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2. Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype.

Author

Schirwani, S., Woods, E., Koolen, D.A., Ockeloen, C.W., Lynch, S.A., Kavanagh, K., Graham Jr., J.M., Grand, K., Pierson, T.M., Chung, J.M., Balasubramanian, M., Schirwani, S., Woods, E., Koolen, D.A., Ockeloen, C.W., Lynch, S.A., Kavanagh, K., Graham Jr., J.M., Grand, K., Pierson, T.M., Chung, J.M., and Balasubramanian, M.

Abstract

01 januari 2023, Item does not contain fulltext, De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder.

Published
2023

3. POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum

Author

Rossi, A, Snijders Blok, L., Neuser, S., Klöckner, C., Platzer, K., Faivre, L.O., Weigand, H., Dentici, M.L., Tartaglia, M., Niceta, M., Alfieri, P., Srivastava, S., Coulter, D., Smith, Lacey, Vinorum, K., Cappuccio, G., Brunetti-Pierri, N., Torun, D., Arslan, M., Lauridsen, M.F., Murch, O., Irving, R., Lynch, S.A., Mehta, S.G., Carmichael, J., Zonneveld-Huijssoon, E., Vries, B.B. de, Kleefstra, T., Johannesen, K.M., Westphall, I.T., Hughes, S.S., Smithson, S., Evans, J., Dudding-Byth, T., Simon, M., Binsbergen, E. van, Herkert, J.C., Beunders, G., Oppermann, H., Bakal, M., Møller, R.S., Rubboli, G., Bayat, A., Rossi, A, Snijders Blok, L., Neuser, S., Klöckner, C., Platzer, K., Faivre, L.O., Weigand, H., Dentici, M.L., Tartaglia, M., Niceta, M., Alfieri, P., Srivastava, S., Coulter, D., Smith, Lacey, Vinorum, K., Cappuccio, G., Brunetti-Pierri, N., Torun, D., Arslan, M., Lauridsen, M.F., Murch, O., Irving, R., Lynch, S.A., Mehta, S.G., Carmichael, J., Zonneveld-Huijssoon, E., Vries, B.B. de, Kleefstra, T., Johannesen, K.M., Westphall, I.T., Hughes, S.S., Smithson, S., Evans, J., Dudding-Byth, T., Simon, M., Binsbergen, E. van, Herkert, J.C., Beunders, G., Oppermann, H., Bakal, M., Møller, R.S., Rubboli, G., and Bayat, A.

Abstract

Item does not contain fulltext, POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Published
2023

7. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., and Clinical Genetics

Subjects
Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Hypertelorism, Developmental Disabilities, speech impairment, Genetic Variation, ASXL3, BRPS, Young Adult, Phenotype, ASXL3-related syndrome, Bainbridge–Ropers syndrome, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Mutation, Humans, Muscle Hypotonia, Female, Genetic Predisposition to Disease, Child, Transcription Factors
Abstract

Item does not contain fulltext The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

9. A health survey of the reef forming scleractinian cold-water corals Lophelia pertusa and Madrepora oculata in a remote submarine canyon on the European continental margin, NE Atlantic

Author

Appah, J.K.M., Lynch, S.A., Lim, A., O' Riordan, R., O'Reilly, L., de Oliveira, L., and Wheeler, A.J.

Subjects
Bacteria, Animals, Water, Anthozoa, Health Surveys, Ecology, Evolution, Behavior and Systematics, Ecosystem
Abstract

Monitoring of cold-water corals (CWCs) for pathogens and diseases is limited due to the environment, protected nature of the corals and their habitat and as well as the challenging and sampling effort required. It is recognised that environmental factors such as temperature and pH can expedite the ability of pathogens to cause diseases in cold-water corals therefore the characterisation of pathogen diversity, prevalence and associated pathologies is essential. The present study combined histology and polymerase chain reaction (PCR) diagnostic techniques to screen for two significant pathogen groups (bacteria of the genus Vibrio and the protozoan Haplosporidia) in the dominant NE Atlantic deep-water framework corals Lophelia pertusa (13 colonies) and Madrepora oculata (2 colonies) at three sampling locations (canyon head, south branch and the flank) in the Porcupine Bank Canyon (PBC), NE Atlantic. One M. oculata colony and four L. pertusa colonies were collected from both the canyon flank and the south branch whilst five L. pertusa colonies were collected from the canyon head. No pathogens were detected in the M. oculata samples. Neither histology nor PCR detected Vibrio spp. in L. pertusa, although Illumina technology used in this study to profile the CWCs microbiome, detected V. shilonii (0.03%) in a single L. pertusa individual, from the canyon head, that had also been screened in this study. A macroborer was observed at a prevalence of 0.07% at the canyon head only. Rickettsiales-like organisms (RLOs) were visualised with an overall prevalence of 40% and with a low intensity of 1 to 4 (RLO) colonies per individual polyp by histology. L. pertusa from the PBC canyon head had an RLO prevalence of 13.3% with the highest detection of 26.7% recorded in the south branch corals. Similarly, unidentified cells observed in L. pertusa from the south branch (20%) were more common than those observed in L. pertusa from the canyon head (6.7%). No RLOs or unidentified cells were observed in corals from the flank. Mean particulate organic matter concentration is highest in the south branch (2,612 μg l

Published
2021

10. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Author

Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., Barakat, T.S., Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., and Barakat, T.S.

