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1. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Author

Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., Stessman, H.A.F., Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., and Stessman, H.A.F.

Abstract

Item does not contain fulltext, Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

2. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

Author

Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., Maroofian, R., Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., and Maroofian, R.

Abstract

01 januari 2023, Item does not contain fulltext, PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Published
2023

6. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., Ravenswaaij-Arts, C.M.A. van, Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., Belnap, N., Benoit, V., Delplancq, G., Vries, B.B.A. de, Grotto, S., Lacombe, D., Larson, A., Mourmans, J., Õunap, K., Petrilli, G., Pfundt, R.P., Ramsey, K., Snijders Blok, L., Tsatsaris, V., Vitobello, A., Faivre, L., Wheeler, P.G., Wevers, M.R., Wojcik, M., Zweier, M., Gozani, O., Rauch, A., Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., Ravenswaaij-Arts, C.M.A. van, Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., Belnap, N., Benoit, V., Delplancq, G., Vries, B.B.A. de, Grotto, S., Lacombe, D., Larson, A., Mourmans, J., Õunap, K., Petrilli, G., Pfundt, R.P., Ramsey, K., Snijders Blok, L., Tsatsaris, V., Vitobello, A., Faivre, L., Wheeler, P.G., Wevers, M.R., Wojcik, M., Zweier, M., Gozani, O., and Rauch, A.

Abstract

Contains fulltext : 237837.pdf (Publisher’s version ) (Open Access), PURPOSE: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. METHODS: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. RESULTS: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2's folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. CONCLUSION: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch-Steindl syndrome after the delineators of this phenotype.

Published
2021

7. 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

8. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., Tartaglia, M., Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., and Tartaglia, M.

Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access), Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

9. CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Author

Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, Aggarwal, V, Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, and Aggarwal, V

Abstract

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Published
2021

10. Loss-of-function truncating and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct neurodevelopmental phenotype

Author

Zanoni, P., Steindl, K., Sengupta, D., Sticht, H., Joset, P., Baar, A., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Maystadt, I., Belnap, N., Benoit, V., de Vries, B. B. A., Lacombe, D., Larson, A., Pfundt, R., Ramsey, K., Blok, L. Snijders, Wheeler, P. G., Wevers, M. R., Gozani, O., Rauch, A., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Published
2020

12. Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

Author

Schneeberger, Peter M., Elsner, L. Von, Barker, E.L., Meinecke, P., Marquardt, I., Alawi, M., Steindl, K., Joset, P., Rauch, A., Zwijnenburg, P.J., Weiss, M.M., Merry, C.L., Kutsche, K., Schneeberger, Peter M., Elsner, L. Von, Barker, E.L., Meinecke, P., Marquardt, I., Alawi, M., Steindl, K., Joset, P., Rauch, A., Zwijnenburg, P.J., Weiss, M.M., Merry, C.L., and Kutsche, K.

Abstract

Contains fulltext : 229371.pdf (Publisher’s version ) (Closed access)

Published
2020

13. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author

Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., Jolly, L.A., Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., and Jolly, L.A.

Abstract

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access), BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hi

Published
2020

14. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

Author

Nasser, H., Vera, L., Elmaleh-Berges, M., Steindl, K., Letard, P., Teissier, N., Ernault, A., Guimiot, F., Afenjar, A., Moutard, M. L., Heron, D., Alembik, Y., Momtchilova, M., Milani, P., Kubis, N., Pouvreau, N., Zollino, Marcella, Guilmin Crepon, S., Kaguelidou, F., Gressens, P., Verloes, A., Rauch, A., El Ghouzzi, V., Drunat, S., Passemard, S., Zollino M. (ORCID:0000-0003-4871-9519), Nasser, H., Vera, L., Elmaleh-Berges, M., Steindl, K., Letard, P., Teissier, N., Ernault, A., Guimiot, F., Afenjar, A., Moutard, M. L., Heron, D., Alembik, Y., Momtchilova, M., Milani, P., Kubis, N., Pouvreau, N., Zollino, Marcella, Guilmin Crepon, S., Kaguelidou, F., Gressens, P., Verloes, A., Rauch, A., El Ghouzzi, V., Drunat, S., Passemard, S., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Background: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. Methods: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. Results: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. Conclusion: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. Trial registration number: NCT01565005.

