87 results on '"Cytrynbaum C"'
Search Results
2. An online survey to understand the needs of caregivers of family members with 22q11 deletion syndrome.
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Cosman, T., Finless, A., Rideout, A. L., Lingley‐Pottie, P., Palmer, L. D., Shugar, A., McDonald‐McGinn, D. M., Swillen, A., McGrath, P. J., Bassett, A. S., Cytrynbaum, C., Orr, M., and Meier, S.
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SERVICES for caregivers ,OCCUPATIONAL roles ,WELL-being ,ONLINE education ,22Q11 deletion syndrome ,CAREGIVERS ,BURDEN of care ,FAMILIES ,SURVEYS ,RESEARCH funding ,NEEDS assessment ,MEDICAL needs assessment ,WORLD Wide Web - Abstract
Background: Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi‐system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well‐being, suggesting a need for additional support for this community who currently have no specialised interventions available. Method: This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. Results: The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. Conclusions: Future studies are planned that will build on these results by designing and testing online interventions tailored to this community. [ABSTRACT FROM AUTHOR]
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- 2023
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- View/download PDF
3. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder
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Chaudhry, A., Noor, A., Degagne, B., Baker, K., Bok, L. A., Brady, A. F., Chitayat, D., Chung, B. H., Cytrynbaum, C., Dyment, D., Filges, I., Helm, B., Hutchison, H. T., Jeng, L. J. B., Laumonnier, F., Marshall, C. R., Menzel, M., Parkash, S., Parker, M. J., Raymond, L. F., Rideout, A. L., Roberts, W., Rupps, R., Schanze, I., Schrander-Stumpel, C. T. R. M., Speevak, M. D., Stavropoulos, D. J., Stevens, S. J. C., Thomas, E. R. A., Toutain, A., Vergano, S., Weksberg, R., Scherer, S. W., Vincent, J. B., and Carter, M. T.
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- 2015
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- View/download PDF
4. Location, location, location: protein truncating variants in different loci of SRCAP cause three distinct neurodevelopmental disorders, associated with distinctive DNA methylation signatures
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Rots, D., Chater-Diehl, E., Dingemans, A. J. M., Siu, M., Cytrynbaum, C., Hoang, N., Walker, S., Scherer, S., Pfundt, R., Rinne, T., Gardeitchik, T., Vries, B. B. A., Stumpel, C. T. R. M., Stevens, S. J. C., Harssel, J., Bosch, D. G. M., Gassen, K. L. I., Binsbergen, E., Geus, C. M., Hempel, M., Lessel, D., Denecke, J., Slavotinek, A., Strober, J., Lilian Bomme Ousager, Martin Jakob Larsen, Schultz-Rogers, L., Morava, E., Klee, E. W., Berry, I. R., Campbell, J., Lindstrom, K., Neumeyer, A. M., Radley, J. A., Phornphutkul, C., Wilson, W. G., Schmidt, B., Meyn, S., Ounap, K., Reinson, K., Pajusalu, S., Ruivenkamp, C., Haeringen, A., Cuperus, R., Vissers, L. E. L. M., Brunner, H. G., Kleefstra, T., Koolen, D. A., Weksberg, R., and GeneDx Inc
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- 2020
5. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
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Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H
- Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
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- 2020
6. The adult phenotype in Costello syndrome
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White, Susan M., Graham, J. M., Jr, Kerr, B., Gripp, K., Weksberg, R., Cytrynbaum, C., Reeder, J. L., Stewart, F. J., Edwards, M., Wilson, M., and Bankier, A.
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- 2005
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7. Microdeletion 22q11.2: clinical data and deletion size
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KERSTJENS-FREDERIKSE, W S, KURAHASHI, H, DRISCOLL, D A, BUDARF, M L, EMANUEL, B S, BEATTY, B, SCHEIDL, T, SIEGEL-BARTELT, J, HENDERSON, K, CYTRYNBAUM, C, NIE, G, and TESHIMA, I
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- 1999
8. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes
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Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics
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0301 basic medicine ,Male ,Microcephaly ,Autism Spectrum Disorder ,Obesity/genetics ,Settore MED/03 - GENETICA MEDICA ,Body Mass Index ,Microcephaly/genetics ,Gene duplication ,Chromosome Duplication ,ddc:576.5 ,Copy-number variation ,Child ,In Situ Hybridization ,In Situ Hybridization, Fluorescence ,Genetics ,medicine.diagnostic_test ,Chromosome Mapping ,Middle Aged ,Phenotype ,Chromatin ,Chemistry ,Psychiatry and Mental Health ,Child, Preschool ,Female ,Original Article ,Chromosomes, Human, Pair 16/genetics ,Megalencephaly/genetics ,Chromosome Deletion ,Autistic Disorder/genetics ,Molecular Biology ,Cellular and Molecular Neuroscience ,Human ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Adult ,Adolescent ,DNA Copy Number Variations ,Locus (genetics) ,DNA Copy Number Variations/genetics ,Biology ,Aged ,Autistic Disorder ,Chromosomes, Human, Pair 16 ,Humans ,Infant ,Intellectual Disability ,Megalencephaly ,Obesity ,Chromosomes ,Fluorescence ,Chromatin/metabolism ,03 medical and health sciences ,medicine ,Preschool ,Gene ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Pair 16 ,medicine.disease ,Intellectual Disability/genetics ,Autism Spectrum Disorder/genetics ,030104 developmental biology ,Human medicine ,Chromosome Mapping/methods ,Fluorescence in situ hybridization - Abstract
Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
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- 2015
9. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder
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Chaudhry, A., Noor, A., Degagne, B., Baker, K., Bok, L. A., Brady, A. F., Chitayat, D., Chung, B. H., Cytrynbaum, C., Dyment, D., Filges, I., Helm, B., Hutchison, H. T., Jeng, L. J. B., Laumonnier, F., Marshall, C. R., Menzel, M., Parkash, S., Parker, M. J., Raymond, L. F., Rideout, A. L., Roberts, W., Rupps, R., Schanze, I., Schrander-Stumpel, C. T. R. M., Speevak, M. D., Stavropoulos, D. J., Stevens, S. J. C., Thomas, E. R. A., Toutain, A., Vergano, S., Weksberg, R., Scherer, S. W., Vincent, J. B., Carter, M. T., RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Afdeling Onderwijs FHML, and MUMC+: DA Pat Cytologie (9)
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X-linked ,Adult ,Male ,Adolescent ,Autism Spectrum Disorder ,PTCHD1 ,Facies ,Infant ,Membrane Proteins ,Exons ,Young Adult ,Phenotype ,Child, Preschool ,Intellectual Disability ,Mutation ,Humans ,Female ,Child ,Sequence Deletion - Abstract
Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.
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- 2014
10. NSD1 mutations generate a genome-wide DNA methylation signature
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Choufani, S., primary, Cytrynbaum, C., additional, Chung, B. H. Y., additional, Turinsky, A. L., additional, Grafodatskaya, D., additional, Chen, Y. A., additional, Cohen, A. S. A., additional, Dupuis, L., additional, Butcher, D. T., additional, Siu, M. T., additional, Luk, H. M., additional, Lo, I. F. M., additional, Lam, S. T. S., additional, Caluseriu, O., additional, Stavropoulos, D. J., additional, Reardon, W., additional, Mendoza-Londono, R., additional, Brudno, M., additional, Gibson, W. T., additional, Chitayat, D., additional, and Weksberg, R., additional
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- 2015
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- View/download PDF
11. Functional impact of global rare copy number variation in autism spectrum disorders
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Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.