Abstract

Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access), PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Published
2021

11. De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

Author

Polla, D.L., Bhoj, E.J., Verheij, J., Wassink-Ruiter, J.S., Reis, A., Deshpande, C., Gregor, A., Hill-Karfe, K., Vulto-van Silfhout, A.T., Pfundt, R.P., Bongers, E.M.H.F., Hakonarson, H., Berland, S., Gradek, G., Banka, S., Chandler, K., Gompertz, L., Huffels, S.C., Stumpel, C., Wennekes, R., Stegmann, A.P.A., Reardon, W., Leenders, E.K.S.M., Vries, B.B.A. de, Li, D., Zackai, E., Ragge, N., Lynch, S.A., Cuddapah, S., Bokhoven, H. van, Zweier, C., Brouwer, A.P.M. de, Polla, D.L., Bhoj, E.J., Verheij, J., Wassink-Ruiter, J.S., Reis, A., Deshpande, C., Gregor, A., Hill-Karfe, K., Vulto-van Silfhout, A.T., Pfundt, R.P., Bongers, E.M.H.F., Hakonarson, H., Berland, S., Gradek, G., Banka, S., Chandler, K., Gompertz, L., Huffels, S.C., Stumpel, C., Wennekes, R., Stegmann, A.P.A., Reardon, W., Leenders, E.K.S.M., Vries, B.B.A. de, Li, D., Zackai, E., Ragge, N., Lynch, S.A., Cuddapah, S., Bokhoven, H. van, Zweier, C., and Brouwer, A.P.M. de

Abstract

Contains fulltext : 234992.pdf (Publisher’s version ) (Closed access), PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Published
2021

14. De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

Author

Polla, D.L., primary, Bhoj, E.J., additional, Verheij, J.B.G.M., additional, Wassink-Ruiter, J.S. Klein, additional, Reis, A., additional, Deshpande, C., additional, Gregor, A., additional, Hill-Karfe, K., additional, Silfhout, A.T. Vulto-van, additional, Pfundt, R., additional, Bongers, E.M.H.F., additional, Hakonarson, H., additional, Berland, S., additional, Gradek, G., additional, Banka, S., additional, Chandler, K., additional, Gompertz, L., additional, Huffels, S.C., additional, Stumpel, C.T.R.M., additional, Wennekes, R., additional, Stegmann, A.P.A., additional, Reardon, W., additional, Leenders, E.K.S.M., additional, de Vries, B.B.A., additional, Li, D., additional, Zackai, E., additional, Ragge, N., additional, Lynch, S.A., additional, Cuddapah, S., additional, van Bokhoven, H., additional, Zweier, C., additional, and de Brouwer, A.P.M., additional

Published
2021
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15. Silicon as a model ion trap: time domain measurements of donor Rydberg states

Author

Vinh, N.Q., Greenland, P.T., Litvinenko, K., Redlich, B., van der Meer, A.F.G., Lynch, S.A., Warner, M., Stoneham, A.M., Aeppli, G., Paul, D.J., Pidgeon, C.R., and Murdin, B.N.

Subjects
Silicon -- Properties, Population biology -- Research, Ions -- Properties, Free electron lasers -- Research, Science and technology
Abstract

One of the great successes of quantum physics is the description of the long-lived Rydberg states of atoms and ions. The Bohr model is equally applicable to donor impurity atoms in semiconductor physics, where the conduction band corresponds to the vacuum, and the loosely bound electron orbiting a singly charged core has a hydrogen-like spectrum according to the usual Bohr-Sommerfeld formula, shifted to the far-infrared because of the small effective mass and high dielectric constant. Manipulation of Rydberg states in free atoms and ions by single and multiphoton processes has been tremendously productive since the development of pulsed visible laser spectroscopy. The analogous manipulations have not been conducted for donor impurities in silicon. Here, we use the FELIX pulsed free electron laser to perform time-domain measurements of the Rydberg state dynamics in phosphorus- and arsenic-doped silicon and we have obtained lifetimes consistent with frequency domain linewidths for isotopically purified silicon. This implies that the dominant decoherence mechanism for excited Rydberg states is lifetime broadening, just as for atoms in ion traps. The experiments are important because they represent a step toward coherent control and manipulation of atomic-like quantum levels in the most common semiconductor and complement magnetic resonance experiments in the literature, which show extraordinarily long spin lattice relaxation times--key to many well known schemes for quantum computing qubits--for the same impurities. Our results, taken together with the magnetic resonance data and progress in precise placement of single impurities, suggest that doped silicon, the basis for modern microelectronics, is also a model ion trap. coherence | free electron laser | quantum information | picosecond population dynamics | hydrogenic donor impurity

Published
2008

17. The susceptibility of young prespawning oysters, Ostrea edulis, to Bonamia ostreae

Author

Lynch, S.A., Armitage, D.V., Wylde, S., Mulcahy, M.F., and Culloty, S.C.

