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1. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

2. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, H.K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C.S., Soucy, A., Genetti, C.A., Suslovitch, V., Rodan, L.H., Tiller, G.E., Lesca, G., Gripp, K.W., Asadollahi, R., Hamosh, A., Applegate, C.D., Turnpenny, P.D., Simon, M.E., Volker-Touw, C.M., Gassen, K. van, Binsbergen, E.V., Pfundt, R.P., Gardeitchik, T., Vries, B.B. de, Immken, L.L., Buchanan, C., Willing, M., Toler, T.L., Fassi, E., Baker, L., Vansenne, F., Wang, X, Ambrus, J.L., Jr., Fannemel, M., Posey, J.E., Agolini, E., Novelli, A., Rauch, A., Boonsawat, P., Fagerberg, C.R., Larsen, M.J., Kibaek, M., Labalme, A., Poisson, A., Payne, K.K., Walsh, L.E., Aldinger, K.A., Balciuniene, J., Skraban, C., Gray, C., Murrell, J., Bupp, C.P., Pascolini, G., Grammatico, P., Broly, M., Küry, S., Nizon, M., Rasool, I.G., Zahoor, M.Y., Kraus, C., Reis, A., Iqbal, M., Uguen, K., Audebert-Bellanger, S., Ferec, C., Redon, S., Baker, J., Wu, Y., Zampino, G., Syrbe, S., Brosse, I., Jamra, R.A., Dobyns, W.B., Cohen, L.L., Blomhoff, A., Mignot, C., Keren, B., Courtin, T., Agrawal, P.B., Beggs, A.H., Yu, T.W., Harris, H.K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C.S., Soucy, A., Genetti, C.A., Suslovitch, V., Rodan, L.H., Tiller, G.E., Lesca, G., Gripp, K.W., Asadollahi, R., Hamosh, A., Applegate, C.D., Turnpenny, P.D., Simon, M.E., Volker-Touw, C.M., Gassen, K. van, Binsbergen, E.V., Pfundt, R.P., Gardeitchik, T., Vries, B.B. de, Immken, L.L., Buchanan, C., Willing, M., Toler, T.L., Fassi, E., Baker, L., Vansenne, F., Wang, X, Ambrus, J.L., Jr., Fannemel, M., Posey, J.E., Agolini, E., Novelli, A., Rauch, A., Boonsawat, P., Fagerberg, C.R., Larsen, M.J., Kibaek, M., Labalme, A., Poisson, A., Payne, K.K., Walsh, L.E., Aldinger, K.A., Balciuniene, J., Skraban, C., Gray, C., Murrell, J., Bupp, C.P., Pascolini, G., Grammatico, P., Broly, M., Küry, S., Nizon, M., Rasool, I.G., Zahoor, M.Y., Kraus, C., Reis, A., Iqbal, M., Uguen, K., Audebert-Bellanger, S., Ferec, C., Redon, S., Baker, J., Wu, Y., Zampino, G., Syrbe, S., Brosse, I., Jamra, R.A., Dobyns, W.B., Cohen, L.L., Blomhoff, A., Mignot, C., Keren, B., Courtin, T., Agrawal, P.B., Beggs, A.H., and Yu, T.W.

Abstract

Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access), PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Published
2021

3. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder

Author

den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

5. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TATA-box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.

Published
2020

12. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author

Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T.T.M., Spillmann, R.C., Sullivan, J.A., Shashi, V., Jiang, Y.H., Stong, N., Fiala, E., Willing, M., Pfundt, R.P., Kleefstra, T., Cho, M.T., McLaughlin, H., Piera, M. Rosello, Orellana, C., Martinez, F., Caro-Llopis, A., Monfort, S., Roscioli, T., Nixon, C.Y., Buckley, M.F., Turner, A., Jones, W.D., Hasselt, P.M. van, Hofstede, F.C., Gassen, K.L.I. van, Brooks, A.S., Slegtenhorst, M.A. van, Lachlan, K., Sebastian, J., Madan-Khetarpal, S., Sonal, D., Sakkubai, N., Thevenon, J., Faivre, L., Maurel, A., Petrovski, S., Krantz, I.D., Tarpinian, J.M., Rosenfeld, J.A., Lee, B.H., Campeau, P.M., Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T.T.M., Spillmann, R.C., Sullivan, J.A., Shashi, V., Jiang, Y.H., Stong, N., Fiala, E., Willing, M., Pfundt, R.P., Kleefstra, T., Cho, M.T., McLaughlin, H., Piera, M. Rosello, Orellana, C., Martinez, F., Caro-Llopis, A., Monfort, S., Roscioli, T., Nixon, C.Y., Buckley, M.F., Turner, A., Jones, W.D., Hasselt, P.M. van, Hofstede, F.C., Gassen, K.L.I. van, Brooks, A.S., Slegtenhorst, M.A. van, Lachlan, K., Sebastian, J., Madan-Khetarpal, S., Sonal, D., Sakkubai, N., Thevenon, J., Faivre, L., Maurel, A., Petrovski, S., Krantz, I.D., Tarpinian, J.M., Rosenfeld, J.A., Lee, B.H., and Campeau, P.M.

