- 2019
- Full Text
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37. Functional characterization of TBR1 variants in neurodevelopmental disorder
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Hoed, J. den, Sollis, E., Venselaar, H., Estruch, S.B., Deriziotis, P., Fisher, S.E., Hoed, J. den, Sollis, E., Venselaar, H., Estruch, S.B., Deriziotis, P., and Fisher, S.E.
- Abstract
Contains fulltext : 196222.pdf (publisher's version ) (Open Access), Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.
- Published
- 2018
38. Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate
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Cox, L., Cox, T.C., Uribe, Lina M.Moreno, Zhu, Y., Richter, C., Nidey, Nichole, Venselaar, H., Bokhoven, H. van, Zhou, H., Lidral, A.C., Roscioli, Tony, Cox, L., Cox, T.C., Uribe, Lina M.Moreno, Zhu, Y., Richter, C., Nidey, Nichole, Venselaar, H., Bokhoven, H. van, Zhou, H., Lidral, A.C., and Roscioli, Tony
- Abstract
Contains fulltext : 192476.pdf (publisher's version ) (Closed access)
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- 2018
39. Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis
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Pol, A., Renkema, G.H., Tangerman, A., Winkel, E., Engelke, U.F.H., Brouwer, A.P.M. de, Gilissen, C.F.H.A., Rodenburg, R.J.T., Venselaar, H., Camp, H.J.M. op den, Wevers, R.A., Pol, A., Renkema, G.H., Tangerman, A., Winkel, E., Engelke, U.F.H., Brouwer, A.P.M. de, Gilissen, C.F.H.A., Rodenburg, R.J.T., Venselaar, H., Camp, H.J.M. op den, and Wevers, R.A.
- Abstract
Contains fulltext : 183968.pdf (Publisher’s version ) (Open Access)
- Published
- 2018
40. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene
- Author
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Schoot, Vyne van der, Munnik, S.A. de, Venselaar, H., Elting, M., Mancini, G.M.S., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., Stevens, S.J.C., Schoot, Vyne van der, Munnik, S.A. de, Venselaar, H., Elting, M., Mancini, G.M.S., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., and Stevens, S.J.C.
- Abstract
Contains fulltext : 193058.pdf (publisher's version ) (Open Access)
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- 2018
41. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
- Author
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Snijders Blok, C., Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, H., Pfundt, R.P., Jansen, S, Kleefstra, T., Brunner, H.G., Fisher, S.E., Campeau, Philippe M., Snijders Blok, C., Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, H., Pfundt, R.P., Jansen, S, Kleefstra, T., Brunner, H.G., Fisher, S.E., and Campeau, Philippe M.
- Abstract
Contains fulltext : 198005.pdf (publisher's version ) (Open Access)
- Published
- 2018
42. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations
- Author
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Lee, Eric, Le, T., Zhu, Y., Elakis, G., Turner, Anne, Lo, William, Venselaar, H., Buckley, Michael Francis, Roscioli, Tony, Lee, Eric, Le, T., Zhu, Y., Elakis, G., Turner, Anne, Lo, William, Venselaar, H., Buckley, Michael Francis, and Roscioli, Tony
- Abstract
Item does not contain fulltext
- Published
- 2018
43. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
- Author
-
Wesdorp, F.M., Koning Gans, P.A.M. de, Schraders, M., Oostrik, J., Huijnen, M.A., Venselaar, H., Beynon, A.J., Gaalen, J. van, Piai, V., Voermans, N.C., Rossum, M.M. van, Hartel, B.P., Lelieveld, S.H., Wiel, L.J.M. van de, Verbist, B.M., Rotteveel, L.J.C., Dooren, M.F. van, Lichtner, P., Kunst, H.P.M., Feenstra, I., Admiraal, R.J.C., Yntema, H.G., Hoefsloot, L.H., Pennings, R.J.E., Kremer, H., Wesdorp, F.M., Koning Gans, P.A.M. de, Schraders, M., Oostrik, J., Huijnen, M.A., Venselaar, H., Beynon, A.J., Gaalen, J. van, Piai, V., Voermans, N.C., Rossum, M.M. van, Hartel, B.P., Lelieveld, S.H., Wiel, L.J.M. van de, Verbist, B.M., Rotteveel, L.J.C., Dooren, M.F. van, Lichtner, P., Kunst, H.P.M., Feenstra, I., Admiraal, R.J.C., Yntema, H.G., Hoefsloot, L.H., Pennings, R.J.E., and Kremer, H.
- Abstract
Contains fulltext : 198579pub.pdf (publisher's version ) (Open Access), Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.
- Published
- 2018
44. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations
- Author
-
Lee, E, Le, T, Zhu, Y, Elakis, G, Turner, A, Lo, W, Venselaar, H, Verrenkamp, CA, Snow, N, Mowat, D, Kirk, EP, Sachdev, R, Smith, J, Brown, NJ, Wallis, M, Barnett, C, McKenzie, F, Freckmann, ML, Collins, F, Chopra, M, Gregersen, N, Hayes, I, Rajagopalan, S, Tan, TY, Stark, Z, Savarirayan, R, Yeung, A, Adès, L, Gattas, M, Gibson, K, Gabbett, M, Amor, DJ, Lattanzi, W, Boyd, S, Haan, E, Gianoutsos, M, Cox, TC, Buckley, MF, Roscioli, T, Lee, E, Le, T, Zhu, Y, Elakis, G, Turner, A, Lo, W, Venselaar, H, Verrenkamp, CA, Snow, N, Mowat, D, Kirk, EP, Sachdev, R, Smith, J, Brown, NJ, Wallis, M, Barnett, C, McKenzie, F, Freckmann, ML, Collins, F, Chopra, M, Gregersen, N, Hayes, I, Rajagopalan, S, Tan, TY, Stark, Z, Savarirayan, R, Yeung, A, Adès, L, Gattas, M, Gibson, K, Gabbett, M, Amor, DJ, Lattanzi, W, Boyd, S, Haan, E, Gianoutsos, M, Cox, TC, Buckley, MF, and Roscioli, T
- Abstract
Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.
- Published
- 2018
45. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene
- Author
-
van der Schoot, V. (Vyne), Munnik, S.A. (Sonja) de, Venselaar, H. (Hanka), Elting, M. (Mariet), Mancini, G.M.S. (Grazia), Ravenswaaij-Arts, C.M.A. (Conny M. A.), Anderlid, B.-M.M. (Britt-Marie M.), Brunner, H.G., Stevens, S.J.C. (Servi J. C.), van der Schoot, V. (Vyne), Munnik, S.A. (Sonja) de, Venselaar, H. (Hanka), Elting, M. (Mariet), Mancini, G.M.S. (Grazia), Ravenswaaij-Arts, C.M.A. (Conny M. A.), Anderlid, B.-M.M. (Britt-Marie M.), Brunner, H.G., and Stevens, S.J.C. (Servi J. C.)
- Abstract
Background: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development. Methods: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein. Results: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found. Conclusion: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.
- Published
- 2018
- Full Text
- View/download PDF
46. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
- Author
-
Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), Kremer, H. (Hannie), Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), and Kremer, H. (Hannie)
- Abstract
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.
- Published
- 2018
- Full Text
- View/download PDF
47. Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome
- Author
-
Berg, M.P van den, Almomani, R., Biaggioni, Italo, Faassen, Martijn van, Harst, P. van der, Sillje, H.H.W., Brouwer, A.P.M. de, Venselaar, H., Verbeek, M.M., Wevers, R.A., Kema, I.P., Berg, M.P van den, Almomani, R., Biaggioni, Italo, Faassen, Martijn van, Harst, P. van der, Sillje, H.H.W., Brouwer, A.P.M. de, Venselaar, H., Verbeek, M.M., Wevers, R.A., and Kema, I.P.
- Abstract
Contains fulltext : 190722.pdf (publisher's version ) (Closed access)
- Published
- 2018
48. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
- Author
-
Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, Kremer, H, Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, and Kremer, H
- Published
- 2018
49. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene
- Author
-
van der Schoot, V, de Munnik, S, Venselaar, H, Elting, M, Verheijen - Mancini, Grazia, van Ravenswaaij-Arts, CMA, Anderlid, BM, Brunner, HG, Stevens, SJC, van der Schoot, V, de Munnik, S, Venselaar, H, Elting, M, Verheijen - Mancini, Grazia, van Ravenswaaij-Arts, CMA, Anderlid, BM, Brunner, HG, and Stevens, SJC
- Published
- 2018
50. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations
- Author
-
Lee, E., Le, T., Zhu, Y., Elakis, G., Turner, A., Lo, W., Venselaar, H., Verrenkamp, C. -A., Snow, N., Mowat, D., Kirk, E. P., Sachdev, R., Smith, J., Brown, N. J., Wallis, M., Barnett, C., Mckenzie, F., Freckmann, M. -L., Collins, F., Chopra, M., Gregersen, N., Hayes, I., Rajagopalan, S., Tan, T. Y., Stark, Z., Savarirayan, R., Yeung, A., Ades, L., Gattas, M., Gibson, K., Gabbett, M., Amor, D. J., Lattanzi, Wanda, Boyd, S., Haan, E., Gianoutsos, M., Cox, T. C., Buckley, M. F., Roscioli, T., Lattanzi W. (ORCID:0000-0003-3092-4936), Lee, E., Le, T., Zhu, Y., Elakis, G., Turner, A., Lo, W., Venselaar, H., Verrenkamp, C. -A., Snow, N., Mowat, D., Kirk, E. P., Sachdev, R., Smith, J., Brown, N. J., Wallis, M., Barnett, C., Mckenzie, F., Freckmann, M. -L., Collins, F., Chopra, M., Gregersen, N., Hayes, I., Rajagopalan, S., Tan, T. Y., Stark, Z., Savarirayan, R., Yeung, A., Ades, L., Gattas, M., Gibson, K., Gabbett, M., Amor, D. J., Lattanzi, Wanda, Boyd, S., Haan, E., Gianoutsos, M., Cox, T. C., Buckley, M. F., Roscioli, T., and Lattanzi W. (ORCID:0000-0003-3092-4936)
- Abstract
Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.
- Published
- 2018
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