Subjects
Crassostrea -- Sexual behavior -- Research, Oysters -- Sexual behavior -- Research, Biological sciences, Zoology and wildlife conservation, Research, Sexual behavior
Abstract

ABSTRACT Young prespawning oysters, Ostrea edulis, were held over 6 mo at two different Bonamia ostreae-endemic sites in Ireland, to determine to what extent they could become infected with this [...]

Published
2005

21. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Dijck, A. van, Vulto-van Silfhout, A.T., Cappuyns, E., Werf, I.M. van der, Mancini, G.M., Tzschach, A., Bernier, R., Gozes, I., Eichler, E.E., Romano, C., Lindstrand, A., Nordgren, A., Kvarnung, M., Kleefstra, T., Vries, B.B.A. de, Kury, S., Rosenfeld, J.A., Meuwissen, M.E., Vandeweyer, G., Kooy, R.F., Bakshi, M., Wilson, M., Berman, Y., Dickson, R., Fransen, E., Helsmoortel, C., Ende, J. van den, Aa, N. van der, Wijdeven, M.J. van de, Rosenblum, J., Monteiro, F., Kok, F., Quercia, N., Bowdin, S., Dyment, D., Chitayat, D., Alkhunaizi, E., Boonen, S.E., Keren, B., Jacquette, A., Faivre, L., Bezieau, S., Isidor, B., Riess, A., Moog, U., Lynch, S.A., McVeigh, T., Elpeleg, O., Smeland, M.F., Fannemel, M., Haeringen, A. van, Maas, S.M., Veenstra-Knol, H.E., Schouten, M., Willemsen, M.H., Marcelis, C.L., Ockeloen, C., Burgt, I. van der, Feenstra, I., Smagt, J. van der, Jezela-Stanek, A., Krajewska-Walasek, M., Gonzalez-Lamuno, D., Anderlid, B.M., Malmgren, H., Nordenskjold, M., Clement, E., Hurst, J., Metcalfe, K., Mansour, S., Lachlan, K., Clayton-Smith, J., Hendon, L.G., Abdulrahman, O.A., Morrow, E., McMillan, C., Gerdts, J., Peeden, J., Vergano, S.A.S., Valentino, C., Chung, W.K., Ozmore, J.R., Bedrosian-Sermone, S., Dennis, A., Treat, K., Hughes, S.S., Safina, N., Pichon, J.B. le, McGuire, M., Infante, E., Madan-Khetarpal, S., Desai, S., Benke, P., Krokosky, A., Cristian, I., Baker, L., Gripp, K., Stessman, H.A., Eichenberger, J., Jayakar, P., Pizzino, A., Manning, M.A., Slattery, L., ADNP Consortium, Universidad de Cantabria, ADNP Consortium, Human Genetics, ANS - Complex Trait Genetics, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Pediatrics, Autism Spectrum Disorder, Autism, Intellectual disability, Cohort Studies, Epilepsy, 0302 clinical medicine, Genotype-phenotype distinction, Neurodevelopmental disorder, Neurodevelopmental Disorder, Helsmoortel-Van der Aa syndrome, Child, ADNP, Syndrome, Hypotonia, Autism spectrum disorder, Child, Preschool, Cohort, Female, Abnormalities, medicine.symptom, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Helsmoortel-Van der Aa Síndrome, medicine, Genetics, Humans, Abnormalities, Multiple, Preschool, Biology, Biological Psychiatry, Homeodomain Proteins, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, medicine.disease, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Published
2019

22. Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients

Author

Zweier, C., Sticht, H., Bijlsma, E.K., Clayton-Smith, J., Boonen, S.E., Fryer, A., Greally, M.T., Hoffmann, L., den Hollander, N.S., Jongmans, M., Kant, S.G., King, M.D., Lynch, S.A., McKee, S., Midro, A.T., Park, S.-M., Ricotti, V., Tarantino, E., Wessels, M., Peippo, M., and Rauch, A.

