83 results on '"Bhoj E"'
Search Results
2. Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis
- Author
-
Bhoj, E. J., Li, M., Ahrens-Nicklas, R., Pyle, L. C., Wang, J., Zhang, V. W., Clarke, C., Wong, L. J., Sondheimer, N., Ficicioglu, C., Yudkoff, M., Zschocke, Johannes, Editor-in-chief, Baumgartner, Matthias, editor, Morava, Eva, editor, Patterson, Marc, editor, Rahman, Shamima, editor, and Peters, Verena, editor
- Published
- 2015
- Full Text
- View/download PDF
3. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype
- Author
-
Smol, T., Petit, F., Piton, A., Keren, B., Sanlaville, D., Afenjar, A., Baker, S., Bedoukian, E. C., Bhoj, E. J., Bonneau, D., Boudry-Labis, E., Bouquillon, S., Boute-Benejean, O., Caumes, R., Chatron, N., Colson, C., Coubes, C., Coutton, C., Devillard, F., Dieux-Coeslier, A., Doco-Fenzy, M., Ewans, L. J., Faivre, L., Fassi, E., Field, M., Fournier, C., Francannet, C., Genevieve, D., Giurgea, I., Goldenberg, A., Green, A. K., Guerrot, A. M., Heron, D., Isidor, B., Keena, B. A., Krock, B. L., Kuentz, P., Lapi, E., Le Meur, N., Lesca, G., Li, D., Marey, I., Mignot, C., Nava, C., Nesbitt, A., Nicolas, G., Roche-Lestienne, C., Roscioli, T., Satre, V., Santani, A., Stefanova, M., Steinwall Larsen, S., Saugier-Veber, P., Picker-Minh, S., Thuillier, C., Verloes, A., Vieville, G., Wenzel, M., Willems, M., Whalen, S., Zarate, Y. A., Ziegler, A., Manouvrier-Hanu, S., Kalscheuer, V. M., Gerard, B., and Ghoumid, Jamal
- Published
- 2018
- Full Text
- View/download PDF
4. A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.
- Author
-
Strong, A., Rao, S., Hardenberg, S. von, Li, D., Cox, L.L., Lee, P.C., Zhang, L.Q., Awotoye, W., Diamond, T., Gold, Jessica, Gooch, C., Gowans, L.J.J., Hakonarson, H., Hing, A., Loomes, K., Martin, N., Marazita, M.L., Mononen, T., Piccoli, D., Pfundt, R.P., Raskin, S., Scherer, S.W., Sobriera, N., Vaccaro, C., Wang, Xiang, Watson, D., Weksberg, R., Bhoj, E., Murray, J.C., Lidral, A.C., Butali, A., Buckley, M.F., Roscioli, T., Koolen, D.A., Seaver, L.H., Prows, C.A., Stottmann, R.W., Cox, T.C., Strong, A., Rao, S., Hardenberg, S. von, Li, D., Cox, L.L., Lee, P.C., Zhang, L.Q., Awotoye, W., Diamond, T., Gold, Jessica, Gooch, C., Gowans, L.J.J., Hakonarson, H., Hing, A., Loomes, K., Martin, N., Marazita, M.L., Mononen, T., Piccoli, D., Pfundt, R.P., Raskin, S., Scherer, S.W., Sobriera, N., Vaccaro, C., Wang, Xiang, Watson, D., Weksberg, R., Bhoj, E., Murray, J.C., Lidral, A.C., Butali, A., Buckley, M.F., Roscioli, T., Koolen, D.A., Seaver, L.H., Prows, C.A., Stottmann, R.W., and Cox, T.C.
- Abstract
Item does not contain fulltext, AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.
- Published
- 2023
5. Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.
- Author
-
Patterson, V., Ullah, F., Bryant, L., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, Xuyun, Mireguli, M., Luo, Y, Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R., Bhoj, E., Patterson, V., Ullah, F., Bryant, L., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, Xuyun, Mireguli, M., Luo, Y, Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R., and Bhoj, E.
- Abstract
Item does not contain fulltext, We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
- Published
- 2023
6. Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis
- Author
-
Bhoj, E. J., primary, Li, M., additional, Ahrens-Nicklas, R., additional, Pyle, L. C., additional, Wang, J., additional, Zhang, V. W., additional, Clarke, C., additional, Wong, L. J., additional, Sondheimer, N., additional, Ficicioglu, C., additional, and Yudkoff, M., additional
- Published
- 2014
- Full Text
- View/download PDF
7. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature
- Author
-
Rots, D., Chater-Diehl, E., Dingemans, A.J.M., Goodman, S.J., Siu, M.T., Cytrynbaum, C., Choufani, S., Hoang, N., Walker, S., Awamleh, Z., Charkow, J., Meyn, S., Pfundt, R.P., Rinne, T.K., Gardeitchik, T., Vries, B.B.A. de, Deden, A.C., Leenders, E.K.S.M., Kwint, M.P., Stumpel, C., Stevens, S.J.C., Vermeulen, J.R., Harssel, J.V.T. van, Bosch, D.G.M., Gassen, K.L.I. van, Binsbergen, E. van, Geus, C.M. de, Brackel, H., Hempel, M., Lessel, D., Denecke, J., Slavotinek, A., Strober, J., Crunk, A., Folk, L., Wentzensen, I.M., Yang, H., Zou, F., Millan, F., Person, R., Xie, Y., Liu, S., Ousager, L.B., Larsen, M., Schultz-Rogers, L., Morava, E., Klee, E.W., Berry, I.R., Campbell, J., Lindstrom, K., Pruniski, B., Neumeyer, A.M., Radley, J.A., Phornphutkul, C., Schmidt, B., Wilson, W.G., Õunap, K., Reinson, K., Pajusalu, S., Haeringen, A. van, Ruivenkamp, C., Cuperus, R., Santos-Simarro, F., Palomares-Bralo, M., Pacio-Míguez, M., Ritter, A., Bhoj, E., Tønne, E., Tveten, K., Cappuccio, G., Brunetti-Pierri, N., Rowe, L., Bunn, J., Saenz, M., Platzer, K., Mertens, M., Caluseriu, O., Nowaczyk, M.J., Cohn, R.D., Kannu, P., Alkhunaizi, E., Chitayat, D., Scherer, S.W., Brunner, H.G., Vissers, L.E., Kleefstra, T., Koolen, D.A., Weksberg, R., Rots, D., Chater-Diehl, E., Dingemans, A.J.M., Goodman, S.J., Siu, M.T., Cytrynbaum, C., Choufani, S., Hoang, N., Walker, S., Awamleh, Z., Charkow, J., Meyn, S., Pfundt, R.P., Rinne, T.K., Gardeitchik, T., Vries, B.B.A. de, Deden, A.C., Leenders, E.K.S.M., Kwint, M.P., Stumpel, C., Stevens, S.J.C., Vermeulen, J.R., Harssel, J.V.T. van, Bosch, D.G.M., Gassen, K.L.I. van, Binsbergen, E. van, Geus, C.M. de, Brackel, H., Hempel, M., Lessel, D., Denecke, J., Slavotinek, A., Strober, J., Crunk, A., Folk, L., Wentzensen, I.M., Yang, H., Zou, F., Millan, F., Person, R., Xie, Y., Liu, S., Ousager, L.B., Larsen, M., Schultz-Rogers, L., Morava, E., Klee, E.W., Berry, I.R., Campbell, J., Lindstrom, K., Pruniski, B., Neumeyer, A.M., Radley, J.A., Phornphutkul, C., Schmidt, B., Wilson, W.G., Õunap, K., Reinson, K., Pajusalu, S., Haeringen, A. van, Ruivenkamp, C., Cuperus, R., Santos-Simarro, F., Palomares-Bralo, M., Pacio-Míguez, M., Ritter, A., Bhoj, E., Tønne, E., Tveten, K., Cappuccio, G., Brunetti-Pierri, N., Rowe, L., Bunn, J., Saenz, M., Platzer, K., Mertens, M., Caluseriu, O., Nowaczyk, M.J., Cohn, R.D., Kannu, P., Alkhunaizi, E., Chitayat, D., Scherer, S.W., Brunner, H.G., Vissers, L.E., Kleefstra, T., Koolen, D.A., and Weksberg, R.
- Abstract
Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access), Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
- Published
- 2021
8. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome
- Author
-
Sheppard, SE, Campbell, IM, Harr, MH, Gold, N, Li, D, Bjornsson, HT, Cohen, JS, Fahrner, JA, Fatemi, A, Harris, JR, Nowak, C, Stevens, CA, Grand, K, Au, M, Graham, JM, Sanchez-Lara, PA, Del Campo, M, Jones, MC, Abdul-Rahman, O, Alkuraya, FS, Bassetti, JA, Bergstrom, K, Bhoj, E, Dugan, S, Kaplan, JD, Derar, N, Gripp, KW, Hauser, N, Innes, AM, Keena, B, Kodra, N, Miller, R, Nelson, B, Nowaczyk, MJ, Rahbeeni, Z, Ben-Shachar, S, Shieh, JT, Slavotinek, A, Sobering, AK, Abbott, M-A, Allain, DC, Amlie-Wolf, L, Au, PYB, Bedoukian, E, Beek, G, Barry, J, Berg, J, Bernstein, JA, Cytrynbaum, C, Chung, BH-Y, Donoghue, S, Dorrani, N, Eaton, A, Flores-Daboub, JA, Dubbs, H, Felix, CA, Fong, C-T, Fung, JLF, Gangaram, B, Goldstein, A, Greenberg, R, Ha, TK, Hersh, J, Izumi, K, Kallish, S, Kravets, E, Kwok, P-Y, Jobling, RK, Johnson, AEK, Kushner, J, Lee, BH, Levin, B, Lindstrom, K, Manickam, K, Mardach, R, McCormick, E, McLeod, DR, Mentch, FD, Minks, K, Muraresku, C, Nelson, SF, Porazzi, P, Pichurin, PN, Powell-Hamilton, NN, Powis, Z, Ritter, A, Rogers, C, Rohena, L, Ronspies, C, Schroeder, A, Stark, Z, Starr, L, Stoler, J, Suwannarat, P, Velinov, M, Weksberg, R, Wilnai, Y, Zadeh, N, Zand, DJ, Falk, MJ, Hakonarson, H, Zackai, EH, Quintero-Rivera, F, Sheppard, SE, Campbell, IM, Harr, MH, Gold, N, Li, D, Bjornsson, HT, Cohen, JS, Fahrner, JA, Fatemi, A, Harris, JR, Nowak, C, Stevens, CA, Grand, K, Au, M, Graham, JM, Sanchez-Lara, PA, Del Campo, M, Jones, MC, Abdul-Rahman, O, Alkuraya, FS, Bassetti, JA, Bergstrom, K, Bhoj, E, Dugan, S, Kaplan, JD, Derar, N, Gripp, KW, Hauser, N, Innes, AM, Keena, B, Kodra, N, Miller, R, Nelson, B, Nowaczyk, MJ, Rahbeeni, Z, Ben-Shachar, S, Shieh, JT, Slavotinek, A, Sobering, AK, Abbott, M-A, Allain, DC, Amlie-Wolf, L, Au, PYB, Bedoukian, E, Beek, G, Barry, J, Berg, J, Bernstein, JA, Cytrynbaum, C, Chung, BH-Y, Donoghue, S, Dorrani, N, Eaton, A, Flores-Daboub, JA, Dubbs, H, Felix, CA, Fong, C-T, Fung, JLF, Gangaram, B, Goldstein, A, Greenberg, R, Ha, TK, Hersh, J, Izumi, K, Kallish, S, Kravets, E, Kwok, P-Y, Jobling, RK, Johnson, AEK, Kushner, J, Lee, BH, Levin, B, Lindstrom, K, Manickam, K, Mardach, R, McCormick, E, McLeod, DR, Mentch, FD, Minks, K, Muraresku, C, Nelson, SF, Porazzi, P, Pichurin, PN, Powell-Hamilton, NN, Powis, Z, Ritter, A, Rogers, C, Rohena, L, Ronspies, C, Schroeder, A, Stark, Z, Starr, L, Stoler, J, Suwannarat, P, Velinov, M, Weksberg, R, Wilnai, Y, Zadeh, N, Zand, DJ, Falk, MJ, Hakonarson, H, Zackai, EH, and Quintero-Rivera, F
- Abstract
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
- Published
- 2021
9. 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
10. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay
- Author
-
Vissers, L.E.L.M., Kalvakuri, S., Boer, E. de, Geuer, S., Oud, M.M., Outersterp, I. van, Kwint, M.P., Witmond, M., Kersten, S., Polla, D.L., Weijers, D., Begtrup, A., McWalter, K., Ruiz, A., Gabau, E., Morton, J.E., Griffith, C., Weiss, K., Gamble, C., Bartley, J., Vernon, H.J., Brunet, K., Ruivenkamp, C., Kant, S.G., Kruszka, P., Larson, A., Afenjar, A., Billette de Villemeur, T., Nugent, K., Raymond, F.L., Venselaar, H., Demurger, F., Soler-Alfonso, C., Li, D., Bhoj, E., Hayes, I., Hamilton, N.P., Ahmad, A., Fisher, R., Born, M. van den, Willems, M., Sorlin, A., Delanne, J., Moutton, S., Christophe, P., Mau-Them, F.T., Vitobello, A., Goel, H., Massingham, L., Phornphutkul, C., Schwab, J., Keren, B., Charles, P., Vreeburg, M., Simone, L. De, Hoganson, G., Iascone, M., Milani, D., Evenepoel, L., Revencu, N., Ward, D.I., Burns, K., Krantz, I., Raible, S.E., Murrell, J.R., Wood, K., Cho, M.T., Bokhoven, H. van, Muenke, M., Kleefstra, T., Bodmer, R., Brouwer, A.P.M. de, Vissers, L.E.L.M., Kalvakuri, S., Boer, E. de, Geuer, S., Oud, M.M., Outersterp, I. van, Kwint, M.P., Witmond, M., Kersten, S., Polla, D.L., Weijers, D., Begtrup, A., McWalter, K., Ruiz, A., Gabau, E., Morton, J.E., Griffith, C., Weiss, K., Gamble, C., Bartley, J., Vernon, H.J., Brunet, K., Ruivenkamp, C., Kant, S.G., Kruszka, P., Larson, A., Afenjar, A., Billette de Villemeur, T., Nugent, K., Raymond, F.L., Venselaar, H., Demurger, F., Soler-Alfonso, C., Li, D., Bhoj, E., Hayes, I., Hamilton, N.P., Ahmad, A., Fisher, R., Born, M. van den, Willems, M., Sorlin, A., Delanne, J., Moutton, S., Christophe, P., Mau-Them, F.T., Vitobello, A., Goel, H., Massingham, L., Phornphutkul, C., Schwab, J., Keren, B., Charles, P., Vreeburg, M., Simone, L. De, Hoganson, G., Iascone, M., Milani, D., Evenepoel, L., Revencu, N., Ward, D.I., Burns, K., Krantz, I., Raible, S.E., Murrell, J.R., Wood, K., Cho, M.T., Bokhoven, H. van, Muenke, M., Kleefstra, T., Bodmer, R., and Brouwer, A.P.M. de
- Abstract
Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access), CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
- Published
- 2020
11. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome
- Author
-
Drivas, T. G., Li, D., Nair, D., Alaimo, J. T., Alders, M., Altmuller, J., Barakat, T. S., Bebin, E. M., Bertsch, N. L., Blackburn, P. R., Blesson, A., Bouman, A. M., Brockmann, K., Brunelle, P., Burmeister, M., Cooper, G. M., Denecke, J., Dieux-Coeslier, A., Dubbs, H., Ferrer, A., Gal, D., Bartik, L. E., Gunderson, L. B., Hasadsri, L., Jain, M., Karimov, C., Keena, B., Klee, E. W., Kloth, K., Lace, B., Macchiaiolo, M., Marcadier, J. L., Milunsky, J. M., Napier, M. P., Ortiz-Gonzalez, X. R., Pichurin, P. N., Pinner, J., Powis, Z., Prasad, C., Radio, F. C., Rasmussen, K. J., Renaud, D. L., Rush, E. T., Saunders, C., Selcen, D., Seman, A. R., Shinde, D. N., Smith, E. D., Smol, T., Snijders Blok, L., Stoler, J. M., Tang, S., Tartaglia, M., Thompson, M. L., van de Kamp, J. M., Wang, J., Weise, D., Weiss, K., Woitschach, R., Wollnik, B., Yan, H., Zackai, E. H., Zampino, Giuseppe, Campeau, P., Bhoj, E., Zampino G. (ORCID:0000-0003-3865-3253), Drivas, T. G., Li, D., Nair, D., Alaimo, J. T., Alders, M., Altmuller, J., Barakat, T. S., Bebin, E. M., Bertsch, N. L., Blackburn, P. R., Blesson, A., Bouman, A. M., Brockmann, K., Brunelle, P., Burmeister, M., Cooper, G. M., Denecke, J., Dieux-Coeslier, A., Dubbs, H., Ferrer, A., Gal, D., Bartik, L. E., Gunderson, L. B., Hasadsri, L., Jain, M., Karimov, C., Keena, B., Klee, E. W., Kloth, K., Lace, B., Macchiaiolo, M., Marcadier, J. L., Milunsky, J. M., Napier, M. P., Ortiz-Gonzalez, X. R., Pichurin, P. N., Pinner, J., Powis, Z., Prasad, C., Radio, F. C., Rasmussen, K. J., Renaud, D. L., Rush, E. T., Saunders, C., Selcen, D., Seman, A. R., Shinde, D. N., Smith, E. D., Smol, T., Snijders Blok, L., Stoler, J. M., Tang, S., Tartaglia, M., Thompson, M. L., van de Kamp, J. M., Wang, J., Weise, D., Weiss, K., Woitschach, R., Wollnik, B., Yan, H., Zackai, E. H., Zampino, Giuseppe, Campeau, P., Bhoj, E., and Zampino G. (ORCID:0000-0003-3865-3253)
- Abstract
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
- Published
- 2020
12. Phenotypic spectrum associated with SPECC1L pathogenic variants:new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes
- Author
-
Verloes, A., Haye, D., Toutain, A., Bonneau, D., Nielsen, I. Kibaek, Lund, I. Bay, Bogaard, P., Leenskjold, S., Karaer, K., Wild, K. T., Grand, K. L., Astiazaran, M. C., Gonzalez-Nieto, L. A., Carvalho, A., Lehalle, D., Amudhavalli, S. M., Repnikova, E., Saunders, C., Thiffault, I., Saadi, I., Li, D., Hakonarson, H., Vial, Y., Zackai, E., Callier, P., Drunat, S., and Bhoj, E. E.
- Published
- 2019
13. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
- Author
-
Fregeau, B., Kim, B.J., Hernandez-Garcia, A., Jordan, V.K., Cho, M.T., Schnur, R.E., Monaghan, K.G., Juusola, J., Rosenfeld, J.A., Bhoj, E., Zackai, E.H., Sacharow, S., Baranano, K., Bosch, D.G.M., Vries, B.B.A. de, Lindstrom, K., Schroeder, A., James, P., Kulch, P., Lalani, S.R., Haelst, M.M. van, Gassen, K.L. van, Binsbergen, E. van, Barkovich, A.J., Scott, D.A., Sherr, E.H., Fregeau, B., Kim, B.J., Hernandez-Garcia, A., Jordan, V.K., Cho, M.T., Schnur, R.E., Monaghan, K.G., Juusola, J., Rosenfeld, J.A., Bhoj, E., Zackai, E.H., Sacharow, S., Baranano, K., Bosch, D.G.M., Vries, B.B.A. de, Lindstrom, K., Schroeder, A., James, P., Kulch, P., Lalani, S.R., Haelst, M.M. van, Gassen, K.L. van, Binsbergen, E. van, Barkovich, A.J., Scott, D.A., and Sherr, E.H.
- Abstract
Item does not contain fulltext, Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.
- Published
- 2016
14. CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases
- Author
-
Wenger, Tl, Harr, M, Ricciardi, Stefania, Bhoj, E, Santani, A, Adam, Mp, Barnett, S, Ganetzky, R, Mcdonald Mcginn, Dm, Battaglia, Domenica Immacolata, Bigoni, S, Selicorni, A, Sorge, G, Monica, Md, Mari, F, Andreucci, E, Romano, S, Cocchi, G, Savasta, S, Malbora, B, Marangi, Giuseppe, Garavelli, L, Zollino, Marcella, Zackai, Eh, Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zollino, Marcella (ORCID:0000-0003-4871-9519), Wenger, Tl, Harr, M, Ricciardi, Stefania, Bhoj, E, Santani, A, Adam, Mp, Barnett, S, Ganetzky, R, Mcdonald Mcginn, Dm, Battaglia, Domenica Immacolata, Bigoni, S, Selicorni, A, Sorge, G, Monica, Md, Mari, F, Andreucci, E, Romano, S, Cocchi, G, Savasta, S, Malbora, B, Marangi, Giuseppe, Garavelli, L, Zollino, Marcella, Zackai, Eh, Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), and Zollino, Marcella (ORCID:0000-0003-4871-9519)
- Abstract
Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.
- Published
- 2014
15. MODY-like diabetes associated with an apparently balanced translocation: possible involvement of MPP7 gene and cell polarity in the pathogenesis of diabetes
- Author
-
Bartov Guy, Baroni Marco G, Romeo Stefano, Bhoj Elizabeth J, Schultz Roger A, and Zinn Andrew R
- Subjects
Genetics ,QH426-470 - Abstract
Abstract Background Characterization of disease-associated balanced translocations has led to the discovery of genes responsible for many disorders, including syndromes that include various forms of diabetes mellitus. We studied a man with unexplained maturity onset diabetes of the young (MODY)-like diabetes and an apparently balanced translocation [46,XY,t(7;10)(q22;p12)] and sought to identify a novel diabetes locus by characterizing the translocation breakpoints. Results Mutations in coding exons and splice sites of known MODY genes were first ruled out by PCR amplification and DNA sequencing. Fluorescent in situ hybridization (FISH) studies demonstrated that the translocation did not disrupt two known diabetes-related genes on 10p12. The translocation breakpoints were further mapped to high resolution using FISH and somatic cell hybrids and the junctions PCR-amplified and sequenced. The translocation did not disrupt any annotated transcription unit. However, the chromosome 10 breakpoint was 220 kilobases 5' to the Membrane Protein, Palmitoylated 7 (MPP7) gene, which encodes a protein required for proper cell polarity. This biological function is shared by HNF4A, a known MODY gene. Databases show MPP7 is highly expressed in mouse pancreas and is expressed in human islets. The translocation did not appear to alter lymphoblastoid expression of MPP7 or other genes near the breakpoints. Conclusion The balanced translocation and MODY-like diabetes in the proband could be coincidental. Alternatively, the translocation may cause islet cell dysfunction by altering MPP7 expression in a subtle or tissue-specific fashion. The potential roles of MPP7 mutations in diabetes and perturbed islet cell polarity in insulin secretion warrant further study.
- Published
- 2009
- Full Text
- View/download PDF
16. Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.
- Author
-
Strong A, March ME, Cardinale CJ, Liu Y, Battig MR, Finoti LS, Matsuoka LS, Watson D, Sridhar S, Jarrett JF, Cannon I, Li D, Bhoj E, Zackai EH, Rand EB, Wenger T, Lerman BB, Shikany A, Weaver KN, and Hakonarson H
- Subjects
- Humans, Female, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, YAP-Signaling Proteins genetics, Mediator Complex genetics, Child, Preschool, Child, Infant, Signal Transduction genetics, Aortic Coarctation genetics, Aortic Coarctation pathology, Mutation genetics, Male, Adolescent, Adaptor Proteins, Signal Transducing genetics, Adult, Cilia pathology, Cilia genetics, Phenotype, Abnormalities, Multiple genetics, Abnormalities, Multiple pathology
- Abstract
Purpose: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown. We aim to expand the phenotypic and molecular landscape of HS and elucidate the mechanism by which MED12 variants cause disease., Methods: We clinically assembled and molecularly characterized a cohort of 11 previously unreported individuals with HS. Additionally, we studied the effect of MED12 deficiency on ciliary biology, hedgehog, and yes-associated protein (YAP) signaling; pathways implicated in diseases with phenotypic overlap with HS., Results: We report novel phenotypes associated with HS, including cardiomyopathy, arrhythmia, and vascular anomalies, and expand the molecular landscape of HS to include splice site variants. We additionally demonstrate that MED12 deficiency causes decreased cell ciliation, and impairs hedgehog and YAP signaling., Conclusion: Our data support updating HS standard-of-care to include regular cardiac imaging, arrhythmia screening, and vascular imaging. We further propose that dysregulation of ciliogenesis and YAP and hedgehog signaling contributes to the pathogenesis of HS., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
17. Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants.
- Author
-
Saeidian AH, March ME, Youssefian L, Watson DJ, Bhandari E, Wang X, Zhao X, Owen NM, Strong A, Harr MH, Bhoj E, Zackai E, Vahidnezhad H, Gudjonsson JE, Cederbaum SD, Deignan JL, Glessner J, Grody WW, and Hakonarson H
- Abstract
Purpose: Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of a large pediatric cohort at the Center for Applied Genomics at The Children's Hospital of Philadelphia., Methods: We systematically identified pathogenic (P) and likely pathogenic (LP) variants in established disease-causing genes, adhering to ACMG v3.2 secondary finding guidelines and beyond. For non-ACMG SFs, akin to incidental findings in clinical settings, we utilized a set of criteria focusing on pediatric onset, high penetrance, moderate to severe phenotypes, and the clinical actionability of the variants. This criteria-based approach was applied rather than using a fixed gene list to ensure that the variants identified are likely to affect participant health significantly. To identify and categorize these variants, we used a clinical-grade variant classification standard per ACMG/AMP recommendations; additionally, we conducted a detailed literature search to ensure a comprehensive exploration of potential SFs relevant to pediatric participants., Results: We report a distinctive distribution of 1464 P/LP SF variants in 16,713 participants. There were 427 unique variants in ACMG genes and 265 in non-ACMG genes. The most frequently mutated genes among the ACMG and non-ACMG gene lists were TTR(41.6%) and CHEK2 (7.16%), respectively. Overall, variants of possible medical importance were found in 8.76% of participants in both ACMG (5.81%) and non-ACMG (2.95%) genes., Conclusion: Our study revealed that 8.76% of a large, multiethnic pediatric cohort carried actionable secondary genetic findings, with 5.81% in ACMG genes and 2.95% in non-ACMG genes. These findings emphasize the importance of including diverse populations in genetic research to ensure that all groups benefit from early identification of disease risks. Our results provide a foundation for expanding the ACMG gene list and improving clinical care through early interventions., Competing Interests: Conflict of Interest Hakon Hakonarson and Children’s Hospital of Philadelphia are equity holders in Nobias Therapeutics, developing mitogen-activated protein kinase inhibitor therapy for complex lymphatic anomalies. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
18. Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species.
- Author
-
Bryant L, Sangree A, Clark K, and Bhoj E
- Subjects
- Humans, Animals, Neurodevelopmental Disorders genetics, Mutation, Missense, Histones genetics, Histones metabolism, Chromatin genetics
- Abstract
There has been considerable recent interest in the role that germline variants in histone genes play in Mendelian syndromes. Specifically, missense variants in H3-3A and H3-3B, which both encode Histone 3.3, were discovered to cause a novel neurodevelopmental disorder, Bryant-Li-Bhoj syndrome. Most of the causative variants are private and scattered throughout the protein, but all seem to have either a gain-of-function or dominant negative effect on protein function. This is highly unusual and not well understood. However, there is extensive literature about the effects of Histone 3.3 mutations in model organisms. Here, we collate the previous data to provide insight into the elusive pathogenesis of missense variants in Histone 3.3., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
19. The spectrum of heart defects in the TRAF7 -related multiple congenital anomalies-intellectual disability syndrome.
- Author
-
Pisan E, De Luca C, Brancati F, Sanchez Russo R, Li D, Bhoj E, Wenger T, Marwaha A, Johnson N, Beneteau C, Brischoux-Boucher E, Houge G, Paulsen J, Hammer TB, Ek J, Schweitzer D, Russell BE, Dutra-Clarke M, Nelson S, Douine ED, Corona RI, Dudding T, Thomson H, Low K, Belnap N, Iascone M, Priolo M, Carli D, Mussa A, Bijlsma EK, Kopp N, Jais JP, Amiel J, and Gordon CT
- Subjects
- Humans, Phenotype, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Intellectual Disability genetics, Abnormalities, Multiple genetics, Heart Defects, Congenital
- Abstract
Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
- View/download PDF
20. Role of CAMK2D in neurodevelopment and associated conditions.
- Author
-
Rigter PMF, de Konink C, Dunn MJ, Proietti Onori M, Humberson JB, Thomas M, Barnes C, Prada CE, Weaver KN, Ryan TD, Caluseriu O, Conway J, Calamaro E, Fong CT, Wuyts W, Meuwissen M, Hordijk E, Jonkers CN, Anderson L, Yuseinova B, Polonia S, Beysen D, Stark Z, Savva E, Poulton C, McKenzie F, Bhoj E, Bupp CP, Bézieau S, Mercier S, Blevins A, Wentzensen IM, Xia F, Rosenfeld JA, Hsieh TC, Krawitz PM, Elbracht M, Veenma DCM, Schulman H, Stratton MM, Küry S, and van Woerden GM
- Subjects
- Animals, Humans, Mice, Heart, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Cardiomyopathy, Dilated, Intellectual Disability, Neurodevelopmental Disorders genetics
- Abstract
The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. A.B. and I.M.W. are employees of GeneDx, LLC; H.S. is a consultant for Vasa Therapeutics (Poland)., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
21. Listening to patients with suspected genetic diagnoses: A narrative perspective.
- Author
-
Slocum RB, Hurst ACE, Shelley E, Berry L, Hopkin RJ, Rippert AL, Bhoj E, Graham JM Jr, Grand K, Gonzalez A, and Zarate YA
- Published
- 2023
- Full Text
- View/download PDF
22. Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice.
- Author
-
Nair D, Diaz-Rosado A, Varella-Branco E, Ramos I, Black A, Angireddy R, Park J, Murali S, Yoon A, Ciesielski B, O'Brien WT, Passos-Bueno MR, and Bhoj E
- Subjects
- Humans, Child, Animals, Mice, Heterozygote, Syndrome, Phenotype, Protein Serine-Threonine Kinases genetics, Brain Diseases genetics
- Abstract
TBCK-related encephalopathy is a rare pediatric neurodegenerative disorder caused by biallelic loss-of-function variants in the TBCK gene. After receiving anecdotal reports of neurologic phenotypes in both human and mouse TBCK heterozygotes, we quantified if TBCK haploinsufficiency causes a phenotype in mice and humans. Using the tbck
+/- mouse model, we performed a battery of behavioral assays and mTOR pathway analysis to investigate potential alterations in neurophysiology. We conducted as well a phenome-wide association study (PheWAS) analysis in a large adult biobank to determine the presence of potential phenotypes associated to this variant. The tbck+/- mouse model demonstrates a reduction of exploratory behavior in animals with significant sex and genotype interactions. The concurrent PheWAS analysis of 10,900 unrelated individuals showed that patients with one copy of a TBCK loss-of-function allele had a significantly higher rate of acquired toe and foot deformities, likely indicative of a mild peripheral neuropathy phenotype. This study presents an example of what may be the underappreciated occurrence of mild neurogenic symptoms in heterozygote individuals of recessive neurogenetic syndromes., (© 2023 Wiley Periodicals LLC.)- Published
- 2023
- Full Text
- View/download PDF
23. Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.
- Author
-
Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, White SM, Lachlan K, Ahimaz P, Sewda A, Bastarache L, Thomas-Wilson A, Stoler JM, Bramswig NC, Baptista J, Stals K, Demurger F, Cogne B, Isidor B, Bedeschi MF, Peron A, Amiel J, Zackai E, Schacht JP, Iglesias AD, Morton J, Schmetz A, Seidel V, Lucia S, Baskin SM, Thiffault I, Cogan JD, Gordon CT, Chung WK, Bowdin S, and Bhoj E
- Subjects
- Animals, Humans, COUP Transcription Factor II genetics, Muscle Hypotonia, Syndrome, Abnormalities, Multiple genetics, Abnormalities, Multiple diagnosis, Heart Defects, Congenital genetics, Hernias, Diaphragmatic, Congenital genetics, Intellectual Disability genetics
- Abstract
Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2023
- Full Text
- View/download PDF
24. A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.
- Author
-
Strong A, Rao S, von Hardenberg S, Li D, Cox LL, Lee PC, Zhang LQ, Awotoye W, Diamond T, Gold J, Gooch C, Gowans LJJ, Hakonarson H, Hing A, Loomes K, Martin N, Marazita ML, Mononen T, Piccoli D, Pfundt R, Raskin S, Scherer SW, Sobriera N, Vaccaro C, Wang X, Watson D, Weksberg R, Bhoj E, Murray JC, Lidral AC, Butali A, Buckley MF, Roscioli T, Koolen DA, Seaver LH, Prows CA, Stottmann RW, and Cox TC
- Subjects
- Humans, Mutation, Mutation, Missense genetics, Angiomotins, Cleft Palate diagnosis, Cleft Palate genetics, Cleft Lip diagnosis, Cleft Lip genetics, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics
- Abstract
AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region., (© 2023 Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
- View/download PDF
25. Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.
- Author
-
Patterson V, Ullah F, Bryant L, Griffin JN, Sidhu A, Saliganan S, Blaile M, Saenz MS, Smith R, Ellingwood S, Grange DK, Hu X, Mireguli M, Luo Y, Shen Y, Mulhern M, Zackai E, Ritter A, Izumi K, Hoefele J, Wagner M, Riedhammer KM, Seitz B, Robin NH, Goodloe D, Mignot C, Keren B, Cox H, Jarvis J, Hempel M, Gibson CF, Tran Mau-Them F, Vitobello A, Bruel AL, Sorlin A, Mehta S, Raymond FL, Gilmore K, Powell BC, Weck K, Li C, Vulto-van Silfhout AT, Giacomini T, Mancardi MM, Accogli A, Salpietro V, Zara F, Vora NL, Davis EE, Burdine R, and Bhoj E
- Subjects
- Animals, Humans, Protein Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Zebrafish, Signal Transduction
- Abstract
We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 ( MAP4K4 ). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
- Published
- 2023
- Full Text
- View/download PDF
26. The Virtual Summer Research Program: supporting future physician-scientists from underrepresented backgrounds.
- Author
-
Macedo B, Christophers B, Barrere-Cain R, Albrecht YS, Granovetter MC, Kumar R, Daye D, Bhoj E, Brass L, and Rodrigues JA
- Abstract
Introduction: Physician-scientist training programs expect applicants to have had extensive research experience prior to applying. Even at the best of times, this leaves individuals from underserved and underrepresented backgrounds at a competitive disadvantage, especially those remote from major academic centers. The COVID-19 pandemic exacerbated that disadvantage by closing research laboratories and suspending summer research opportunities., Methods: The Virtual Summer Research Program (VSRP) was designed to combat this shortfall by helping participating students become better informed and better prepared for applying to MD/DO-PhD programs. 156 participants were recruited from historically black colleges and universities and from national organizations for underrepresented trainees. Participants were paired with medical school faculty members and current MD/DO-PhD students from 35 participating institutions. The program lasted for at least 4 weeks and included a short research project, interactive sessions, journal clubs, social events, and attendance at a regional American Physician Scientists Association conference., Results: In follow-up surveys, participants reported improvements in their science-related skills and in their confidence in becoming a physician-scientist, applying to training programs, and navigating mentorship relationships. A follow-up study completed one year later indicated that participants felt they had benefited from an enhanced skill set, long-term relationships with their mentors, and connections to the physician-scientist community at large., Discussion: The results suggest that VSRP met its primary goals, which were to provide a diverse group of trainees with mentors, provide skills and resources for MD/DO-PhD application and matriculation and to support the development of longitudinal relationships between VSRP mentees and APSA. VSRP provides an approach that can be applied at an even larger scale when the constraints caused by a global pandemic have lifted., (© The Author(s) 2022.)
- Published
- 2022
- Full Text
- View/download PDF
27. Analysis of histone variant constraint and tissue expression suggests five potential novel human disease genes: H2AFY2, H2AFZ, H2AFY, H2AFV, H1F0.
- Author
-
Lubin E, Bryant L, Aicher J, Li D, and Bhoj E
- Subjects
- Humans, Mutation, Phenotype, Syndrome, Craniofacial Abnormalities genetics, Histones genetics
- Abstract
While germline variants in histone protein-encoding genes are emerging as the pathogenic mutations underlying rare, Mendelian disorders characterized by a conserved phenotype of neurodevelopmental syndrome coupled with craniofacial abnormalities, a systematic assessment of all human genes encoding histone proteins has not been performed to predict novel disease-candidate genes. We first defined a comprehensive list of 89 histone-encoding genes. We then analyzed which are most likely to underlay this conserved phenotype when mutated based on their intolerance to either missense or loss-of-function variation and based on their tissue expression profile. Strikingly few genes were found to be both ubiquitously expressed and significantly constrained against missense (7.9%, n = 7) or loss-of-function (6.7%, n = 6) variation. Notably, most of those significantly constrained genes encode replication-independent, variant histone proteins (7/7 in the missense analysis, 5/6 in the loss-of-function analysis). Of the seven genes predicted to be disease-causing when germline missense variation is present, three (H2AFV, H2AFY, H2AFY2) are novel disease-candidate genes. Five of the six genes predicted to be disease-causing with an underlying germline loss-of-function variant are novel disease-candidate genes (H2AFY2, H2AFZ, H2AFY, H2AFV, H1F0). These findings may serve as a focused reference for future sequencing of patients with the conserved phenotype., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
28. Brain Abnormalities in Patients with Germline Variants in H3F3 : Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors.
- Author
-
Alves CAPF, Sherbini O, D'Arco F, Steel D, Kurian MA, Radio FC, Ferrero GB, Carli D, Tartaglia M, Balci TB, Powell-Hamilton NN, Schrier Vergano SA, Reutter H, Hoefele J, Günthner R, Roeder ER, Littlejohn RO, Lessel D, Lüttgen S, Kentros C, Anyane-Yeboa K, Catarino CB, Mercimek-Andrews S, Denecke J, Lyons MJ, Klopstock T, Bhoj EJ, Bryant L, and Vanderver A
- Subjects
- Brain diagnostic imaging, Brain pathology, Child, Germ Cells pathology, Humans, Male, Retrospective Studies, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms pathology, Histones genetics, Malformations of Cortical Development pathology, Neurodevelopmental Disorders pathology
- Abstract
Background and Purpose: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B ( H3F3 ) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants., Materials and Methods: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range., Results: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation., Conclusions: Imaging phenotypes in germline H3F3- affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles., (© 2022 by American Journal of Neuroradiology.)
- Published
- 2022
- Full Text
- View/download PDF
29. Expanding the phenotypic spectrum of ARCN1-related syndrome.
- Author
-
Ritter AL, Gold J, Hayashi H, Ackermann AM, Hanke S, Skraban C, Cuddapah S, Bhoj E, Li D, Kuroda Y, Wen J, Takeda R, Bibb A, El Chehadeh S, Piton A, Ohl J, Kukolich MK, Nagasaki K, Kato K, Ogi T, Bhatti T, Russo P, Krock B, Murrell JR, Sullivan JA, Shashi V, Stong N, Hakonarson H, Sawano K, Torti E, Willaert R, Si Y, Wilcox WR, Wirgenes KV, Thomassen K, Carlotti K, Erwin A, Lazier J, Marquardt T, He M, Edmondson AC, and Izumi K
- Subjects
- Child, Female, Fetal Growth Retardation genetics, Humans, Male, Phenotype, Syndrome, Cataract, Dwarfism, Hepatoblastoma, Intellectual Disability genetics, Liver Neoplasms, Micrognathism
- Abstract
Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome., Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient., Results: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported., Conclusion: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required., Competing Interests: Conflict of Interest The following authors declare no conflicts of interest: A.L.R., J.G., Hi.H., A.M.A., S.H., C.S., S.C., E.B., D.L., Y.K., A.B., S.E.C., A.P., J.O., M.K.K., K.N., K.K., T.O., T.B., P.R., B.K., J.R.M., J.A.S., V.S., N.S., Ha.H., K.S., R.T., W.R.W., K.V.W., K.T., K.C., A.E., J.L., T.M., M.H., A.C.E., and K.I. J.W. receives research support from Gilead Sciences, Inc; AbbVie; and Alexion and has consulting relationship with Gilead Sciences, Inc. E.T., R.W., and Y.S. are employees of GeneDx, Inc., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
30. Inborn error of metabolism patients after liver transplantation: Outcomes of 35 patients over 27 years in one pediatric quaternary hospital.
- Author
-
Pritchard AB, Izumi K, Payan-Walters I, Yudkoff M, Rand EB, and Bhoj E
- Subjects
- Child, Hospitals, Humans, Retrospective Studies, Amino Acid Metabolism, Inborn Errors therapy, Liver Transplantation adverse effects, Maple Syrup Urine Disease therapy, Propionic Acidemia surgery
- Abstract
Liver transplantation (LT) has been used for many years as a therapeutic option for certain inborn errors of metabolism (IEMs). Here we present one institution's 27 years of experience with LT in IEMs. Our objective is to assess the outcomes of IEM patients who have undergone LT, which we hypothesize to be generally successful for prevention of metabolic decompensation. A retrospective chart review was performed on patients with urea cycle defects, organic acidemias, and amino acidopathies who underwent LT at the Children's Hospital of Philadelphia. Thirty-five patients with the following conditions have undergone LT: tyrosinemia (8), methylmalonic acidemia (7), maple syrup urine disease (6), citrullinemia (6), ornithine transcarbamylase deficiency (4), propionic acidemia (2), and argininosuccinate lyase deficiency (2). Average age at transplantation was 3.6 years. Three patients are now deceased. One patient suffered a metabolic stroke posttransplant. No episodes of metabolic decompensation have been noted. Thirty-five patients received LT with generally favorable outcome. None sustained metabolic decompensation posttransplant. As has been reported previously, LT does not ameliorate pre-existing developmental differences or risk to other organ systems. Further research is needed to aid in standardization of care and follow-up, as most patients no longer follow with a geneticist., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
- Full Text
- View/download PDF
31. Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
- Author
-
Fasham J, Lin S, Ghosh P, Radio FC, Farrow EG, Thiffault I, Kussman J, Zhou D, Hemming R, Zahka K, Chioza BA, Rawlins LE, Wenger OK, Gunning AC, Pizzi S, Onesimo R, Zampino G, Barker E, Osawa N, Rodriguez MC, Neuhann TM, Zackai EH, Keena B, Capasso J, Levin AV, Bhoj E, Li D, Hakonarson H, Wentzensen IM, Jackson A, Chandler KE, Coban-Akdemir ZH, Posey JE, Banka S, Lupski JR, Sheppard SE, Tartaglia M, Triggs-Raine B, Crosby AH, and Baple EL
- Subjects
- Alleles, Animals, Cell Adhesion Molecules genetics, GPI-Linked Proteins genetics, Genetic Association Studies, Humans, Hyaluronoglucosaminidase genetics, Mice, Phenotype, Cleft Lip genetics, Cleft Palate genetics
- Abstract
Purpose: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism., Methods: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants., Results: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein., Conclusion: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition., Competing Interests: Conflict of Interest I.M.W is an employee of GeneDx, Inc. All other authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
32. Molecular Diagnostic Outcomes from 700 Cases: What Can We Learn from a Retrospective Analysis of Clinical Exome Sequencing?
- Author
-
Murrell JR, Nesbitt AMI, Baker SW, Pechter KB, Balciuniene J, Zhao X, Denenberg EH, DeChene ET, Wu C, Jayaraman P, Cao K, Gonzalez M, Devoto M, Testori A, Monos JD, Dulik MC, Conlin LK, Luo M, McDonald Gibson K, Guan Q, Sarmady M, Bhoj E, Helbig I, Zackai EH, Bedoukian EC, Wilkens A, Tarpinian J, Izumi K, Skraban CM, Deardorff MA, Medne L, Krantz ID, Krock BL, and Santani AB
- Subjects
- Child, Humans, Mutation, Rare Diseases genetics, Retrospective Studies, Exome Sequencing methods, Exome genetics, Pathology, Molecular
- Abstract
Clinical exome sequencing (CES) aids in the diagnosis of rare genetic disorders. Herein, we report the molecular diagnostic yield and spectrum of genetic alterations contributing to disease in 700 pediatric cases analyzed at the Children's Hospital of Philadelphia. The overall diagnostic yield was 23%, with three cases having more than one molecular diagnosis and 2.6% having secondary/additional findings. A candidate gene finding was reported in another 8.4% of cases. The clinical indications with the highest diagnostic yield were neurodevelopmental disorders (including seizures), whereas immune- and oncology-related indications were negatively associated with molecular diagnosis. The rapid expansion of knowledge regarding the genome's role in human disease necessitates reanalysis of CES samples. To capture these new discoveries, a subset of cases (n = 240) underwent reanalysis, with an increase in diagnostic yield. We describe our experience reporting CES results in a pediatric setting, including reporting of secondary findings, reporting newly discovered genetic conditions, and revisiting negative test results. Finally, we highlight the challenges associated with implementing critical updates to the CES workflow. Although these updates are necessary, they demand an investment of time and resources from the laboratory. In summary, these data demonstrate the clinical utility of exome sequencing and reanalysis, while highlighting the critical considerations for continuous improvement of a CES test in a clinical laboratory., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
33. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.
- Author
-
Yap ZY, Efthymiou S, Seiffert S, Vargas Parra K, Lee S, Nasca A, Maroofian R, Schrauwen I, Pendziwiat M, Jung S, Bhoj E, Striano P, Mankad K, Vona B, Cuddapah S, Wagner A, Alvi JR, Davoudi-Dehaghani E, Fallah MS, Gannavarapu S, Lamperti C, Legati A, Murtaza BN, Nadeem MS, Rehman MU, Saeidi K, Salpietro V, von Spiczak S, Sandoval A, Zeinali S, Zeviani M, Reich A, Jang C, Helbig I, Barakat TS, Ghezzi D, Leal SM, Weber Y, Houlden H, and Yoon WH
- Subjects
- Alleles, Animals, Cells, Cultured, Child, Cohort Studies, DNA Mutational Analysis, Drosophila melanogaster genetics, Family Health, Female, Fibroblasts, Humans, Male, RNA Splicing, Ataxia genetics, Epilepsy genetics, Hearing Loss genetics, Ketoglutarate Dehydrogenase Complex genetics, Mutation, Neurodevelopmental Disorders genetics, Vision Disorders genetics
- Abstract
The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs
∗ 16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans., Competing Interests: Declaration of interests I.H. serves on the Scientific Advisory Board of Biogen. A.R. is an employee of GeneDx. The remaining authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
34. Clinical Phenotypic Spectrum of 4095 Individuals with Down Syndrome from Text Mining of Electronic Health Records.
- Author
-
Havrilla JM, Zhao M, Liu C, Weng C, Helbig I, Bhoj E, and Wang K
- Subjects
- Humans, Natural Language Processing, Data Mining, Down Syndrome pathology, Electronic Health Records, Phenotype
- Abstract
Human genetic disorders, such as Down syndrome, have a wide variety of clinical phenotypic presentations, and characterizing each nuanced phenotype and subtype can be difficult. In this study, we examined the electronic health records of 4095 individuals with Down syndrome at the Children's Hospital of Philadelphia to create a method to characterize the phenotypic spectrum digitally. We extracted Human Phenotype Ontology (HPO) terms from quality-filtered patient notes using a natural language processing (NLP) approach MetaMap. We catalogued the most common HPO terms related to Down syndrome patients and compared the terms with those from a baseline population. We characterized the top 100 HPO terms by their frequencies at different ages of clinical visits and highlighted selected terms that have time-dependent distributions. We also discovered phenotypic terms that have not been significantly associated with Down syndrome, such as "Proptosis", "Downslanted palpebral fissures", and "Microtia". In summary, our study demonstrated that the clinical phenotypic spectrum of individual with Mendelian diseases can be characterized through NLP-based digital phenotyping on population-scale electronic health records (EHRs).
- Published
- 2021
- Full Text
- View/download PDF
35. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.
- Author
-
Rots D, Chater-Diehl E, Dingemans AJM, Goodman SJ, Siu MT, Cytrynbaum C, Choufani S, Hoang N, Walker S, Awamleh Z, Charkow J, Meyn S, Pfundt R, Rinne T, Gardeitchik T, de Vries BBA, Deden AC, Leenders E, Kwint M, Stumpel CTRM, Stevens SJC, Vermeulen JR, van Harssel JVT, Bosch DGM, van Gassen KLI, van Binsbergen E, de Geus CM, Brackel H, Hempel M, Lessel D, Denecke J, Slavotinek A, Strober J, Crunk A, Folk L, Wentzensen IM, Yang H, Zou F, Millan F, Person R, Xie Y, Liu S, Ousager LB, Larsen M, Schultz-Rogers L, Morava E, Klee EW, Berry IR, Campbell J, Lindstrom K, Pruniski B, Neumeyer AM, Radley JA, Phornphutkul C, Schmidt B, Wilson WG, Õunap K, Reinson K, Pajusalu S, van Haeringen A, Ruivenkamp C, Cuperus R, Santos-Simarro F, Palomares-Bralo M, Pacio-Míguez M, Ritter A, Bhoj E, Tønne E, Tveten K, Cappuccio G, Brunetti-Pierri N, Rowe L, Bunn J, Saenz M, Platzer K, Mertens M, Caluseriu O, Nowaczyk MJM, Cohn RD, Kannu P, Alkhunaizi E, Chitayat D, Scherer SW, Brunner HG, Vissers LELM, Kleefstra T, Koolen DA, and Weksberg R
- Subjects
- Abnormalities, Multiple genetics, Case-Control Studies, Cohort Studies, Craniofacial Abnormalities genetics, Female, Genetic Predisposition to Disease, Growth Disorders genetics, Heart Septal Defects, Ventricular genetics, Humans, Infant, Newborn, Male, Neurodevelopmental Disorders genetics, Abnormalities, Multiple pathology, Adenosine Triphosphatases genetics, Craniofacial Abnormalities pathology, DNA Methylation, Epigenesis, Genetic, Growth Disorders pathology, Heart Septal Defects, Ventricular pathology, Mutation, Neurodevelopmental Disorders pathology, Phenotype
- Abstract
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
36. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.
- Author
-
Sheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM Jr, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BH, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, Hakonarson H, Zackai EH, and Quintero-Rivera F
- Subjects
- Black People genetics, Constipation epidemiology, Constipation genetics, Constipation pathology, Failure to Thrive epidemiology, Failure to Thrive genetics, Failure to Thrive pathology, Genetic Association Studies, Growth Disorders epidemiology, Growth Disorders pathology, Humans, Hypertrichosis epidemiology, Hypertrichosis genetics, Hypertrichosis pathology, Intellectual Disability epidemiology, Intellectual Disability pathology, Loss of Function Mutation genetics, Retrospective Studies, White People genetics, Genetic Predisposition to Disease, Growth Disorders genetics, Histone-Lysine N-Methyltransferase genetics, Hypertrichosis congenital, Intellectual Disability genetics, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
37. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.
- Author
-
White SM, Bhoj E, Nellåker C, Lachmeijer AMA, Marshall AE, Boycott KM, Li D, Smith W, Hartley T, McBride A, Ernst ME, May AS, Wieczorek D, Abou Jamra R, Koch-Hogrebe M, Õunap K, Pajusalu S, van Gassen KLI, Sadedin S, Ellingwood S, Tan TY, Christodoulou J, Barea J, Lockhart PJ, Nezarati MM, and Kernohan KD
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Male, Phenotype, Syndrome, Alleles, DNA Repair genetics, DNA-Binding Proteins genetics, Mutation, Neurodevelopmental Disorders genetics
- Abstract
The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
38. De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.
- Author
-
Li D, Strong A, Shen KM, Cassiman D, Van Dyck M, Linhares ND, Valadares ER, Wang T, Pena SDJ, Jaeken J, Vergano S, Zackai E, Hing A, Chow P, Ganguly A, Scholz T, Bierhals T, Philipp D, Hakonarson H, and Bhoj E
- Subjects
- Adult, Cholestasis, Cleft Palate, Female, Genes, X-Linked, Humans, Phenotype, Young Adult, Intellectual Disability genetics, Mediator Complex genetics, Mental Retardation, X-Linked genetics, Retinitis Pigmentosa
- Abstract
Purpose: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder., Methods: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed., Results: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing., Conclusion: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
- Published
- 2021
- Full Text
- View/download PDF
39. EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients.
- Author
-
Cohen JL, Schrier Vergano SA, Mazzola S, Strong A, Keena B, McDougall C, Ritter A, Li D, Bedoukian EC, Burke LW, Hoffman A, Zurcher V, Krantz ID, Izumi K, Bhoj E, Zackai EH, and Deardorff MA
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Infant, Male, Prognosis, Rubinstein-Taybi Syndrome genetics, E1A-Associated p300 Protein genetics, Mutation, Rubinstein-Taybi Syndrome pathology
- Abstract
Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. We present 12 unreported patients with RSTS found to have EP300 variants discovered through gene sequencing and chromosomal microarray. Our cohort highlights rare phenotypic features associated with EP300 variants, including imperforate anus, retained fetal finger pads, and spina bifida occulta. Our findings support the previously noted prevalence of pregnancy-related hypertension/preeclampsia seen with this disease. We additionally performed a meta-analysis on our newly reported 12 patients and 62 of the 90 previously reported patients. We demonstrated no statistically significant correlation between phenotype severity (within the domains of intellectual disability and major organ involvement, as defined in our Methods section) and variant location and type; this is in contrast to the conclusions of some smaller studies and highlights the importance of large patient cohorts in characterization of this rare disease., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
- Full Text
- View/download PDF
40. Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder.
- Author
-
Gold NB, Li D, Chassevent A, Kaiser FJ, Parenti I, Strom TM, Ramos FJ, Puisac B, Pié J, McWalter K, Guillen Sacoto MJ, Cui H, Saadeh-Haddad R, Smith-Hicks C, Rodan L, Blair E, and Bhoj E
- Subjects
- Adolescent, Adult, Autism Spectrum Disorder pathology, Casein Kinase II genetics, Child, Child, Preschool, Comparative Genomic Hybridization, Developmental Disabilities pathology, Female, Heterozygote, Humans, Male, Whole Genome Sequencing, Young Adult, Autism Spectrum Disorder genetics, Developmental Disabilities genetics, Genetic Predisposition to Disease
- Abstract
The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
41. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.
- Author
-
Drivas TG, Li D, Nair D, Alaimo JT, Alders M, Altmüller J, Barakat TS, Bebin EM, Bertsch NL, Blackburn PR, Blesson A, Bouman AM, Brockmann K, Brunelle P, Burmeister M, Cooper GM, Denecke J, Dieux-Coëslier A, Dubbs H, Ferrer A, Gal D, Bartik LE, Gunderson LB, Hasadsri L, Jain M, Karimov C, Keena B, Klee EW, Kloth K, Lace B, Macchiaiolo M, Marcadier JL, Milunsky JM, Napier MP, Ortiz-Gonzalez XR, Pichurin PN, Pinner J, Powis Z, Prasad C, Radio FC, Rasmussen KJ, Renaud DL, Rush ET, Saunders C, Selcen D, Seman AR, Shinde DN, Smith ED, Smol T, Snijders Blok L, Stoler JM, Tang S, Tartaglia M, Thompson ML, van de Kamp JM, Wang J, Weise D, Weiss K, Woitschach R, Wollnik B, Yan H, Zackai EH, Zampino G, Campeau P, and Bhoj E
- Subjects
- Adolescent, Adult, Catalytic Domain, Child, Child, Preschool, Craniofacial Abnormalities pathology, DNA Helicases chemistry, Developmental Disabilities pathology, Female, Humans, Infant, Intellectual Disability pathology, Male, Mi-2 Nucleosome Remodeling and Deacetylase Complex chemistry, Mutation, Phenotype, Syndrome, Craniofacial Abnormalities genetics, DNA Helicases genetics, Developmental Disabilities genetics, Intellectual Disability genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics
- Abstract
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
- Published
- 2020
- Full Text
- View/download PDF
42. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.
- Author
-
Zhang LX, Lemire G, Gonzaga-Jauregui C, Molidperee S, Galaz-Montoya C, Liu DS, Verloes A, Shillington AG, Izumi K, Ritter AL, Keena B, Zackai E, Li D, Bhoj E, Tarpinian JM, Bedoukian E, Kukolich MK, Innes AM, Ediae GU, Sawyer SL, Nair KM, Soumya PC, Subbaraman KR, Probst FJ, Bassetti JA, Sutton RV, Gibbs RA, Brown C, Boone PM, Holm IA, Tartaglia M, Ferrero GB, Niceta M, Dentici ML, Radio FC, Keren B, Wells CF, Coubes C, Laquerrière A, Aziza J, Dubucs C, Nampoothiri S, Mowat D, Patel MS, Bracho A, Cammarata-Scalisi F, Gezdirici A, Fernandez-Jaen A, Hauser N, Zarate YA, Bosanko KA, Dieterich K, Carey JC, Chong JX, Nickerson DA, Bamshad MJ, Lee BH, Yang XJ, Lupski JR, and Campeau PM
- Subjects
- Exons, Histone Acetyltransferases genetics, Humans, Mutation, Blepharophimosis genetics, Intellectual Disability diagnosis, Intellectual Disability genetics
- Abstract
Purpose: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized., Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum., Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent., Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.
- Published
- 2020
- Full Text
- View/download PDF
43. Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.
- Author
-
Alharatani R, Ververi A, Beleza-Meireles A, Ji W, Mis E, Patterson QT, Griffin JN, Bhujel N, Chang CA, Dixit A, Konstantino M, Healy C, Hannan S, Neo N, Cash A, Li D, Bhoj E, Zackai EH, Cleaver R, Baralle D, McEntagart M, Newbury-Ecob R, Scott R, Hurst JA, Au PYB, Hosey MT, Khokha M, Marciano DK, Lakhani SA, and Liu KJ
- Subjects
- Adolescent, Adult, Animals, Anodontia diagnostic imaging, Anodontia genetics, Anodontia physiopathology, Child, Child, Preschool, Cleft Lip diagnostic imaging, Cleft Lip physiopathology, Cleft Palate diagnostic imaging, Cleft Palate physiopathology, Craniofacial Abnormalities diagnostic imaging, Craniofacial Abnormalities physiopathology, Disease Models, Animal, Ectropion diagnostic imaging, Ectropion physiopathology, Female, Genetic Predisposition to Disease, Heart Defects, Congenital diagnostic imaging, Heart Defects, Congenital physiopathology, Humans, Male, Mice, Tooth Abnormalities diagnostic imaging, Tooth Abnormalities physiopathology, Xenopus, Young Adult, Delta Catenin, Catenins genetics, Cleft Lip genetics, Cleft Palate genetics, Craniofacial Abnormalities genetics, Ectropion genetics, Heart Defects, Congenital genetics, Tooth Abnormalities genetics
- Abstract
CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome., (© The Author(s) 2020. Published by Oxford University Press.)
- Published
- 2020
- Full Text
- View/download PDF
44. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.
- Author
-
Vissers LELM, Kalvakuri S, de Boer E, Geuer S, Oud M, van Outersterp I, Kwint M, Witmond M, Kersten S, Polla DL, Weijers D, Begtrup A, McWalter K, Ruiz A, Gabau E, Morton JEV, Griffith C, Weiss K, Gamble C, Bartley J, Vernon HJ, Brunet K, Ruivenkamp C, Kant SG, Kruszka P, Larson A, Afenjar A, Billette de Villemeur T, Nugent K, Raymond FL, Venselaar H, Demurger F, Soler-Alfonso C, Li D, Bhoj E, Hayes I, Hamilton NP, Ahmad A, Fisher R, van den Born M, Willems M, Sorlin A, Delanne J, Moutton S, Christophe P, Mau-Them FT, Vitobello A, Goel H, Massingham L, Phornphutkul C, Schwab J, Keren B, Charles P, Vreeburg M, De Simone L, Hoganson G, Iascone M, Milani D, Evenepoel L, Revencu N, Ward DI, Burns K, Krantz I, Raible SE, Murrell JR, Wood K, Cho MT, van Bokhoven H, Muenke M, Kleefstra T, Bodmer R, and de Brouwer APM
- Subjects
- Alleles, Female, Genetic Variation genetics, Haploinsufficiency genetics, Heterozygote, Humans, Male, Nervous System Malformations genetics, Phenotype, Protein Stability, Developmental Disabilities genetics, Gene Expression genetics, Neurodevelopmental Disorders genetics, Nuclear Receptor Subfamily 4, Group A, Member 2 genetics, RNA genetics, Receptors, CCR4 genetics, Transcription Factors genetics
- Abstract
CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
45. What not to expect when you're expecting: Unusual cases of placental mosaicism detected on non-invasive prenatal screening.
- Author
-
Pritchard AB, Grand K, Hopkins M, Schindewolf E, Dugoff L, and Bhoj E
- Subjects
- Adult, Cell-Free Nucleic Acids genetics, Female, Humans, Placenta diagnostic imaging, Pregnancy, Trophoblasts cytology, Trophoblasts pathology, Chromosomes genetics, Mosaicism embryology, Placenta pathology, Prenatal Diagnosis
- Abstract
Competing Interests: Declaration of competing interest L.D. hasreceived research support from Progenity, Inc and Sequenom/LabCorp. The other authors declare no conflicts of interest.
- Published
- 2020
- Full Text
- View/download PDF
46. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.
- Author
-
Nambot S, Faivre L, Mirzaa G, Thevenon J, Bruel AL, Mosca-Boidron AL, Masurel-Paulet A, Goldenberg A, Le Meur N, Charollais A, Mignot C, Petit F, Rossi M, Metreau J, Layet V, Amram D, Boute-Bénéjean O, Bhoj E, Cousin MA, Kruisselbrink TM, Lanpher BC, Klee EW, Fiala E, Grange DK, Meschino WS, Hiatt SM, Cooper GM, Olivié H, Smith WE, Dumas M, Lehman A, Inglese C, Nizon M, Guerrini R, Vetro A, Kaplan ES, Miramar D, Van Gils J, Fergelot P, Bodamer O, Herkert JC, Pajusalu S, Õunap K, Filiano JJ, Smol T, Piton A, Gérard B, Chantot-Bastaraud S, Bienvenu T, Li D, Juusola J, Devriendt K, Bilan F, Poé C, Chevarin M, Jouan T, Tisserant E, Rivière JB, Tran Mau-Them F, Philippe C, Duffourd Y, Dobyns WB, Hevner R, and Thauvin-Robinet C
- Subjects
- Adolescent, Adult, Animals, Autistic Disorder pathology, Child, Child, Preschool, Cognition, Craniofacial Abnormalities pathology, Female, Hippocampus diagnostic imaging, Hippocampus pathology, Humans, Intellectual Disability pathology, Male, Mice, Mutation, Neocortex diagnostic imaging, Neocortex pathology, Syndrome, T-Box Domain Proteins metabolism, Autistic Disorder genetics, Craniofacial Abnormalities genetics, Intellectual Disability genetics, Phenotype, T-Box Domain Proteins genetics
- Abstract
TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.
- Published
- 2020
- Full Text
- View/download PDF
47. Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2.
- Author
-
Blackburn PR, Schultz MJ, Lahner CA, Li D, Bhoj E, Fisher LJ, Renaud DL, Kenney A, Ibrahim N, Hashem M, Zain Seidahmed M, Hasadsri L, Schrier Vergano SA, Alkuraya FS, and Lanpher BC
- Subjects
- Adolescent, Adult, Child, Cohort Studies, Female, Humans, Infant, Male, Nervous System Diseases metabolism, Pedigree, Phenotype, Aconitate Hydratase genetics, Nervous System Diseases genetics, Nervous System Diseases physiopathology
- Abstract
Objective: We describe the clinical characteristics and genetic etiology of several new cases within the ACO2-related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear-encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice-site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities., Methods: We describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature., Results: Two siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy-like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months., Interpretation: In this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2020
- Full Text
- View/download PDF
48. Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.
- Author
-
Muir AM, Cohen JL, Sheppard SE, Guttipatti P, Lo TY, Weed N, Doherty D, DeMarzo D, Fagerberg CR, Kjærsgaard L, Larsen MJ, Rump P, Löhner K, Hirsch Y, Zeevi DA, Zackai EH, Bhoj E, Song Y, and Mefford HC
- Subjects
- Active Transport, Cell Nucleus, Animals, Cell Nucleus metabolism, Child, Preschool, Dendrites metabolism, Dendrites pathology, Drosophila melanogaster, Eye Abnormalities mortality, Female, Fibroblasts, Genes, Recessive, Heart Defects, Congenital mortality, Humans, Infant, Infant, Newborn, Jews genetics, Male, Nuclear Pore Complex Proteins deficiency, Seizures metabolism, Syndrome, beta Karyopherins metabolism, Alleles, Brain abnormalities, Drosophila Proteins genetics, Eye Abnormalities genetics, Heart Defects, Congenital genetics, Loss of Function Mutation genetics, Nuclear Pore Complex Proteins genetics
- Abstract
Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
49. Further delineation of the phenotypic spectrum of nevus comedonicus syndrome to include congenital pulmonary airway malformation of the lung and aneurysm.
- Author
-
Sheppard SE, Smith A, Grand K, Pogoriler J, Rubin AI, Schindewolf E, Fitzgerald MP, Moldenhauer J, Laje P, Peranteau W, Bhoj E, McMahon P, and Castelo-Soccio L
- Subjects
- Humans, Infant, Male, Nevus genetics, Phenotype, Pigmentation Disorders genetics, Skin Neoplasms genetics, Aneurysm physiopathology, Cystic Adenomatoid Malformation of Lung, Congenital physiopathology, Mutation, NIMA-Related Kinases genetics, Nevus pathology, Pigmentation Disorders pathology, Skin Neoplasms pathology
- Abstract
Nevus comedonicus syndrome (NCS) is a rare epidermal nevus syndrome characterized by ocular, skeletal, and central nervous system anomalies. We present a 23-month-old boy with a history of a congenital pulmonary airway malformation (CPAM) of the lung and a congenital cataract who developed progressive linear and curvilinear plaques of dilated follicular openings with keratin plugs (comedones) on parts of his scalp, face, and body consistent with nevus comedonicus. MRI of the brain demonstrated an aneurysm of the right internal carotid artery. Genetic testing identified NEK9 c.1755_1757del (p.Thr586del) at mean allele frequency of 28% in the nevus comedonicus. This same mutation was present in the CPAM tissue. This is the first case of a CPAM in a patient with an epidermal nevus syndrome. This case expands the phenotype of nevus comedonicus syndrome to include CPAM and vascular anomalies., (© 2020 Wiley Periodicals, Inc.)
- Published
- 2020
- Full Text
- View/download PDF
50. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.
- Author
-
Johnson BV, Kumar R, Oishi S, Alexander S, Kasherman M, Vega MS, Ivancevic A, Gardner A, Domingo D, Corbett M, Parnell E, Yoon S, Oh T, Lines M, Lefroy H, Kini U, Van Allen M, Grønborg S, Mercier S, Küry S, Bézieau S, Pasquier L, Raynaud M, Afenjar A, Billette de Villemeur T, Keren B, Désir J, Van Maldergem L, Marangoni M, Dikow N, Koolen DA, VanHasselt PM, Weiss M, Zwijnenburg P, Sa J, Reis CF, López-Otín C, Santiago-Fernández O, Fernández-Jaén 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 JA, Pinto E Vairo F, Pichurin PN, Ewing SA, Barnett SS, Klee EW, Perry MS, Koenig MK, Keegan CE, Schuette JL, Asher S, Perilla-Young Y, Smith LD, Rosenfeld JA, Bhoj E, Kaplan P, Li D, Oegema R, van Binsbergen E, van der Zwaag B, Smeland MF, Cutcutache I, Page M, Armstrong M, Lin AE, Steeves MA, Hollander ND, Hoffer MJV, Reijnders MRF, Demirdas S, Koboldt DC, Bartholomew D, Mosher TM, Hickey SE, Shieh C, Sanchez-Lara PA, Graham JM Jr, