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11 results on '"Genetti, C.A."'

1. Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Author

Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, Curry, C.J., Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, and Curry, C.J.

Abstract

01 juli 2023, Item does not contain fulltext, Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Published
2023

2. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., Kleefstra, T., Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., and Kleefstra, T.

Abstract

Item does not contain fulltext, Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Published
2021

3. 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

4. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., Kleefstra, T., Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., and Kleefstra, T.

Abstract

Contains fulltext : 237819.pdf (Publisher’s version ) (Closed access), Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Published
2021

5. 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

6. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., Kleefstra, T., Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., and Kleefstra, T.

Abstract

Contains fulltext : 237819.pdf (Publisher’s version ) (Closed access), Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Published
2021

7. 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

8. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author

Duncan, A.R. (Anna R.), Vitobello, A. (Antonio), Collins, S.C. (Stephan C.), Vancollie, V.E. (Valerie E.), Lelliott, C.J. (Christopher J.), Rodan, L. (Lance), Shi, J. (Jiahai), Seman, A.R. (Ann R.), Agolini, E. (Emanuele), Novelli, A. (Antonio), Prontera, P. (Paolo), Guillen Sacoto, M.J. (Maria J.), Santiago-Sim, T. (Teresa), Trimouille, A. (Aurélien), Goizet, C. (Cyril), Nizon, M. (Mathilde), Bruel, A.-L. (Ange-Line), Philippe, C. (Christophe), Grant, P.E. (Patricia E.), Wojcik, M.H. (Monica H.), Stoler, J. (Joan), Genetti, C.A. (Casie A.), Dooren, M.F. (Marieke) van, Maas, S.M. (Saskia), Alders, M. (Mariëlle), Faivre, L. (Laurence), Sorlin, A. (Arthur), Yoon, G. (Grace), Yalcin, B. (Binnaz), Agrawal, P.B. (Pankaj B.), Duncan, A.R. (Anna R.), Vitobello, A. (Antonio), Collins, S.C. (Stephan C.), Vancollie, V.E. (Valerie E.), Lelliott, C.J. (Christopher J.), Rodan, L. (Lance), Shi, J. (Jiahai), Seman, A.R. (Ann R.), Agolini, E. (Emanuele), Novelli, A. (Antonio), Prontera, P. (Paolo), Guillen Sacoto, M.J. (Maria J.), Santiago-Sim, T. (Teresa), Trimouille, A. (Aurélien), Goizet, C. (Cyril), Nizon, M. (Mathilde), Bruel, A.-L. (Ange-Line), Philippe, C. (Christophe), Grant, P.E. (Patricia E.), Wojcik, M.H. (Monica H.), Stoler, J. (Joan), Genetti, C.A. (Casie A.), Dooren, M.F. (Marieke) van, Maas, S.M. (Saskia), Alders, M. (Mariëlle), Faivre, L. (Laurence), Sorlin, A. (Arthur), Yoon, G. (Grace), Yalcin, B. (Binnaz), and Agrawal, P.B. (Pankaj B.)

Abstract

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Published
2020
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9. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

10. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

11. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., Laing, N.G., Oates, E.C., Jones, K.J., Donkervoort, S., Charlton, A., Brammah, S., Smith, J.E., Ware, J.S., Yau, K.S., Swanson, L.C., Whiffin, N., Peduto, A.J., Bournazos, A., Waddell, L.B., Farrar, M.A., Sampaio, H.A., Teoh, H.L., Lamont, P.J., Mowat, D., Fitzsimons, R.B., Corbett, A.J., Ryan, M.M., O'Grady, G.L., Sandaradura, S.A., Ghaoui, R., Joshi, H., Marshall, J.L., Nolan, M.A., Kaur, S., Punetha, J., Topf, A., Harris, E., Bakshi, M., Genetti, C.A., Marttila, M., Werlauff, U., Streichenberger, N., Pestronk, A., Mazanti, I., Pinner, J.R., Vuillerot, C., Grosmann, C., Camacho, A., Mohassel, P., Leach, M.E., Foley, A.R., Bharucha-Goebel, D., Collins, J., Connolly, A.M., Gilbreath, H.R., Iannaccone, S.T., Castro, D., Cummings, B.B., Webster, R.I., Lazaro, L., Vissing, J., Coppens, S., Deconinck, N., Luk, H.M., Thomas, N.H., Foulds, N.C., Illingworth, M.A., Ellard, S., McLean, C.A., Phadke, R., Ravenscroft, G., Witting, N., Hackman, P., Richard, I., Cooper, S.T., Kamsteeg, E.J., Hoffman, E.P., Bushby, K., Straub, V., Udd, B., Ferreiro, A., North, K.N., Clarke, N.F., Lek, M., Beggs, A.H., Bonnemann, C.G., MacArthur, D.G., Granzier, H., Davis, M.R., and Laing, N.G.

Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

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