Subjects
DNA binding proteins -- Research, DNA binding proteins -- Physiological aspects, Mental retardation -- Research, Mental retardation -- Genetic aspects, Mental retardation -- Diagnosis, Phenotype -- Research, Phenotype -- Physiological aspects, Genotype -- Research, Genotype -- Physiological aspects, Health
Published
2008

23. Quantifying the contribution of recessive coding variation to developmental disorders

Author

Martin, H.C., Jones, W.D., McIntyre, R., Sanchez-Andrade, G., Sanderson, M., Stephenson, J.D., Jones, C.P., Handsaker, J., Gallone, G., Bruntraeger, M., McRae, J.F., Prigmore, E., Short, P., Niemi, M., Kaplanis, J., Radford, E.J., Akavvi, N., Balasubramanian, M., Dean, J., Horton, R., Hulbert, A., Johnson, D.S., Johnson, K., Kumar, D., Lynch, S.A., Mehta, S.G., Morton, J., Parker, M.J., Splitt, M., Turnpenny, P.D., Vasudevan, P.C., Wright, M., Bassett, A., Gerety, S.S., Wright, C.F., FitzPatrick, D.R., Firth, H.V., Hurles, M.E., Barrett, J.C., and Study, D.D.D.

Subjects
genetic structures, eye diseases
Abstract

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Published
2018

25. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, Zweier, C., Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, and Zweier, C.

Abstract

Contains fulltext : 215582.pdf (publisher's version ) (Open Access), PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

26. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, Zweier, C. (Christiane), Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, and Zweier, C. (Christiane)

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019
Full Text
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28. Incidence and prevalence of mucopolysaccharidosis type 1 in the Irish republic

Author

Murphy, A.M., Lambert, D., Treacy, E.P., O'Meara, A., and Lynch, S.A.

Subjects
Mucopolysaccharidosis -- Distribution, Mucopolysaccharidosis -- Demographic aspects, Mucopolysaccharidosis -- Reports, Infants (Newborn) -- Medical examination, Infants (Newborn) -- Standards, Company distribution practices
Published
2009

30. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

Author

Verheije, R., Kupchik, G.S., Isidor, B., Kroes, H.Y., Lynch, S.A., Hawkes, L., Hempel, M., Gelb, B.D., Ghoumid, J., D’Amours, G., Chandler, K., Dubourg, C., Loddo, S., Tümer, Z., Shaw-Smith, C., Nizon, M., Shevell, M., Van Hoof, E., Anyane-Yeboa, K., Cerbone, G., Clayton-Smith, J., Cogné, B., Corre, P., Corveleyn, A., De Borre, M., Hjortshøj, T.D., Fradin, M., Gewillig, M., Goldmuntz, E., Hens, G., Lemyre, E., Journel, H., Kini, U., Kortüm, F., Le Caignec, C., Novelli, A., Odent, S., Petit, F., Revah-Politi, A., Stong, N., Strom, T.M., van Binsbergen, E., DDD Study, Devriendt, K., and Breckpot, J.

Subjects
Male, Loss of Function Mutation, Intellectual disability, Genetics(clinical), Non-U.S. Gov't, Child, Genetics (clinical), Heart Defects, Genetics, 0303 health sciences, Congenital/genetics, Research Support, Non-U.S. Gov't, 030305 genetics & heredity, Syndrome, Phenotype, Heart Defects, Congenital/genetics, Cleft Palate, Child, Preschool, Female, Haploinsufficiency, Heart Defects, Congenital, Heterozygote, Adolescent, Transcription Factors/genetics, Locus (genetics), Research Support, Article, N.I.H, 03 medical and health sciences, Young Adult, Research Support, N.I.H., Extramural, Cleft Palate/genetics, Intellectual Disability, medicine, Journal Article, Humans, Preschool, Gene, Loss function, Homeodomain Proteins, business.industry, Chromosome, Extramural, Heterozygote advantage, medicine.disease, Intellectual Disability/genetics, Homeodomain Proteins/genetics, business, Transcription Factors
Abstract

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype–phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.

Published
2018

31. Optimization of the high-throughput synthesis of multiblock copolymer nanoparticles in aqueous media: Via polymerization-induced self-assembly

Author

Cockram, A.A., Bradley, R.D., Lynch, S.A., Fleming, P.C.D., Williams, N.S.J., Murray, M.W., Emmett, S.N., and Armes, S.P.