Published
2020

17. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures

Author

Zweier, M., Begemann, A., Mcwalter, K., Cho, M. T., Abela, L., Banka, S., Behring, B., Berger, A., Brown, C. W., Carneiro, M., Chen, J., Cooper, G. M., Finnila, C. R., Sacoto, M. J. Guillen, Henderson, A., Hueffmeier, U., Joset, P., Kerr, B., Lesca, G., Leszinski, G. S., Mcdermott, J. H., Meltzer, M. R., Monaghan, K. G., Mostafavi, R., Ounap, K., Plecko, B., Powis, Z., Purcarin, G., Reimand, T., Riedhammer, K. M., Schreiber, J. M., Sirsi, D., Wierenga, K. J., Wojcik, M. H., Papuc, S. M., Steindl, K., Sticht, H., and Anita Rauch

Subjects
Male, Models, Molecular, Candidate gene, Cytoplasm, Biology, Article, Seizures, Intellectual Disability, Intellectual disability, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, Intron, Protein primary structure, Facies, Infant, medicine.disease, Phenotype, Exon skipping, Child, Preschool, CYFIP2, Mutation, Female
Abstract

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

Published
2019

18. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., Rodan, L.H., O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., and Rodan, L.H.

Abstract

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

19. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Author

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

Abstract

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

Published
2017

20. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., Talkowski, M.E., Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., and Talkowski, M.E.

Abstract

Item does not contain fulltext, Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Published
2017

21. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Author

Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, de Vries, BBA, Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, and de Vries, BBA

Abstract

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

Published
2017

23. A Combined Metabolic–Genetic Approach to Early-Onset Epileptic Encephalopathies: Results from a Swiss Study Cohort

Author

Abela, L., primary, Steindl, K., additional, Simmons, L., additional, Joset, P., additional, Papuc, M., additional, Mathis, D., additional, Schmitt, B., additional, Wohlrab, G., additional, Klein, A., additional, Asadollahi, R., additional, Crowther, L., additional, Sass, O., additional, Hersberger, M., additional, Rauch, A., additional, and Plecko, B., additional

Published
2016
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25. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Author

May, M. (Melanie), Hwang, K.-S. (Kyu-Seok), Miles, J. (Judith), Williams, C. (Charlie), Niranjan, T. (Tejasvi), Kahler, S.G. (Stephen G.), Chiurazzi, P. (Pietro), Steindl, K. (Katharina), Spek, P.J. (Peter) van der, Swagemakers, S.M.A. (Sigrid), Mueller, J. (Jennifer), Stefl, S. (Shannon), Alexov, E. (Emil), Ryu, J.-I. (Jeong-Im), Choi, J.-H. (Jung-Hwa), Kim, H.-T. (Hyun-Taek), Tarpey, P.S. (Patrick), Neri, G. (Giovanni), Holloway, L. (Lynda), Skinner, C. (Cindy), Stevenson, R.E. (Roger E.), Dorsky, R.I. (Richard I.), Wang, T. (Tao), Schwartz, C.E., Kim, C.-H. (Cheol-Hee), May, M. (Melanie), Hwang, K.-S. (Kyu-Seok), Miles, J. (Judith), Williams, C. (Charlie), Niranjan, T. (Tejasvi), Kahler, S.G. (Stephen G.), Chiurazzi, P. (Pietro), Steindl, K. (Katharina), Spek, P.J. (Peter) van der, Swagemakers, S.M.A. (Sigrid), Mueller, J. (Jennifer), Stefl, S. (Shannon), Alexov, E. (Emil), Ryu, J.-I. (Jeong-Im), Choi, J.-H. (Jung-Hwa), Kim, H.-T. (Hyun-Taek), Tarpey, P.S. (Patrick), Neri, G. (Giovanni), Holloway, L. (Lynda), Skinner, C. (Cindy), Stevenson, R.E. (Roger E.), Dorsky, R.I. (Richard I.), Wang, T. (Tao), Schwartz, C.E., and Kim, C.-H. (Cheol-Hee)

Abstract

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits.

Published
2015
Full Text
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26. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Author

May, M, Hwang, KS, Miles, J, Williams, C, Niranjan, T, Kahler, SG, Chiurazzi, P, Steindl, K, van der Spek, Peter, Swagemakers, Sigrid, Mueller, J, Stefl, S, Alexov, E, Ryu, JI, Choi, JH, Kim, HT, Tarpey, P, Neri, G, Holloway, L, Skinner, C, Stevenson, RE, Dorsky, RI, Wang, T, Schwartz, CE, Kim, CH, May, M, Hwang, KS, Miles, J, Williams, C, Niranjan, T, Kahler, SG, Chiurazzi, P, Steindl, K, van der Spek, Peter, Swagemakers, Sigrid, Mueller, J, Stefl, S, Alexov, E, Ryu, JI, Choi, JH, Kim, HT, Tarpey, P, Neri, G, Holloway, L, Skinner, C, Stevenson, RE, Dorsky, RI, Wang, T, Schwartz, CE, and Kim, CH

Abstract

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66Hor p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits.

Published
2015

27. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Author

May, M., Hwang, K. -S., Miles, J., Williams, C., Niranjan, T., Kahler, S. G., Chiurazzi, Pietro, Steindl, K., Van Der Spek, P. J., Swagemakers, S., Mueller, J., Stefl, S., Alexov, E., Ryu, J. -I., Choi, J. -H., Kim, H. -T., Tarpey, P., Neri, Giovanni, Holloway, L., Skinner, C., Stevenson, R. E., Dorsky, R. I., Wang, T., Schwartz, C. E., Kim, C. -H., Chiurazzi P. (ORCID:0000-0001-5104-1521), Neri G., May, M., Hwang, K. -S., Miles, J., Williams, C., Niranjan, T., Kahler, S. G., Chiurazzi, Pietro, Steindl, K., Van Der Spek, P. J., Swagemakers, S., Mueller, J., Stefl, S., Alexov, E., Ryu, J. -I., Choi, J. -H., Kim, H. -T., Tarpey, P., Neri, Giovanni, Holloway, L., Skinner, C., Stevenson, R. E., Dorsky, R. I., Wang, T., Schwartz, C. E., Kim, C. -H., Chiurazzi P. (ORCID:0000-0001-5104-1521), and Neri G.

Abstract

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits.

Published
2015

31. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder

Author

Zollino, M., Orteschi, D., Ruiter, M., Pfundt, R.P., Steindl, K., Cafiero, C., Ricciardi, S., Contaldo, I., Chieffo, D., Ranalli, D., Acquafondata, C., Murdolo, M., Marangi, G., Asaro, A., Battaglia, D., Zollino, M., Orteschi, D., Ruiter, M., Pfundt, R.P., Steindl, K., Cafiero, C., Ricciardi, S., Contaldo, I., Chieffo, D., Ranalli, D., Acquafondata, C., Murdolo, M., Marangi, G., Asaro, A., and Battaglia, D.

Abstract

Item does not contain fulltext, OBJECTIVE: Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. METHODS: Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1. RESULTS: Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1. SIGNIFICANCE: We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes

Published
2014

32. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder

Author

Zollino, Marcella, Orteschi, Daniela, Ruiter, M, Pfundt, R, Steindl, K, Cafiero, Concetta, Ricciardi, Stefania, Contaldo, Ilaria, Chieffo, Daniela Pia Rosaria, Ranalli, Domiziana, Acquafondata, Celeste, Murdolo, Marina, Marangi, Giuseppe, Asaro, Alessia, Battaglia, Domenica Immacolata, Zollino, Marcella (ORCID:0000-0003-4871-9519), Chieffo, Daniela Pia, Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Zollino, Marcella, Orteschi, Daniela, Ruiter, M, Pfundt, R, Steindl, K, Cafiero, Concetta, Ricciardi, Stefania, Contaldo, Ilaria, Chieffo, Daniela Pia Rosaria, Ranalli, Domiziana, Acquafondata, Celeste, Murdolo, Marina, Marangi, Giuseppe, Asaro, Alessia, Battaglia, Domenica Immacolata, Zollino, Marcella (ORCID:0000-0003-4871-9519), Chieffo, Daniela Pia, Marangi, Giuseppe (ORCID:0000-0002-6898-8882), and Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021)

Abstract

Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside.

Published
2014

39. Autosomal dominant simple microphthalmos.

Author

Vingolo, E M, primary, Steindl, K, additional, Forte, R, additional, Zompatori, L, additional, Iannaccone, A, additional, Sciarra, A, additional, Del Porto, G, additional, and Pannarale, M R, additional

Published
1994
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41. Exome Pool-Seq Reloaded

Author

Popp, B., Vasileiou, G., Zweier, M., Ekici, A. B., Moortgat, S., Lederer, D., Maystadt, I., Destree, A., Drunat, S., Verloes, A., Rauch, A., Steindl, K., Maldergem, L., Piard, J., Brischoux, E. B., Engel, C., Serey-Gaut, M., André Reis, and Zweier, C.

42. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, SHARP, Male, obesity, genotype-phenotype correlations, Autism Spectrum Disorder, PROTEIN, Chromosome Disorders, Haploinsufficiency, RNA-Binding Protein, PHENOTYPE CORRELATIONS, 1p36, distal 1p36 deletion syndrome, DNA methylome analysis, episignature, neurodevelopmental disorder, proximal 1p36 deletion syndrome, SPEN, X chromosome, Adolescent, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult, 0302 clinical medicine, Neurodevelopmental disorder, Neurodevelopmental Disorder, Intellectual disability, MOLECULAR CHARACTERIZATION, Genetics (clinical), Genetics, DNA methylome analysi, SPLIT-ENDS, Hypotonia, Autism spectrum disorder, MONOSOMY 1P36, Pair 1, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, DNA-Binding Protein, Biology, genotype-phenotype correlation, Chromosomes, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Report, REVEALS, medicine, Epigenetics, Preschool, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 1p36 deletion syndrome, IDENTIFICATION, MUTATIONS, medicine.disease, GENE, 030104 developmental biology, Chromosome Disorder, 030217 neurology & neurosurgery, Epigenesis
Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

44. Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

Author

Gökhan Yigit, Filippo Beleggia, Janine Altmüller, Nadine Rosin, Pinar Isguven, Peter Nürnberg, Katharina Steindl, Pascal Joset, Nursel Elcioglu, Holger Thiele, Bernd Wollnik, Anita Rauch, University of Zurich, Wollnik, Bernd, Rosin, Nadine, Elcioglu, Nursel H., Beleggia, Filippo, Isguven, Pinar, Altmueller, Janine, Thiele, Holger, Steindl, Katharina, Joset, Pascal, Rauch, Anita, Nuernberg, Peter, Yigit, Goekhan, Rosin, N, Elcioglu, NH, Beleggia, F, Isguven, P, Altmuller, J, Thiele, H, Steindl, K, Joset, P, Rauch, A, Nurnberg, P, Wollnik, B, Yigit, G, Sakarya Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri Bölümü, and İşgüven, Şükriye Pınar

Subjects
Genome instability, Male, V(D)J RECOMBINATION, Microcephaly, 2716 Genetics (clinical), COMET ASSAY, Adolescent, Turkey, IMPACT, 10039 Institute of Medical Genetics, PROTEIN, 610 Medicine & health, Biology, medicine.disease_cause, Compound heterozygosity, Short stature, Genomic Instability, Exon, 1311 Genetics, MAMMALIAN-CELLS, Genetics, medicine, 1312 Molecular Biology, Humans, Point Mutation, Child, Molecular Biology, Genetics (clinical), Genetics & Heredity, Mutation, IMMUNODEFICIENCY, COMPLEX, IDENTIFICATION, Point mutation, Infant, General Medicine, DNA repair protein XRCC4, medicine.disease, Body Height, DNA-Binding Proteins, Phenotype, STRAND BREAK REPAIR, DNA-LIGASE-IV, 570 Life sciences, biology, Female, medicine.symptom
Abstract

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G > A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C > T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G > A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature.

Published
2015

45. SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.

Author

Wood KA, Tong RS, Motta M, Cordeddu V, Scimone ER, Bush SJ, Maxwell DW, Giannoulatou E, Caputo V, Traversa A, Mancini C, Ferrero GB, Benedicenti F, Grammatico P, Melis D, Steindl K, Brunetti-Pierri N, Trevisson E, Wilkie AO, Lin AE, Cormier-Daire V, Twigg SR, Tartaglia M, and Goriely A

Subjects
Humans, Male, Contracture genetics, Adult, Facies, Spermatozoa metabolism, Spermatozoa pathology, Cryptorchidism genetics, Growth Disorders genetics, Hand Deformities, Congenital genetics, Selection, Genetic, Alleles, Paternal Age, Testis pathology, Testis metabolism, Smad4 Protein genetics, Germ-Line Mutation, Intellectual Disability genetics
Abstract

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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46. Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.

Author

Boonsawat P, Asadollahi R, Niedrist D, Steindl K, Begemann A, Joset P, Bhoj EJ, Li D, Zackai E, Vetro A, Barba C, Guerrini R, Whalen S, Keren B, Khan A, Jing D, Palomares Bralo M, Rikeros Orozco E, Hao Q, Schlott Kristiansen B, Zheng B, Donnelly D, Clowes V, Zweier M, Papik M, Siegel G, Sabatino V, Mocera M, Horn AHC, Sticht H, and Rauch A

Subjects
Humans, Female, Male, Child, Child, Preschool, beta Catenin genetics, beta Catenin metabolism, Adolescent, Mutation, Missense, Genetic Association Studies, Protein Domains, Wnt Signaling Pathway genetics, Germ-Line Mutation, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Phenotype, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Brain metabolism, Brain pathology
Abstract

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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47. De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features.

Author

Harel T, Spicher C, Scheer E, Buchan JG, Cech J, Folland C, Frey T, Holtz AM, Innes AM, Keren B, Macken WL, Marcelis C, Otten CE, Paolucci SA, Petit F, Pfundt R, Pitceathly RDS, Rauch A, Ravenscroft G, Sanchev R, Steindl K, Tammer F, Tyndall A, Devys D, Vincent SD, Elpeleg O, and Tora L

Subjects
Humans, Female, Male, Child, Preschool, Child, Phenotype, Animals, Adolescent, Exome Sequencing, Face abnormalities, Infant, Transcription Factors, Muscle Hypotonia genetics, Developmental Disabilities genetics
Abstract

Deubiquitination is crucial for the proper functioning of numerous biological pathways, such as DNA repair, cell cycle progression, transcription, signal transduction and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders and congenital abnormalities. ATXN7L3 is a component of the DUB module of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex and two other related DUB modules, and it serves as an obligate adaptor protein of three ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and by using GeneMatcher, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia and distinctive facial characteristics, including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set, posteriorly rotated ears. To assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic neurodevelopmental disorder., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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48. Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy.

Author

Clara-Hwang A, Stefani S, Lau T, Scala M, Aynekin B, Bernardo P, Madia F, Bakhtadze S, Kaiyrzhanov R, Maroofian R, Zara F, Srinivasan VM, Gowda V, Guliyeva U, Montavont A, Poulat AL, Güleç A, Berger C, Ville DM, de Bellescize J, Cabet S, Wonneberger A, Schulz A, Rodriguez-Palmero A, Chatron N, Lesca G, Per H, Goel H, Brown J, Frey T, Steindl K, Rauch A, Severino M, Houlden H, Nicolaides P, Striano P, and Efthymiou S

Abstract

Objectives: To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy., Background: CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants., Results: We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2 . All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10)., Discussion: Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations., Competing Interests: P. Striano received support from Italian MoH (Ricerca Corrente 2023) and Fondazione San Paolo. Research supported by PNRR-MUR-M4C2 PE0000006 Research Program MNESYS—A multiscale integrated approach to the study of the nervous system in health and disease. IRCCS G. Gaslini is a member of ERN-Epicare. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2024
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49. Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect.

Author

Yang F, Begemann A, Reichhart N, Haeckel A, Steindl K, Schellenberger E, Sturm RF, Barth M, Bassani S, Boonsawat P, Courtin T, Delobel B, Gunning B, Hardies K, Jennesson M, Legoff L, Linnankivi T, Prouteau C, Smal N, Spodenkiewicz M, Toelle SP, Van Gassen K, Van Paesschen W, Verbeek N, Ziegler A, Zweier M, Horn AHC, Sticht H, Lerche H, Weckhuysen S, Strauß O, and Rauch A

Subjects
Humans, Male, Female, Epilepsy genetics, Child, Phospholipid Transfer Proteins genetics, Phospholipid Transfer Proteins metabolism, Genetic Association Studies, Pedigree, Calcium metabolism, Genes, Dominant, Child, Preschool, HEK293 Cells, Adolescent, Anoctamins genetics, Anoctamins metabolism, Mutation, Missense genetics
Abstract

Anoctamins are a family of Ca 2+ -activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca 2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca 2+ -independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca 2+ -dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease., Competing Interests: Declaration of interests K.H. is currently employed by Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse B-2340, Belgium., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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50. Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor.

Author

Meier-Abt F, Kraemer D, Braun N, Reinehr M, Stutz-Grunder E, Steindl K, and Rauch A

Subjects
Humans, Male, Frameshift Mutation genetics, Germ-Line Mutation genetics, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Child, F-Box-WD Repeat-Containing Protein 7 genetics, Genetic Predisposition to Disease, Wilms Tumor genetics, Wilms Tumor pathology
Abstract

Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Heterozygous loss-of-function germline variants in FBXW7 have recently been described as causative for a neurodevelopmental syndrome. Independently, FBXW7 was also considered as a susceptibility gene for Wilms tumor due to a few observations of heterozygous germline variants in patients with Wilms tumor. Whether the same FBXW7 variants are implicated in both, neurodevelopmental delay and Wilms tumor formation, remained unclear. By clinical testing, we now observed a patient with neurodevelopmental delay due to a de novo constitutional mosaic FBXW7 splice site pathogenic variant who developed Wilms tumor. In the tumor, we identified a second hit frameshift variant in FBXW7. Immunohistochemical staining was consistent with mosaic loss of FBXW7 protein expression in the tumor. Our data support the role of constitutional FBXW7 pathogenic variants in both, neurodevelopmental disorder and the etiology of Wilms tumor. Therefore, Wilms tumor screening should be considered in individuals with constitutional or germline pathogenic variants in FBXW7 and associated neurodevelopmental syndrome., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Published
2024
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