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mental disorders - Abstract
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (
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- 2010
12. Adult phenotype in Costello syndrome (vol 136, pg 128, 2005)
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White, SM, Graham, JM, Kerr, B, Gripp, K, Weksberg, R, Cytrynbaum, C, Reeder, JL, Stewart, FJ, Edwards, M, Wilson, M, Bankier, A, and University of Groningen
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- 2005
13. Adult phenotype in Costello syndrome (Am J Med Genet 136A: 128–135, 2005)
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White, Susaan M., primary, Graham, J.M., additional, Kerr, B., additional, Gripp, K., additional, Weksberg, R., additional, Cytrynbaum, C., additional, Reeder, J.L., additional, Stewart, F.J., additional, Edwards, M., additional, Wilson, M., additional, and Bankier, A., additional
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- 2005
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- View/download PDF
14. Patient perspectives on the process of informed consent for DNA testing
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Cytrynbaum, C, primary, Babul-Hirii, R, additional, Rowell, M, additional, Henderson, K, additional, Australie, K, additional, Druker, H, additional, Dupuis, L, additional, Ouercia, N, additional, Shuman, C, additional, and Kennedy, S, additional
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- 2000
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15. Microdeletion 22q11.2: clinical data and deletion size
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Cytrynbaum, C., Kerstjens-Frederikse, W.S., Nie, G., Kurahashi, H., Teshima, I., Driscoll, D.A., Budarf, M.L., Emanuel, B.S., Beatty, B., Scheidl, T., Siegel-Bartelt, J., and Henderson, K.
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- 1999
16. Velo-cardio-facial syndrome. Volume 1.
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Cytrynbaum C, Klaiman P, and Shugar A
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- 2009
17. RASA1Mutations and Associated Phenotypes in 68 Families with Capillary Malformation-Arteriovenous Malformation
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Marc Abramowicz, Felicity Collins, Philippe Clapuyt, Christine Léauté-Labrèze, Brid O'Donnell, Julie Désir, Eulalia Baselga, María Antonia González-Enseñat, Antonella Mendola, Nicola Brunetti-Pierri, Yim Dwight, Nicole Revencu, Victoria R. Barrio, David J.E. Lord, Lesley C. Adès, David J. Amor, Mariarosaria Cozzolino, Orli Wargon, Shelagh Joss, Frank Hammer, Susan J. Bayliss, Josée Dubois, Didier Bessis, María del Carmen Boente, Leona Fishman, Wendy K. Chung, Miikka Vikkula, Oon T. Tan, Yolanda Gilaberte, Laurence M. Boon, Cheryl Cytrynbaum, Juliette Mazereeuw-Hautier, Carol A. Gardiner, Patricia E. Burrows, Sarah A. Sandaradura, Fred Ghali, Maria R. Cordisco, Alan D. Irvine, Asunción Vicente, Catheline Vilain, John B. Mulliken, Aicha Salhi, Francine Blei, Loreto Martorell, Anne Dompmartin, Janine Smith, Ashley Wilson, S. Syed, Sarah L. Chamlin, Ana Martín-Santiago, Marie Ange Delrue, Reed E. Pyeritz, Revencu, N, Boon, Lm, Mendola, A, Cordisco, Mr, Dubois, J, Clapuyt, P, Hammer, F, Amor, Dj, Irvine, Ad, Baselga, E, Dompmartin, A, Syed, S, Martin Santiago, A, Ades, L, Collins, F, Smith, J, Sandaradura, S, Barrio, Vr, Burrows, Pe, Blei, F, Cozzolino, M, BRUNETTI PIERRI, Nicola, Vicente, A, Abramowicz, M, D?sir, J, Vilain, C, Chung, Wk, Wilson, A, Gardiner, Ca, Dwight, Y, Lord, Dj, Fishman, L, Cytrynbaum, C, Chamlin, S, Ghali, F, Gilaberte, Y, Joss, S, Boente Mdel, C, L?aut? Labr?ze, C, Delrue, Ma, Bayliss, S, Martorell, L, Gonz?lez Ense?at, Ma, Mazereeuw Hautier, J, O'Donnell, B, Bessis, D, Pyeritz, Re, Salhi, A, Tan, Ot, Wargon, O, Mulliken, Jb, and Vikkula, M.
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Capillary malformation ,DNA Mutational Analysis ,Port-Wine Stain ,Sturge–Weber syndrome ,arteriovenous malformation ,P120 GTPase Activating Protein ,Sturge-Weber syndrome ,Biology ,medicine.disease_cause ,Arteriovenous Malformations ,Gene Order ,Genetics ,medicine ,Humans ,Prospective Studies ,Allele ,Genetic Association Studies ,Genetics (clinical) ,Retrospective Studies ,Mutation ,capillary malformation ,p120 GTPase Activating Protein ,Arteriovenous malformation ,medicine.disease ,Parkes Weber syndrome ,Capillaries ,Glomuvenous malformation ,Phenotype ,Amino Acid Substitution ,Female ,RASA1 - Abstract
Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n=100), common CM(s) (port-wine stain; n=100), Sturge-Weber syndrome (n=37), or isolated AVM(s) (n=24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the second-hit hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up. (C) 2013 Wiley Periodicals, Inc.
- Published
- 2013
18. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome
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Isabella Vasta, Bruno Dallapiccola, Francesca Atzeri, Cinzia Neri, Marco Tartaglia, Francesca Pantaleoni, Angelica Bibiana Delogu, Cheryl Cytrynbaum, Giovanni Neri, Emma De Feo, Andrea Ballabio, Anna Sarkozy, Angelo Selicorni, Claudio Carta, Gilda Cobellis, Edgar A. Pogna, Bruce D. Gelb, Katherine A. Rauen, Rosanna Weksberg, Giuseppe Zampino, Zampino, Giuseppe, Pantaleoni, Francesca, Carta, Claudio, Cobellis, Gilda, Vasta, Isabella, Neri, Cinzia, Pogna, Edgar A, De Feo, Emma, Delogu, Angelica, Sarkozy, Anna, Atzeri, Francesca, Selicorni, Angelo, Rauen, Katherine A, Cytrynbaum, Cheryl S, Weksberg, Rosanna, Dallapiccola, Bruno, Ballabio, Andrea, Gelb, Bruce D, Neri, Giovanni, Tartaglia, Marco, Zampino, G, Pantaleoni, F, Carta, C, Cobellis, G, Vasta, I, Neri, C, Pogna, E. A., DE FEO, E, Delogu, A, Sarkozy, A, Atzeri, F, Selicorni, A, Rauen, K. A., Cytrynbaum, C. S., Weksberg, R, Dallapiccola, B, Gelb, B. D., Neri, G, and Tartaglia, M.
- Subjects
Parents ,Adult ,Male ,Models, Molecular ,DNA Mutational Analysis ,Mutation, Missense ,Biology ,Cardiofaciocutaneous syndrome ,medicine.disease_cause ,Germline ,DNA Mutational Analysi ,Germline mutation ,Costello syndrome ,Genetics ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,HRAS de novo ,HRAS ,Genetic Testing ,Genetics (clinical) ,Germ-Line Mutation ,Mutation ,Infant, Newborn ,Infant ,Genetic Variation ,Syndrome ,Middle Aged ,medicine.disease ,Genes, ra ,Pedigree ,Genes, ras ,Phenotype ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Parent ,Child, Preschool ,Noonan syndrome ,Female ,Human - Abstract
Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.