Abstract

Over the past fifteen years or so, polymerization-induced self-assembly (PISA) has become widely recognized as a powerful and versatile platform technology for the synthesis of a wide range of block copolymer nanoparticles of controlled size, shape and surface chemistry. In the present study, we report that PISA formulations are sufficiently robust to enable high-throughput experiments using a commercial synthesis robot (Chemspeed Autoplant A100). More specifically, we use reversible addition-fragmentation chain transfer (RAFT) aqueous emulsion polymerization of either n-butyl methacrylate and/or benzyl methacrylate to prepare various examples of methacrylic multiblock copolymer nanoparticles using a poly(methacrylic acid) stabilizer block. Adequate stirring is essential to generate sufficiently small monomer droplets for such heterogeneous polymerizations to proceed efficiently. Good reproducibility can be achieved under such conditions, with well-defined spherical morphologies being obtained at up to 45% w/w solids. GPC studies indicate high blocking efficiencies but relatively broad molecular weight distributions (Mw/Mn= 1.36-1.85), suggesting well-defined (albeit rather polydisperse) block copolymer chains. These preliminary studies provide a sound basis for high-throughput screening of RAFT-mediated PISA formulations, which is likely to be required for commercialization of this technology. Our results indicate that methacrylic PISA formulations enable the synthesis of diblock and triblock copolymer nanoparticles in high overall yield (94-99%) within 1-3 h at 70 °C. However, tetrablocks suffer from incomplete conversions (87-96% within 5 h) and hence most likely represent the upper limit for this approach.

Published
2018

32. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Aitken, Stuart, primary, Firth, Helen V., additional, McRae, Jeremy, additional, Halachev, Mihail, additional, Kini, Usha, additional, Parker, Michael J., additional, Lees, Melissa M., additional, Lachlan, Katherine, additional, Sarkar, Ajoy, additional, Joss, Shelagh, additional, Splitt, Miranda, additional, McKee, Shane, additional, Németh, Andrea H., additional, Scott, Richard H., additional, Wright, Caroline F., additional, Marsh, Joseph A., additional, Hurles, Matthew E., additional, FitzPatrick, David R., additional, Fitzgerald, T.W., additional, Gerety, S.S., additional, Jones, W.D., additional, van Kogelenberg, M., additional, King, D.A., additional, McRae, J., additional, Morley, K.I., additional, Parthiban, V., additional, Al-Turki, S., additional, Ambridge, K., additional, Barrett, D.M., additional, Bayzetinova, T., additional, Clayton, S., additional, Coomber, E.L., additional, Gribble, S., additional, Jones, P., additional, Krishnappa, N., additional, Mason, L.E., additional, Middleton, A., additional, Miller, R., additional, Prigmore, E., additional, Rajan, D., additional, Sifrim, A., additional, Tivey, A.R., additional, Ahmed, M., additional, Akawi, N., additional, Andrews, R., additional, Anjum, U., additional, Archer, H., additional, Armstrong, R., additional, Balasubramanian, M., additional, Banerjee, R., additional, Barelle, D., additional, Batstone, P., additional, Baty, D., additional, Bennett, C., additional, Berg, J., additional, Bernhard, B., additional, Bevan, A.P., additional, Blair, E., additional, Blyth, M., additional, Bohanna, D., additional, Bourdon, L., additional, Bourn, D., additional, Brady, A., additional, Bragin, E., additional, Brewer, C., additional, Brueton, L., additional, Brunstrom, K., additional, Bumpstead, S.J., additional, Bunyan, D.J., additional, Burn, J., additional, Burton, J., additional, Canham, N., additional, Castle, B., additional, Chandler, K., additional, Clasper, S., additional, Clayton-Smith, J., additional, Cole, T., additional, Collins, A., additional, Collinson, M.N., additional, Connell, F., additional, Cooper, N., additional, Cox, H., additional, Cresswell, L., additional, Cross, G., additional, Crow, Y., additional, D’Alessandro, P.M., additional, Dabir, T., additional, Davidson, R., additional, Davies, S., additional, Dean, J., additional, Deshpande, C., additional, Devlin, G., additional, Dixit, A., additional, Dominiczak, A., additional, Donnelly, C., additional, Donnelly, D., additional, Douglas, A., additional, Duncan, A., additional, Eason, J., additional, Edkins, S., additional, Ellard, S., additional, Ellis, P., additional, Elmslie, F., additional, Evans, K., additional, Everest, S., additional, Fendick, T., additional, Fisher, R., additional, Flinter, F., additional, Foulds, N., additional, Fryer, A., additional, Fu, B., additional, Gardiner, C., additional, Gaunt, L., additional, Ghali, N., additional, Gibbons, R., additional, Pereira, S.L. Gomes, additional, Goodship, J., additional, Goudie, D., additional, Gray, E., additional, Greene, P., additional, Greenhalgh, L., additional, Harrison, L., additional, Hawkins, R., additional, Hellens, S., additional, Henderson, A., additional, Hobson, E., additional, Holden, S., additional, Holder, S., additional, Hollingsworth, G., additional, Homfray, T., additional, Humphreys, M., additional, Hurst, J., additional, Ingram, S., additional, Irving, M., additional, Jarvis, J., additional, Jenkins, L., additional, Johnson, D., additional, Jones, D., additional, Jones, E., additional, Josifova, D., additional, Joss, S., additional, Kaemba, B., additional, Kazembe, S., additional, Kerr, B., additional, Kini, U., additional, Kinning, E., additional, Kirby, G., additional, Kirk, C., additional, Kivuva, E., additional, Kraus, A., additional, Kumar, D., additional, Lachlan, K., additional, Lam, W., additional, Lampe, A., additional, Langman, C., additional, Lees, M., additional, Lim, D., additional, Lowther, G., additional, Lynch, S.A., additional, Magee, A., additional, Maher, E., additional, Mansour, S., additional, Marks, K., additional, Martin, K., additional, Maye, U., additional, McCann, E., additional, McConnell, V., additional, McEntagart, M., additional, McGowan, R., additional, McKay, K., additional, McKee, S., additional, McMullan, D.J., additional, McNerlan, S., additional, Mehta, S., additional, Metcalfe, K., additional, Miles, E., additional, Mohammed, S., additional, Montgomery, T., additional, Moore, D., additional, Morgan, S., additional, Morris, A., additional, Morton, J., additional, Mugalaasi, H., additional, Murday, V., additional, Nevitt, L., additional, Newbury-Ecob, R., additional, Norman, A., additional, O’Shea, R., additional, Ogilvie, C., additional, Park, S., additional, Parker, M.J., additional, Patel, C., additional, Paterson, J., additional, Payne, S., additional, Phipps, J., additional, Pilz, D.T., additional, Porteous, D., additional, Pratt, N., additional, Prescott, K., additional, Price, S., additional, Pridham, A., additional, Proctor, A., additional, Purnell, H., additional, Ragge, N., additional, Rankin, J., additional, Raymond, L., additional, Rice, D., additional, Robert, L., additional, Roberts, E., additional, Roberts, G., additional, Roberts, J., additional, Roberts, P., additional, Ross, A., additional, Rosser, E., additional, Saggar, A., additional, Samant, S., additional, Sandford, R., additional, Sarkar, A., additional, Schweiger, S., additional, Scott, C., additional, Scott, R., additional, Selby, A., additional, Seller, A., additional, Sequeira, C., additional, Shannon, N., additional, Sharif, S., additional, Shaw-Smith, C., additional, Shearing, E., additional, Shears, D., additional, Simonic, I., additional, Simpkin, D., additional, Singzon, R., additional, Skitt, Z., additional, Smith, A., additional, Smith, B., additional, Smith, K., additional, Smithson, S., additional, Sneddon, L., additional, Splitt, M., additional, Squires, M., additional, Stewart, F., additional, Stewart, H., additional, Suri, M., additional, Sutton, V., additional, Swaminathan, G.J., additional, Sweeney, E., additional, Tatton-Brown, K., additional, Taylor, C., additional, Taylor, R., additional, Tein, M., additional, Temple, I.K., additional, Thomson, J., additional, Tolmie, J., additional, Torokwa, A., additional, Treacy, B., additional, Turner, C., additional, Turnpenny, P., additional, Tysoe, C., additional, Vandersteen, A., additional, Vasudevan, P., additional, Vogt, J., additional, Wakeling, E., additional, Walker, D., additional, Waters, J., additional, Weber, A., additional, Wellesley, D., additional, Whiteford, M., additional, Widaa, S., additional, Wilcox, S., additional, Williams, D., additional, Williams, N., additional, Woods, G., additional, Wragg, C., additional, Wright, M., additional, Yang, F., additional, Yau, M., additional, Carter, N.P., additional, Parker, M., additional, Firth, H.V., additional, FitzPatrick, D.R., additional, Wright, C.F., additional, Barrett, J.C., additional, and Hurles, M.E., additional

Published
2019
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34. De novo variants in MED12cause X-linked syndromic neurodevelopmental disorders in 18 females

Author

Polla, D.L., Bhoj, E.J., Verheij, J.B.G.M., Wassink-Ruiter, J.S. Klein, Reis, A., Deshpande, C., Gregor, A., Hill-Karfe, K., Silfhout, A.T. Vulto-van, Pfundt, R., Bongers, E.M.H.F., Hakonarson, H., Berland, S., Gradek, G., Banka, S., Chandler, K., Gompertz, L., Huffels, S.C., Stumpel, C.T.R.M., Wennekes, R., Stegmann, A.P.A., Reardon, W., Leenders, E.K.S.M., de Vries, B.B.A., Li, D., Zackai, E., Ragge, N., Lynch, S.A., Cuddapah, S., van Bokhoven, H., Zweier, C., and de Brouwer, A.P.M.

Abstract

MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes.

Published
2021
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35. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Author

Gabriele, M., Vulto-van Silfhout, A.T., Germain, P.L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., Steindl, K., Frengen, E., Misceo, D., Pedurupillay, C.R., Stromme, P., Rosenfeld, J.A., Shao, Y., Craigen, W.J., Schaaf, C.P., Rodriguez-Buritica, D., Farach, L., Friedman, J., Thulin, P., McLean, S.D., Nugent, K.M., Morton, J., Nicholl, J., Andrieux, J., Stray-Pedersen, A., Chambon, P., Patrier, S., Lynch, S.A., Kjaergaard, S., Torring, P.M., Brasch-Andersen, C., Ronan, A., Haeringen, A. van, Anderson, P.J., Powis, Z., Brunner, H.G., Pfundt, R.P., Schuurs-Hoeijmakers, J.H.M., Bon, B.W.M. van, Lelieveld, S.H., Gilissen, C.F., Nillesen, W.M., Vissers, L.E.L.M., Gecz, J., Koolen, D.A., Testa, G., Vries, B.B. de, Gabriele, M., Vulto-van Silfhout, A.T., Germain, P.L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., Steindl, K., Frengen, E., Misceo, D., Pedurupillay, C.R., Stromme, P., Rosenfeld, J.A., Shao, Y., Craigen, W.J., Schaaf, C.P., Rodriguez-Buritica, D., Farach, L., Friedman, J., Thulin, P., McLean, S.D., Nugent, K.M., Morton, J., Nicholl, J., Andrieux, J., Stray-Pedersen, A., Chambon, P., Patrier, S., Lynch, S.A., Kjaergaard, S., Torring, P.M., Brasch-Andersen, C., Ronan, A., Haeringen, A. van, Anderson, P.J., Powis, Z., Brunner, H.G., Pfundt, R.P., Schuurs-Hoeijmakers, J.H.M., Bon, B.W.M. van, Lelieveld, S.H., Gilissen, C.F., Nillesen, W.M., Vissers, L.E.L.M., Gecz, J., Koolen, D.A., Testa, G., and Vries, B.B. de

Abstract

Contains fulltext : 174704.pdf (publisher's version ) (Open Access), Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

Published
2017

36. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., Vries, B.B. de, Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., and Vries, B.B. de

Abstract

Contains fulltext : 174535.pdf (publisher's version ) (Closed access), Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in approximately 35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017

37. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., Vries, B. (Boukje) de, Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., and Vries, B. (Boukje) de

Abstract

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017
Full Text
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38. Sporadic case of fatal encephalopathy with neonatal onset associated with a T158M missense mutation in MECP2. (Case Report)

Author

Lynch, S.A., Whatley, S.D., Ramesh, V., Sinha, S., and Ravine, D.

Subjects
Gene mutations -- Health aspects -- Case studies, Encephalopathy -- Case studies -- Health aspects, Infants -- Diseases -- Case studies -- Health aspects, Family and marriage, Health, Women's issues/gender studies, Diseases, Case studies, Health aspects
Abstract

The case of a male infant with neonatal encephalopathy and a de novo MECP2 mutation is reported. The presenting phenotype of decelerating head growth, spasticity, scoliosis, and central respiratory disturbance [...]

Published
2003

40. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T.W., Gerety, S.S., Jones, W.D., van Kogelenberg, M., King, D.A., McRae, J., Morley, K.I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D.M., Bayzetinova, T., Clayton, S., Coomber, E.L., Gribble, S., Jones, P., Krishnappa, N., Mason, L.E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A.R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A.P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S.J., Bunyan, D.J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M.N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D'Alessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, S.L.G., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S.A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D.J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., O'Shea, R., Ogilvie, C., Park, S., Parker, M.J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D.T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweier, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Shanrif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G.J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I.K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N.P., Parker, M., Firth, H.V., FitzPatrick, D.R., Wright, C.F., Barrett, J.C., Hurles, M.E., and The Deciphering Developmental Disorders Study, .

Subjects
Male, Parents, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Transposases, SYNGAP1, medicine.disease_cause, Bioinformatics, DEAD-box RNA Helicases, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, Missense mutation, Exome, Protein Phosphatase 2, Child, Dynamin I, Zebrafish, Exome sequencing, Genes, Dominant, Polycomb Repressive Complex 1, 0303 health sciences, Mutation, Multidisciplinary, Gene Expression Regulation, Developmental, Nuclear Proteins, DNA-Binding Proteins, Child, Preschool, Female, Adolescent, Mutation, Missense, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, 030304 developmental biology, Chromosome Aberrations, Homeodomain Proteins, Genome, Human, Mechanism (biology), Infant, Newborn, Infant, Phosphoproteins, United Kingdom, Human genetics, Repressor Proteins, Human genome, Carrier Proteins, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

42. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., Kleefstra, T., Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., and Kleefstra, T.