Abstract

Contains fulltext : 202800.pdf (publisher's version ) (Open Access), SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Published
2019

13. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., Lyon, G.J., Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., and Lyon, G.J.

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.

Published
2019

14. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

Published
2019

20. Genetic Association ofMMP10,MMP14, andMMP16with Dental Caries

Author

Lewis, D. D., primary, Shaffer, J. R., additional, Feingold, E., additional, Cooper, M., additional, Vanyukov, M. M., additional, Maher, B. S., additional, Slayton, R. L., additional, Willing, M. C., additional, Reis, S. E., additional, McNeil, D. W., additional, Crout, R. J., additional, Weyant, R. J., additional, Levy, S. M., additional, Vieira, A. R., additional, and Marazita, M. L., additional

Published
2017
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22. Genetic Association of MMP10, MMP14, and MMP16 with Dental Caries.

Author

Lewis, D. D., Shaffer, J. R., Feingold, E., Cooper, M., Vanyukov, M. M., Maher, B. S., Slayton, R. L., Willing, M. C., Reis, S. E., McNeil, D. W., Crout, R. J., Weyant, R. J., Levy, S. M., Vieira, A. R., and Marazita, M. L.

Subjects
DENTAL caries, MATRIX metalloproteinases, TOOTH demineralization, DENTAL pathology, ADULTS, GENETICS
Abstract

Matrix metalloproteinases (MMPs), which degrade extracellular proteins as part of a variety of physiological processes, and their inhibitors have been implicated in the dental caries process. Here we investigated 28 genetic variants spanning the MMP10, MMP14, and MMP16 genes to detect association with dental caries experience in 13 age- and race-stratified (n=3,587) samples from 6 parent studies. Analyses were performed separately for each sample, and results were combined across samples by meta-analysis. Two SNPs (rs2046315 and rs10429371) upstream of MMP16 were significantly associated with caries in an individual sample of white adults and via meta-analysis across 8 adult samples after gene-wise adjustment for multiple comparisons. Noteworthy is SNP rs2046315 (p=8.14×10-8) association with caries in white adults. This SNP was originally nominated in a genome-wide-association study (GWAS) of dental caries in a sample of white adults and yielded associations in a subsequent GWAS of surface level caries in white adults as well. Therefore, in our study, we were able to recapture the association between rs2046315 and dental caries in white adults. Although we did not strengthen evidence that MMPs 10, 14, and 16 influence caries risk, MMP16 is still a likely candidate gene to pursue. [ABSTRACT FROM AUTHOR]

Published
2017
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23. Genome-wide association scan for childhood caries implicates novel genes

Author

Shaffer, J. R., Feingold, E., Lee, M., Begum, F., Weeks, D. E., Cuenco, K. T., Barmada, M. M., Wendell, S. K., Crosslin, D. R., Laurie, C. C., Doheny, K. F., Pugh, E. W., Feenstra, B., Geller, F., Boyd, H. A., Melbye, M., Murray, J. C., Weyant, R. J., Crout, R., McNeil, D. W., Levy, S. M., Slayton, R. L., Willing, M. C., Broffitt, B., Vieira, A. R., Marazita, M. L., Shaffer, J. R., Feingold, E., Lee, M., Begum, F., Weeks, D. E., Cuenco, K. T., Barmada, M. M., Wendell, S. K., Crosslin, D. R., Laurie, C. C., Doheny, K. F., Pugh, E. W., Feenstra, B., Geller, F., Boyd, H. A., Melbye, M., Murray, J. C., Weyant, R. J., Crout, R., McNeil, D. W., Levy, S. M., Slayton, R. L., Willing, M. C., Broffitt, B., Vieira, A. R., and Marazita, M. L.

Abstract

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

Published
2011

38. Methods

Author

Willing, M. H.

Published
1925

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