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- 2007
19. Sirolimus for vascular anomalies associated with PTEN hamartoma tumor syndrome.
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Zabeida A, Brzezinski JJ, Wasserman JD, Cytrynbaum C, Weksberg R, Zwicker K, Zbuk K, Gasparetto A, Willis L, Fantauzzi M, and Carcao M
- Abstract
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10 years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS., (© 2024 Wiley Periodicals LLC.)
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- 2024
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20. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.
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Stegmann JD, Kalanithy JC, Dworschak GC, Ishorst N, Mingardo E, Lopes FM, Ho YM, Grote P, Lindenberg TT, Yilmaz Ö, Channab K, Seltzsam S, Shril S, Hildebrandt F, Boschann F, Heinen A, Jolly A, Myers K, McBride K, Bekheirnia MR, Bekheirnia N, Scala M, Morleo M, Nigro V, Torella A, Pinelli M, Capra V, Accogli A, Maitz S, Spano A, Olson RJ, Klee EW, Lanpher BC, Jang SS, Chae JH, Steinbauer P, Rieder D, Janecke AR, Vodopiutz J, Vogel I, Blechingberg J, Cohen JL, Riley K, Klee V, Walsh LE, Begemann M, Elbracht M, Eggermann T, Stoppe A, Stuurman K, van Slegtenhorst M, Barakat TS, Mulhern MS, Sands TT, Cytrynbaum C, Weksberg R, Isidori F, Pippucci T, Severi G, Montanari F, Kruer MC, Bakhtiari S, Darvish H, Reutter H, Hagelueken G, Geyer M, Woolf AS, Posey JE, Lupski JR, Odermatt B, and Hilger AC
- Abstract
CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation., (© 2024. The Author(s).)
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- 2024
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21. Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.
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de Kock L, Cuillerier A, Gillespie M, Couse M, Hartley T, Mears W, Bernier FP, Chudley AE, Frosk P, Nikkel SM, Innes AM, Lauzon J, Thomas M, Guerin A, Armour CM, Weksberg R, Scott JN, Watkins D, Harvey S, Cytrynbaum C, Kernohan KD, and Boycott KM
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- Humans, Mutation, Class I Phosphatidylinositol 3-Kinases genetics, High-Throughput Nucleotide Sequencing, Musculoskeletal Abnormalities genetics, Megalencephaly, Vascular Malformations diagnosis, Vascular Malformations genetics, Abnormalities, Multiple, Telangiectasis congenital, Skin Diseases, Vascular
- Abstract
Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population., (© 2023 Wiley Periodicals LLC.)
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- 2024
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22. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.
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Hartley T, Marshall D, Acker M, Fooks K, Gillespie MK, Price EM, Graham ID, White-Brown A, MacKay L, Macdonald SK, Brady L, Hui AY, Andrews JD, Chowdhury A, Wall E, Soubry É, Ediae GU, Rojas S, Assamad D, Dyment D, Tarnopolsky M, Sawyer SL, Chisholm C, Lemire G, Amburgey K, Lazier J, Mendoza-Londono R, Dowling JJ, Balci TB, Armour CM, Bhola PT, Costain G, Dupuis L, Carter M, Badalato L, Richer J, Boswell-Patterson C, Kannu P, Cordeiro D, Warman-Chardon J, Graham G, Siu VM, Cytrynbaum C, Rusnak A, Aul RB, Yoon G, Gonorazky H, McNiven V, Mercimek-Andrews S, Guerin A, Deshwar AR, Marwaha A, Weksberg R, Karp N, Campbell M, Al-Qattan S, Shuen AY, Inbar-Feigenberg M, Cohn R, Szuto A, Inglese C, Poirier M, Chad L, Potter B, Boycott KM, and Hayeems R
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- Humans, Prospective Studies, Exome Sequencing, Genetic Testing methods, Ontario, Rare Diseases diagnosis, Rare Diseases genetics, Exome
- Abstract
Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases., Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests., Results: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses., Conclusion: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2023. Published by Elsevier Inc.)
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- 2024
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23. The mental health and traumatic experiences of mothers of children with 22q11DS.
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Finless A, Rideout AL, Xiong T, Carbyn H, Lingley-Pottie P, Palmer LD, Shugar A, McDonald-McGinn DM, McGrath PJ, Bassett AS, Cytrynbaum C, Orr M, Swillen A, and Meier S
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- Humans, Female, Adult, Child, Male, Surveys and Questionnaires, Mental Health, Stress Disorders, Post-Traumatic psychology, 22q11 Deletion Syndrome psychology, Adolescent, Neurodevelopmental Disorders psychology, Middle Aged, Caregivers psychology, Mothers psychology
- Abstract
Background: 22q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The varied health problems associated with 22q11DS and the evolving phenotype (both medical and developmental/behavioural) across the lifespan can strongly impact the mental health of patients as well as their caregivers. Like caregivers of children with other chronic diseases, caregivers of children with 22q11DS may experience an increased risk of traumatisation and mental health symptoms. Objective: The study's primary objective was to assess the frequency of traumatic experiences and mental health symptoms among mothers of children with 22q11DS. The secondary objective was to compare their traumatic experiences to those of mothers of children with other neurodevelopmental disorders (NDDs). Method: A total of 71 mothers of children diagnosed with 22q11DS completed an online survey about their mental health symptoms and traumatic experiences. Descriptive statistics were used to summarise the prevalence of their mental health symptoms and traumatic experiences. Logistic regression models were run to compare the traumatic experiences of mothers of children with 22q11DS to those of 335 mothers of children with other neurodevelopmental disorders (NDDs). Results: Many mothers of children with 22q11DS experienced clinically significant mental health symptoms, including depression (39%), anxiety (25%), and post-traumatic stress disorder (PTSD) symptoms (30%). The types of traumatic events experienced by mothers of children with 22q11DS differed from those of mothers of children with other NDDs as they were more likely to observe their child undergoing a medical procedure, a life-threatening surgery, or have been with their child in the intensive care unit. Conclusion: 22q11DS caregivers are likely to require mental health support and trauma-informed care, tailored to the specific needs of this population as they experience different kinds of traumatic events compared to caregivers of children with other NDDS.
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- 2024
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24. Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies.
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Nil Z, Deshwar AR, Huang Y, Barish S, Zhang X, Choufani S, Le Quesne Stabej P, Hayes I, Yap P, Haldeman-Englert C, Wilson C, Prescott T, Tveten K, Vøllo A, Haynes D, Wheeler PG, Zon J, Cytrynbaum C, Jobling R, Blyth M, Banka S, Afenjar A, Mignot C, Robin-Renaldo F, Keren B, Kanca O, Mao X, Wegner DJ, Sisco K, Shinawi M, Wangler MF, Weksberg R, Yamamoto S, Costain G, and Bellen HJ
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- Humans, Gain of Function Mutation, Histones genetics, Histones metabolism, Lysine, Methylation, Methyltransferases genetics, Neoplasms genetics, Drosophila genetics, Drosophila Proteins genetics, Histone-Lysine N-Methyltransferase genetics, Developmental Disabilities genetics, Congenital Abnormalities genetics
- Abstract
Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)
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- 2023
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25. Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications.
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Deshwar AR, Cytrynbaum C, Murthy H, Zon J, Chitayat D, Volpatti J, Newbury-Ecob R, Ellard S, Allen HL, Yu EP, Noche R, Walker S, Scherer SW, Mahida S, Elitt CM, Nicolas G, Goldenberg A, Saugier-Veber P, Lecoquierre F, Dabaj I, Meddaugh H, Marble M, Keppler-Noreuil KM, Drayson L, Barañano KW, Chassevent A, Agre K, Létard P, Bilan F, Le Guyader G, Laquerrière A, Ramsey K, Henderson L, Brady L, Tarnopolsky M, Bainbridge M, Friedman J, Capri Y, Athayde L, Kok F, Gurgel-Giannetti J, Ramos LLP, Blaser S, Dowling JJ, and Weksberg R
- Subjects
- Animals, Humans, Claudin-5 genetics, Claudin-5 metabolism, Zebrafish metabolism, Blood-Brain Barrier metabolism, Seizures genetics, Syndrome, Microcephaly genetics
- Abstract
The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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26. ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome.
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Awamleh Z, Choufani S, Cytrynbaum C, Alkuraya FS, Scherer S, Fernandes S, Rosas C, Louro P, Dias P, Neves MT, Sousa SB, and Weksberg R
- Subjects
- Child, Female, Humans, Bone Diseases, Developmental blood, Bone Diseases, Developmental diagnosis, Bone Diseases, Developmental genetics, Chromosome Deletion, DNA Methylation genetics, Epigenesis, Genetic genetics, Facies, Intellectual Disability blood, Intellectual Disability diagnosis, Intellectual Disability genetics, Machine Learning, Mutation, Phenotype, Tooth Abnormalities blood, Tooth Abnormalities diagnosis, Tooth Abnormalities genetics, Transcription Factors genetics, Abnormalities, Multiple blood, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Repressor Proteins genetics
- Abstract
Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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27. Development of a storytelling communication facilitation tool (SCFT) to facilitate discussion of complex genetic diagnoses between parents and their children: A pilot study using 22q11.2 deletion syndrome as a model condition.
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Bogatan S, Shugar A, Wasim S, Ball S, Schmidt C, Chitayat D, Shuman C, and Cytrynbaum C
- Abstract
Objective: To develop and evaluate a storytelling communication facilitation tool designed to help parents overcome barriers to discussing a complex multisystem genetic diagnosis with their affected children, using 22q11.2 deletion syndrome (22q11DS) as an exemplar condition., Methods: A story telling communication facilitation tool (SCFT), entitled 22q and Me , was developed for a target audience of children with 22q11DS aged 9 to 12. The SCFT was evaluated by 14 parents to assess usability and utility by comparing responses to survey questions before and after viewing the SCFT, using a Likert scale., Results: After viewing 22q and Me , parents reported that barriers to discussion were mitigated. Participants indicated they felt more comfortable and better prepared to talk to their children about 22q11DS and worried less that the diagnosis would affect their children's self-esteem. Parents described 22q and Me as engaging and able to address parental concerns., Conclusion: 22q and Me was found to be an effective tool for increasing parental comfort and ability to talk to their children about their diagnosis of 22q11DS., Innovation: This novel storytelling communication facilitation tool can serve as a model for the development of other educational tools geared at facilitating disclosure and discussion of other genetic conditions., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors.)
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- 2022
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28. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.
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Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT, Harris J, Dyment DA, Graham GE, Nezarati MM, Aul RB, Castiglioni C, Breckpot J, Devriendt K, Stewart H, Banos-Pinero B, Mehta S, Sandford R, Dunn C, Mathevet R, van Maldergem L, Piard J, Brischoux-Boucher E, Vitobello A, Faivre L, Bournez M, Tran-Mau F, Maystadt I, Fernández-Jaén A, Alvarez S, García-Prieto ID, Alkuraya FS, Alsaif HS, Rahbeeni Z, El-Akouri K, Al-Mureikhi M, Spillmann RC, Shashi V, Sanchez-Lara PA, Graham JM Jr, Roberts A, Chorin O, Evrony GD, Kraatari-Tiri M, Dudding-Byth T, Richardson A, Hunt D, Hamilton L, Dyack S, Mendelsohn BA, Rodríguez N, Sánchez-Martínez R, Tenorio-Castaño J, Nevado J, Lapunzina P, Tirado P, Carminho Amaro Rodrigues MT, Quteineh L, Innes AM, Kline AD, Au PYB, and Weksberg R
- Subjects
- Abnormalities, Multiple, Chromatin, Epigenesis, Genetic, Face abnormalities, Hematologic Diseases, Heterogeneous-Nuclear Ribonucleoprotein K genetics, Humans, Phenotype, Vestibular Diseases, DNA Methylation genetics, Intellectual Disability genetics
- Abstract
Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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29. The utility of DNA methylation signatures in directing genome sequencing workflow: Kabuki syndrome and CDK13-related disorder.
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Marwaha A, Costain G, Cytrynbaum C, Mendoza-Londono R, Chad L, Awamleh Z, Chater-Diehl E, Choufani S, and Weksberg R
- Subjects
- Abnormalities, Multiple, Artificial Intelligence, CDC2 Protein Kinase genetics, Face abnormalities, Hematologic Diseases, Histone Demethylases genetics, Humans, Mutation, Workflow, DNA Methylation genetics, Vestibular Diseases diagnosis, Vestibular Diseases genetics
- Abstract
Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20-30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome-wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection of another diagnosis in the KS differential, CDK13-related disorder. This approach illustrates the clinical utility of DNAm signatures in the diagnostic workflow for the genome analyst or clinical geneticist-especially for disorders with overlapping clinical phenotypes., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2022
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30. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability.
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Hayeems RZ, Luca S, Ungar WJ, Venkataramanan V, Tsiplova K, Bashir NS, Costain G, Inglese C, McNiven V, Quercia N, Shugar A, Yoon G, Cytrynbaum C, Dupuis L, Shao Z, Hewson S, Shuman C, Aul R, Liston E, Babul-Hirji R, Bushby A, Pullenayegum E, Chad L, and Meyn MS
- Subjects
- Humans, Reproducibility of Results, Surveys and Questionnaires, Genetic Testing
- Abstract
Purpose: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability., Methods: Genetics professionals completed C-GUIDE after disclosure of test results to patients. Construct validity was assessed using regression analysis to measure associations between C-GUIDE and global item scores as well as potentially explanatory variables. Inter-rater reliability was assessed by administering a vignette-based survey to genetics professionals and calculating Krippendorff's α., Results: On average, a 1-point increase in the global item score was associated with an increase of 3.0 in the C-GUIDE score (P < .001). Compared with diagnostic results, partially/potentially diagnostic and nondiagnostic results were associated with a reduction in C-GUIDE score of 9.5 (P < .001) and 10.2 (P < .001), respectively. Across 19 vignettes, Krippendorff's α was 0.68 (95% CI: 0.63-0.72)., Conclusion: C-GUIDE showed acceptable validity and inter-rater reliability. Although further evaluation is required, C-GUIDE version 1.2 can be useful as a standardized approach to assess the clinical utility of genetic testing., Competing Interests: Conflict of Interest This work was funded by the Canadian Institutes of Health Research. The authors declare no conflict of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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31. Novel heterozygous variants in PXDN cause different anterior segment dysgenesis phenotypes in monozygotic twins.
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Zhu AY, Costain G, Cytrynbaum C, Weksberg R, Cohn RD, and Ali A
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- Child, Female, Gestational Age, Glaucoma Drainage Implants, Heterozygote, Humans, Lens, Crystalline surgery, Pedigree, Phenotype, Trabeculectomy, Whole Genome Sequencing, Diseases in Twins genetics, Eye Abnormalities genetics, Frameshift Mutation, Peroxidases genetics, Twins, Monozygotic genetics
- Abstract
Background: Since bi-allelic variants in the PXDN gene were first discovered in 2011 to be associated with anterior segment dysgenesis, a spectrum of ophthalmologic and systemic clinical manifestations has been described. This manuscript reports two distinct clinical phenotypes in monozygotic twin sisters, including the previously unreported ocular manifestation of bilateral primary aphakia, associated with novel compound heterozygous variants in the PXDN gene., Materials and Methods: We used genome sequencing to study a non-consanguineous family with monozygotic twin sister probands: one presenting with bilateral microphthalmia, primary aphakia, total corneal opacification, congenital glaucoma, and complex systemic comorbidities; the other with anterior persistent fetal vasculature in the right eye, and Peters anomaly type 2 with cataract and iris coloboma in the left eye but no systemic issues. These findings were compared to published reports of PXDN -related ocular diseases upon comprehensive review of prior literature., Results: In both affected sisters, genome sequencing identified two novel heterozygous variants in trans in the PXDN gene: c.1569_1570insT, predicting p.(Thr524TyrfsTer53), and c.3206 C > A, predicting p.(Ala1069Asp), respectively. No other potentially diagnostic variants were identified in any other genes., Conclusions: This report on two novel compound heterozygous variants in the PXDN gene associated with previously unreported clinical manifestations further expands the genotypic and phenotypic spectrum associated with this gene. Our finding of distinctive clinical phenotypes associated with identical compound heterozygous PXDN variants in monozygotic twins emphasizes the significant clinical variability that can occur, suggesting a potential role for stochastic developmental and/or epigenetic factors in the ultimate pathophysiologic pathway.
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- 2021
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32. Anatomy of DNA methylation signatures: Emerging insights and applications.
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Chater-Diehl E, Goodman SJ, Cytrynbaum C, Turinsky AL, Choufani S, and Weksberg R
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- Animals, Humans, Neurodevelopmental Disorders genetics, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Mutation, Neurodevelopmental Disorders pathology
- Abstract
DNA methylation (DNAm) signatures are unique patterns of DNAm alterations defined for rare disorders caused by pathogenic variants in epigenetic regulatory genes. The potential of DNAm signatures (also known as "episignatures") is just beginning to emerge as there are >300 known epigenetic regulatory genes, ∼100 of which are linked to neurodevelopmental disorders. To date, approximately 50 signatures have been identified, which have proven unexpectedly successful as predictive tools for classifying variants of uncertain significance as pathogenic or benign. The molecular basis of these signatures is poorly understood. Furthermore, their relationships to primary disease pathophysiology have yet to be adequately investigated, despite clear demonstrations of potential connections. There are currently no published guidelines for signature development. As signatures are highly dependent on the samples and methods used to derive them, we propose a framework for consideration in signature development including sample size, statistical parameters, cell type of origin, and the value of detailed clinical and molecular information. We illustrate the relationship between signature output/efficacy and sample size by generating and testing 837 DNAm signatures of Kleefstra syndrome using downsampling analysis. Our findings highlight that no single DNAm signature encompasses all DNAm alterations present in a rare disorder, and that a substandard study design can generate a DNAm signature that misclassifies variants. Finally, we discuss the importance of further investigating DNAm signatures to inform disease pathophysiology and broaden their scope as a functional assay., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2021
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33. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.
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Rots D, Chater-Diehl E, Dingemans AJM, Goodman SJ, Siu MT, Cytrynbaum C, Choufani S, Hoang N, Walker S, Awamleh Z, Charkow J, Meyn S, Pfundt R, Rinne T, Gardeitchik T, de Vries BBA, Deden AC, Leenders E, Kwint M, Stumpel CTRM, Stevens SJC, Vermeulen JR, van Harssel JVT, Bosch DGM, van Gassen KLI, van Binsbergen E, de Geus CM, Brackel H, Hempel M, Lessel D, Denecke J, Slavotinek A, Strober J, Crunk A, Folk L, Wentzensen IM, Yang H, Zou F, Millan F, Person R, Xie Y, Liu S, Ousager LB, Larsen M, Schultz-Rogers L, Morava E, Klee EW, Berry IR, Campbell J, Lindstrom K, Pruniski B, Neumeyer AM, Radley JA, Phornphutkul C, Schmidt B, Wilson WG, Õunap K, Reinson K, Pajusalu S, van Haeringen A, Ruivenkamp C, Cuperus R, Santos-Simarro F, Palomares-Bralo M, Pacio-Míguez M, Ritter A, Bhoj E, Tønne E, Tveten K, Cappuccio G, Brunetti-Pierri N, Rowe L, Bunn J, Saenz M, Platzer K, Mertens M, Caluseriu O, Nowaczyk MJM, Cohn RD, Kannu P, Alkhunaizi E, Chitayat D, Scherer SW, Brunner HG, Vissers LELM, Kleefstra T, Koolen DA, and Weksberg R
- Subjects
- Abnormalities, Multiple genetics, Case-Control Studies, Cohort Studies, Craniofacial Abnormalities genetics, Female, Genetic Predisposition to Disease, Growth Disorders genetics, Heart Septal Defects, Ventricular genetics, Humans, Infant, Newborn, Male, Neurodevelopmental Disorders genetics, Abnormalities, Multiple pathology, Adenosine Triphosphatases genetics, Craniofacial Abnormalities pathology, DNA Methylation, Epigenesis, Genetic, Growth Disorders pathology, Heart Septal Defects, Ventricular pathology, Mutation, Neurodevelopmental Disorders pathology, Phenotype
- Abstract
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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34. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.
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Sheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM Jr, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BH, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, Hakonarson H, Zackai EH, and Quintero-Rivera F
- Subjects
- Black People genetics, Constipation epidemiology, Constipation genetics, Constipation pathology, Failure to Thrive epidemiology, Failure to Thrive genetics, Failure to Thrive pathology, Genetic Association Studies, Growth Disorders epidemiology, Growth Disorders pathology, Humans, Hypertrichosis epidemiology, Hypertrichosis genetics, Hypertrichosis pathology, Intellectual Disability epidemiology, Intellectual Disability pathology, Loss of Function Mutation genetics, Retrospective Studies, White People genetics, Genetic Predisposition to Disease, Growth Disorders genetics, Histone-Lysine N-Methyltransferase genetics, Hypertrichosis congenital, Intellectual Disability genetics, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS., (© 2021 Wiley Periodicals LLC.)
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- 2021
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35. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
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Manole A, Efthymiou S, O'Connor E, Mendes MI, Jennings M, Maroofian R, Davagnanam I, Mankad K, Lopez MR, Salpietro V, Harripaul R, Badalato L, Walia J, Francklyn CS, Athanasiou-Fragkouli A, Sullivan R, Desai S, Baranano K, Zafar F, Rana N, Ilyas M, Horga A, Kara M, Mattioli F, Goldenberg A, Griffin H, Piton A, Henderson LB, Kara B, Aslanger AD, Raaphorst J, Pfundt R, Portier R, Shinawi M, Kirby A, Christensen KM, Wang L, Rosti RO, Paracha SA, Sarwar MT, Jenkins D, Ahmed J, Santoni FA, Ranza E, Iwaszkiewicz J, Cytrynbaum C, Weksberg R, Wentzensen IM, Guillen Sacoto MJ, Si Y, Telegrafi A, Andrews MV, Baldridge D, Gabriel H, Mohr J, Oehl-Jaschkowitz B, Debard S, Senger B, Fischer F, van Ravenwaaij C, Fock AJM, Stevens SJC, Bähler J, Nasar A, Mantovani JF, Manzur A, Sarkozy A, Smith DEC, Salomons GS, Ahmed ZM, Riazuddin S, Riazuddin S, Usmani MA, Seibt A, Ansar M, Antonarakis SE, Vincent JB, Ayub M, Grimmel M, Jelsig AM, Hjortshøj TD, Karstensen HG, Hummel M, Haack TB, Jamshidi Y, Distelmaier F, Horvath R, Gleeson JG, Becker H, Mandel JL, Koolen DA, and Houlden H
- Subjects
- Alleles, Amino Acyl-tRNA Synthetases genetics, Cell Line, Female, Genetic Predisposition to Disease genetics, Humans, Male, Pedigree, RNA, Transfer genetics, Stem Cells physiology, Aspartate-tRNA Ligase genetics, Gain of Function Mutation genetics, Loss of Function Mutation genetics, Neurodevelopmental Disorders genetics, RNA, Transfer, Amino Acyl genetics
- Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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36. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.
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Guillen Sacoto MJ, Tchasovnikarova IA, Torti E, Forster C, Andrew EH, Anselm I, Baranano KW, Briere LC, Cohen JS, Craigen WJ, Cytrynbaum C, Ekhilevitch N, Elrick MJ, Fatemi A, Fraser JL, Gallagher RC, Guerin A, Haynes D, High FA, Inglese CN, Kiss C, Koenig MK, Krier J, Lindstrom K, Marble M, Meddaugh H, Moran ES, Morel CF, Mu W, Muller EA 2nd, Nance J, Natowicz MR, Numis AL, Ostrem B, Pappas J, Stafstrom CE, Streff H, Sweetser DA, Szybowska M, Walker MA, Wang W, Weiss K, Weksberg R, Wheeler PG, Yoon G, Kingston RE, and Juusola J
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Genetic Diseases, Inborn genetics, Heterozygote, Humans, Infant, Intellectual Disability genetics, Male, Microcephaly genetics, Middle Aged, Phenotype, Young Adult, Adenosine Triphosphatases genetics, Craniofacial Abnormalities genetics, Growth Disorders genetics, Mutation genetics, Neurodevelopmental Disorders genetics, Transcription Factors genetics
- Abstract
MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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37. DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.
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Choufani S, Gibson WT, Turinsky AL, Chung BHY, Wang T, Garg K, Vitriolo A, Cohen ASA, Cyrus S, Goodman S, Chater-Diehl E, Brzezinski J, Brudno M, Ming LH, White SM, Lynch SA, Clericuzio C, Temple IK, Flinter F, McConnell V, Cushing T, Bird LM, Splitt M, Kerr B, Scherer SW, Machado J, Imagawa E, Okamoto N, Matsumoto N, Testa G, Iascone M, Tenconi R, Caluseriu O, Mendoza-Londono R, Chitayat D, Cytrynbaum C, Tatton-Brown K, and Weksberg R
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Mosaicism, Mutation, Missense genetics, Neoplasm Proteins, Reproducibility of Results, Transcription Factors, Young Adult, Abnormalities, Multiple genetics, Congenital Hypothyroidism genetics, Craniofacial Abnormalities genetics, DNA Methylation, Enhancer of Zeste Homolog 2 Protein genetics, Hand Deformities, Congenital genetics, Intellectual Disability genetics, Mutation, Polycomb Repressive Complex 2 genetics
- Abstract
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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38. Epigenetic signatures in overgrowth syndromes: Translational opportunities.
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Cytrynbaum C, Choufani S, and Weksberg R
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- DNA Methylation, Humans, Sotos Syndrome diagnosis, Sotos Syndrome genetics, Sotos Syndrome physiopathology, Syndrome, Epigenesis, Genetic, Growth Disorders genetics, Translational Research, Biomedical
- Abstract
In recent years, numerous overgrowth syndromes have been found to be caused by pathogenic DNA sequence variants in "epigenes," genes that encode proteins that function in epigenetic regulation. Epigenetic marks, including DNA methylation (DNAm), histone modifications and chromatin conformation, have emerged as a vital genome-wide regulatory mechanism that modulate the transcriptome temporally and spatially to drive normal developmental and cellular processes. Evidence suggests that epigenetic marks are layered and engage in crosstalk, in that disruptions of any one component of the epigenetic machinery impact the others. This interdependence of epigenetic marks underpins the recent identification of gene-specific DNAm signatures for a variety of disorders caused by pathogenic variants in epigenes. Here, we discuss the power of DNAm signatures with respect to furthering our understanding of disease pathophysiology, enhancing the efficacy of molecular diagnostics and identifying new targets for therapeutics of overgrowth syndromes. These findings highlight the promise of the field of epigenomics to provide unprecedented insights into disease mechanisms generating a host of opportunities to advance precision medicine., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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39. A large data resource of genomic copy number variation across neurodevelopmental disorders.
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Zarrei M, Burton CL, Engchuan W, Young EJ, Higginbotham EJ, MacDonald JR, Trost B, Chan AJS, Walker S, Lamoureux S, Heung T, Mojarad BA, Kellam B, Paton T, Faheem M, Miron K, Lu C, Wang T, Samler K, Wang X, Costain G, Hoang N, Pellecchia G, Wei J, Patel RV, Thiruvahindrapuram B, Roifman M, Merico D, Goodale T, Drmic I, Speevak M, Howe JL, Yuen RKC, Buchanan JA, Vorstman JAS, Marshall CR, Wintle RF, Rosenberg DR, Hanna GL, Woodbury-Smith M, Cytrynbaum C, Zwaigenbaum L, Elsabbagh M, Flanagan J, Fernandez BA, Carter MT, Szatmari P, Roberts W, Lerch J, Liu X, Nicolson R, Georgiades S, Weksberg R, Arnold PD, Bassett AS, Crosbie J, Schachar R, Stavropoulos DJ, Anagnostou E, and Scherer SW
- Abstract
Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1 , SEH1L , LDLRAD4 , GNAL , GNG13 , MKRN1 , DCTN2, KNDC1 , PCMTD2 , KIF5A , SYNM , and long non-coding RNAs: AK127244 and PTCHD1-AS . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants., Competing Interests: Competing interestsS.W.S. serves on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property originating from his research and held at the Hospital for Sick Children is licensed to Lineagen, and separately Athena Diagnostics. D.M. is a full-time employee of Deep Genomics and is entitled to a stock option. R.J.S., P.D.A., and J.C. consult for Highland Therapeutics. Intellectual property from ADHD research at the Hospital for Sick Children is licensed to Ehave and the National Research Council of Canada. Other authors declare no competing interests for the data and interpretation presented in this study. R.J.S., P.D.A., and J.C. consults for Highland Therapeutics. Intellectual property from their research at the Hospital for Sick Children is licensed to Ehave and the National Research Council. D.M. is a full-time employee of Deep Genomics and is entitled to stock options. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately to Lineagen. These relationships did not influence data interpretation or presentation during this study, but are disclosed for potential future consideration., (© The Author(s) 2019.)
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- 2019
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40. HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals.
- Author
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Burkardt DD, Zachariou A, Loveday C, Allen CL, Amor DJ, Ardissone A, Banka S, Bourgois A, Coubes C, Cytrynbaum C, Faivre L, Marion G, Horton R, Kotzot D, Lay-Son G, Lees M, Low K, Luk HM, Mark P, McConkie-Rosell A, McDonald M, Pappas J, Phillipe C, Shears D, Skotko B, Stewart F, Stewart H, Temple IK, Mau-Them FT, Verdugo RA, Weksberg R, Zarate YA, Graham JM, and Tatton-Brown K
- Subjects
- Behavior, Growth and Development, Heterozygote, Humans, Learning, Phenotype, Syndrome, Facies, Histones genetics, Intellectual Disability genetics, Mutation genetics
- Abstract
Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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41. New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.
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Chater-Diehl E, Ejaz R, Cytrynbaum C, Siu MT, Turinsky A, Choufani S, Goodman SJ, Abdul-Rahman O, Bedford M, Dorrani N, Engleman K, Flores-Daboub J, Genevieve D, Mendoza-Londono R, Meschino W, Perrin L, Safina N, Townshend S, Scherer SW, Anagnostou E, Piton A, Deardorff M, Brudno M, Chitayat D, and Weksberg R
- Subjects
- Adolescent, Case-Control Studies, Child, Child, Preschool, CpG Islands genetics, Facies, Female, Humans, Male, Phenotype, DNA Methylation, Foot Deformities, Congenital genetics, Genetic Variation, Hypotrichosis genetics, Intellectual Disability genetics, Transcription Factors genetics
- Abstract
Background: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures., Methods: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity., Results: We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation., Conclusions: Here we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary "benign" versus "pathogenic" scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.
- Published
- 2019
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42. Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.
- Author
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Chan AJS, Cytrynbaum C, Hoang N, Ambrozewicz PM, Weksberg R, Drmic I, Ritzema A, Schachar R, Walker S, Uddin M, Zarrei M, Yuen RKC, and Scherer SW
- Abstract
De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann-Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A . Our genotype-phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A ., Competing Interests: S.W.S. is on the Scientific Advisory committees of Population Bio and Deep Genomics. Athena Diagnostics and Lineagen license intellectual property from the Hospital for Sick Children based on research from his laboratory. These relationships did not influence data interpretation or presentation during this study, but are still being disclosed for potential future considerations. The other authors declare no competing interests.
- Published
- 2019
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43. Genome-wide copy number variation analysis identifies novel candidate loci associated with pediatric obesity.
- Author
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Selvanayagam T, Walker S, Gazzellone MJ, Kellam B, Cytrynbaum C, Stavropoulos DJ, Li P, Birken CS, Hamilton J, Weksberg R, and Scherer SW
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adolescent, Child, Preschool, DNA-Binding Proteins genetics, Female, Genome-Wide Association Study, Hepatocyte Nuclear Factor 4 genetics, Humans, Male, Receptor-Like Protein Tyrosine Phosphatases, Class 8 genetics, Receptors, G-Protein-Coupled genetics, Secretagogins genetics, Transcription Factors genetics, DNA Copy Number Variations, Genetic Loci, Obesity genetics
- Abstract
Obesity is a multifactorial condition that is highly heritable. There have been ~60 susceptibility loci identified, but they only account for a fraction of cases. As copy number variations (CNVs) have been implicated in the etiology of a multitude of human disorders including obesity, here, we investigated the contribution of rare (<1% population frequency) CNVs in pediatric cases of obesity. We genotyped 67 such individuals, including 22 with co-morbid developmental delay and prioritized rare CNVs at known obesity-associated loci, as well as, those impacting genes involved in energy homeostasis or related processes. We identified clinically relevant or potentially clinically relevant CNVs in 15% (10/67) of individuals. Of these, 4% (3/67) had 16p11.2 microdeletions encompassing the known obesity risk gene SH2B1. Notably, we identified two unrelated probands harboring different 6p22.2 microduplications encompassing SCGN, a potential novel candidate gene for obesity. Further, we identified other biologically relevant candidate genes for pediatric obesity including ARID5B, GPR39, PTPRN2, and HNF4G. We found previously reported candidate loci for obesity, and new ones, suggesting CNV analysis may assist in the diagnosis of pediatric obesity.
- Published
- 2018
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44. Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2 -related disorders.
- Author
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Jobling R, Stavropoulos DJ, Marshall CR, Cytrynbaum C, Axford MM, Londero V, Moalem S, Orr J, Rossignol F, Lopes FD, Gauthier J, Alos N, Rupps R, McKinnon M, Adam S, Nowaczyk MJM, Walker S, Scherer SW, Nassif C, Hamdan FF, Deal CL, Soucy JF, Weksberg R, Macleod P, Michaud JL, and Chitayat D
- Subjects
- Adolescent, Adult, Arthrogryposis physiopathology, Child, Exome genetics, Female, Growth Hormone deficiency, Humans, Intellectual Disability physiopathology, Male, Pedigree, Phenotype, Exome Sequencing, Young Adult, Arthrogryposis genetics, Growth Hormone genetics, Intellectual Disability genetics, Proteins genetics
- Abstract
Background: Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified., Methods and Results: We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion., Conclusions: Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2 -related disorders is expanded to include growth hormone deficiency as an important and treatable complication., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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45. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
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Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Thiruvahindrapuram B, Merico D, Jobling R, Nalpathamkalam T, Pellecchia G, Sung WWL, Wang Z, Bikangaga P, Boelman C, Carter MT, Cordeiro D, Cytrynbaum C, Dell SD, Dhir P, Dowling JJ, Heon E, Hewson S, Hiraki L, Inbar-Feigenberg M, Klatt R, Kronick J, Laxer RM, Licht C, MacDonald H, Mercimek-Andrews S, Mendoza-Londono R, Piscione T, Schneider R, Schulze A, Silverman E, Siriwardena K, Snead OC, Sondheimer N, Sutherland J, Vincent A, Wasserman JD, Weksberg R, Shuman C, Carew C, Szego MJ, Hayeems RZ, Basran R, Stavropoulos DJ, Ray PN, Bowdin S, Meyn MS, Cohn RD, Scherer SW, and Marshall CR
- Subjects
- Computational Biology methods, DNA Copy Number Variations, Exome, Female, Genetic Variation, Humans, Male, Molecular Sequence Annotation, Phenotype, Exome Sequencing methods, Exome Sequencing standards, Genetic Association Studies methods, Genetic Association Studies standards, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genetic Predisposition to Disease, Genetic Testing methods, Genetic Testing standards, Sequence Analysis, DNA methods, Sequence Analysis, DNA standards, Whole Genome Sequencing methods, Whole Genome Sequencing standards
- Abstract
PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.
- Published
- 2018
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46. Communicating complex genomic information: A counselling approach derived from research experience with Autism Spectrum Disorder.
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Hoang N, Cytrynbaum C, and Scherer SW
- Subjects
- Humans, Autism Spectrum Disorder genetics, Communication, Counseling, Genomics
- Abstract
Individuals with Autism Spectrum Disorder (ASD) share characteristics (impairments in socialization and communication, and repetitive interests and behaviour), but differ in their developmental course, pattern of symptoms, and cognitive and language abilities. The development of standardized phenotyping has revealed ASD to clinically be vastly heterogeneous, ranging from milder presentations to more severe forms associated with profound intellectual disability. Some 100 genes have now been implicated in the etiology of ASD, and advances in genome-wide testing continue to yield new data at an unprecedented rate. As the translation of this data is incorporated into clinical care, genetic professionals/counsellors, as well as other health care providers, will benefit from guidelines and tools to effectively communicate such genomic information. Here, we present a model to facilitate communication regarding the complexities of ASD, where clinical and genetic heterogeneity, as well as overlapping neurological conditions are inherent. We outline an approach for counselling families about their genomic results grounded in our direct experience from counselling families participating in an ASD research study, and supported by rationale from the literature., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2018
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47. CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions.
- Author
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Butcher DT, Cytrynbaum C, Turinsky AL, Siu MT, Inbar-Feigenberg M, Mendoza-Londono R, Chitayat D, Walker S, Machado J, Caluseriu O, Dupuis L, Grafodatskaya D, Reardon W, Gilbert-Dussardier B, Verloes A, Bilan F, Milunsky JM, Basran R, Papsin B, Stockley TL, Scherer SW, Choufani S, Brudno M, and Weksberg R
- Subjects
- Abnormalities, Multiple diagnosis, CHARGE Syndrome diagnosis, Cell Line, DNA Helicases genetics, DNA Helicases metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Gene Expression Regulation, Genome, Human, Hematologic Diseases diagnosis, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear metabolism, Mutation, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Reproducibility of Results, Sensitivity and Specificity, Vestibular Diseases diagnosis, Abnormalities, Multiple genetics, CHARGE Syndrome genetics, DNA Methylation, Epigenesis, Genetic, Face abnormalities, Hematologic Diseases genetics, Vestibular Diseases genetics
- Abstract
Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7
LOF ) and lysine (K) methyltransferase 2D (KMT2DLOF ), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7LOF or KMT2DLOF identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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48. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
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C Yuen RK, Merico D, Bookman M, L Howe J, Thiruvahindrapuram B, Patel RV, Whitney J, Deflaux N, Bingham J, Wang Z, Pellecchia G, Buchanan JA, Walker S, Marshall CR, Uddin M, Zarrei M, Deneault E, D'Abate L, Chan AJ, Koyanagi S, Paton T, Pereira SL, Hoang N, Engchuan W, Higginbotham EJ, Ho K, Lamoureux S, Li W, MacDonald JR, Nalpathamkalam T, Sung WW, Tsoi FJ, Wei J, Xu L, Tasse AM, Kirby E, Van Etten W, Twigger S, Roberts W, Drmic I, Jilderda S, Modi BM, Kellam B, Szego M, Cytrynbaum C, Weksberg R, Zwaigenbaum L, Woodbury-Smith M, Brian J, Senman L, Iaboni A, Doyle-Thomas K, Thompson A, Chrysler C, Leef J, Savion-Lemieux T, Smith IM, Liu X, Nicolson R, Seifer V, Fedele A, Cook EH, Dager S, Estes A, Gallagher L, Malow BA, Parr JR, Spence SJ, Vorstman J, Frey BJ, Robinson JT, Strug LJ, Fernandez BA, Elsabbagh M, Carter MT, Hallmayer J, Knoppers BM, Anagnostou E, Szatmari P, Ring RH, Glazer D, Pletcher MT, and Scherer SW
- Subjects
- Chromosome Aberrations, DNA Copy Number Variations, Humans, Mutagenesis, Insertional genetics, Phenotype, Polymorphism, Single Nucleotide genetics, Sequence Deletion genetics, Autism Spectrum Disorder genetics, Databases, Genetic, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods
- Abstract
We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10
-4 ). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.- Published
- 2017
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49. Genomic imbalance in the centromeric 11p15 imprinting center in three families: Further evidence of a role for IC2 as a cause of Russell-Silver syndrome.
- Author
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Cytrynbaum C, Chong K, Hannig V, Choufani S, Shuman C, Steele L, Morgan T, Scherer SW, Stavropoulos DJ, Basran RK, and Weksberg R
- Subjects
- Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, DNA Methylation, Facies, Female, Genetic Association Studies, Humans, Infant, Male, Pedigree, Phenotype, Sequence Analysis, DNA, Centromere genetics, Chromosomes, Human, Pair 11, Genomic Imprinting, Silver-Russell Syndrome diagnosis, Silver-Russell Syndrome genetics
- Abstract
Russell-Silver syndrome is a heterogeneous disorder characterized by intrauterine growth retardation, postnatal growth deficiency, characteristic facial appearance, and other variable features. Genetic and epigenetic alterations are identified in about 60% of individuals with Russell-Silver syndrome. Most frequently, Russell-Silver syndrome is caused by altered gene expression on chromosome 11p15 due to loss of methylation at the telomeric imprinting center. To date there have been a handful of isolated clinical reports implicating the centromeric imprinting center 2 in the etiology of Russell-Silver syndrome. Here we report three new families with genomic imbalances, involving imprinting center 2 resulting in gain of methylation at this center and a Russell-Silver syndrome phenotype, including two families with a maternally inherited microduplication and the first pediatric patient with a paternally derived microdeletion. The findings in our families provide additional evidence of a role for imprinting center 2 in the etiology of Russell-Silver syndrome and suggest that imprinting center 2 imprinting abnormalities may be a more common cause of Russell-Silver syndrome than previously recognized. Furthermore, our findings together with previous clinical reports of genomic imbalances involving imprinting center 2 serve to underscore the complexity of the epigenetic regulation of the 11p15 region making it challenging to predict phenotype on the basis of genotype alone. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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50. Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.
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Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G, Yuen RKC, Szego MJ, Hayeems RZ, Shaul RZ, Brudno M, Girdea M, Frey B, Alipanahi B, Ahmed S, Babul-Hirji R, Porras RB, Carter MT, Chad L, Chaudhry A, Chitayat D, Doust SJ, Cytrynbaum C, Dupuis L, Ejaz R, Fishman L, Guerin A, Hashemi B, Helal M, Hewson S, Inbar-Feigenberg M, Kannu P, Karp N, Kim R, Kronick J, Liston E, MacDonald H, Mercimek-Mahmutoglu S, Mendoza-Londono R, Nasr E, Nimmo G, Parkinson N, Quercia N, Raiman J, Roifman M, Schulze A, Shugar A, Shuman C, Sinajon P, Siriwardena K, Weksberg R, Yoon G, Carew C, Erickson R, Leach RA, Klein R, Ray PN, Meyn MS, Scherer SW, Cohn RD, and Marshall CR
- Abstract
The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis., Competing Interests: Competing Interests: DM RJ, NM, BT, TN, GP, RKCY, MS, RH, RZS, MB, MG, BF, BA, SA, MTC, LC, AC, CC, LD, RE, LF, AG, BH, MH, SH, MIF, PK, NK, RK, JK, EL, HM, SMM, RML, EN, GN, NP, NQ, JR, MR, AS, AS, CS, PS, KS, RW, GY, CC, SWS, RDC, and CRM declare no conflicts of interest. SB, DJS, PNR and MSM are scientific advisors for Gene42 Inc., which provides support services for the free (open source) PhenoTips software. RE and RK are employees of Complete Genomics. RAL was an employee of Complete Genomics at the time of the study and is currently employed by WuXi NextCODE Genomics.
- Published
- 2016
- Full Text
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