Abstract

Contains fulltext : 153453.pdf (publisher's version ) (Closed access), Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

46. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Author

Kaiser, F.J., Ansari, M., Braunholz, D., Concepcion Gil-Rodriguez, M., Decroos, C., Wilde, J.J., Fincher, C.T., Kaur, M., Bando, M., Amor, D.J., Atwal, P.S., Bahlo, M., Bowman, C.M., Bradley, J.J., Brunner, H.G., Clark, D., Campo, M. del, Donato, N. Di, Diakumis, P., Dubbs, H., Dyment, D.A., Eckhold, J., Ernst, S., Ferreira, J.C., Francey, L.J., Gehlken, U., Guillen-Navarro, E., Gyftodimou, Y., Hall, B.D., Hennekam, R., Hudgins, L., Hullings, M., Hunter, J.M., Yntema, H.G., Innes, A.M., Kline, A.D., Krumina, Z., Lee, H. van der, Leppig, K., Lynch, S.A., Mallozzi, M.B., Mannini, L., McKee, S., Mehta, S.G., Micule, I., Mohammed, S., Moran, E., Mortier, G.R., Moser, J.A., Noon, S.E., Nozaki, N., Nunes, L., Pappas, J.G., Penney, L.S., Perez-Aytes, A., Petersen, M.B., Puisac, B., Revencu, N., Roeder, E., Saitta, S., Scheuerle, A.E., Schindeler, K.L., Siu, V.M., Stark, Z., Strom, S.P., Thiese, H., Vater, I., Willems, P., Williamson, K., Wilson, L.C., Baylor-Hopkins Mendelian, G., Hakonarson, H., Quintero-Rivera, F., Wierzba, J., Musio, A., Gillessen-Kaesbach, G., Ramos, F.J., Jackson, L.G., Shirahige, K., Pie, J., Christianson, D.W., Krantz, I.D., FitzPatrick, D.R., Deardorff, M.A., et al., Kaiser, F.J., Ansari, M., Braunholz, D., Concepcion Gil-Rodriguez, M., Decroos, C., Wilde, J.J., Fincher, C.T., Kaur, M., Bando, M., Amor, D.J., Atwal, P.S., Bahlo, M., Bowman, C.M., Bradley, J.J., Brunner, H.G., Clark, D., Campo, M. del, Donato, N. Di, Diakumis, P., Dubbs, H., Dyment, D.A., Eckhold, J., Ernst, S., Ferreira, J.C., Francey, L.J., Gehlken, U., Guillen-Navarro, E., Gyftodimou, Y., Hall, B.D., Hennekam, R., Hudgins, L., Hullings, M., Hunter, J.M., Yntema, H.G., Innes, A.M., Kline, A.D., Krumina, Z., Lee, H. van der, Leppig, K., Lynch, S.A., Mallozzi, M.B., Mannini, L., McKee, S., Mehta, S.G., Micule, I., Mohammed, S., Moran, E., Mortier, G.R., Moser, J.A., Noon, S.E., Nozaki, N., Nunes, L., Pappas, J.G., Penney, L.S., Perez-Aytes, A., Petersen, M.B., Puisac, B., Revencu, N., Roeder, E., Saitta, S., Scheuerle, A.E., Schindeler, K.L., Siu, V.M., Stark, Z., Strom, S.P., Thiese, H., Vater, I., Willems, P., Williamson, K., Wilson, L.C., Baylor-Hopkins Mendelian, G., Hakonarson, H., Quintero-Rivera, F., Wierzba, J., Musio, A., Gillessen-Kaesbach, G., Ramos, F.J., Jackson, L.G., Shirahige, K., Pie, J., Christianson, D.W., Krantz, I.D., FitzPatrick, D.R., Deardorff, M.A., and et al.

Abstract

Item does not contain fulltext, Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Published
2014

47. Familial neurofibromatosis microdeletion syndrome complicated by rhabdomyosarcoma. (Short Report)

Author

Lampe, A.K., Seymour, G., Thompson, P.W., Toutain, A., and Lynch, S.A.

Subjects
Children -- Diseases, Neurofibromatosis -- Care and treatment, Rhabdomyosarcoma -- Care and treatment, Family and marriage, Health, Care and treatment
Abstract

Neurofibromatosis type 1 with dysmorphism and developmental delay is reported in a mother and two children. The son required treatment for a prostatic rhabdomyosarcoma. His sister has an optic pathway [...]

Published
2002

50. Time-Resolved Dynamics of Shallow Acceptor Transitions in Silicon

Author

Vinh, N.Q., Redlich, B., Meer, A.F.G. van der, Pidgeon, C.R., Greenland, P.T., Lynch, S.A., Aeppli, G., Murdin, B.N., Vinh, N.Q., Redlich, B., Meer, A.F.G. van der, Pidgeon, C.R., Greenland, P.T., Lynch, S.A., Aeppli, G., and Murdin, B.N.

Abstract

Contains fulltext : 111451.pdf (publisher's version ) (Open Access)

Published
2013

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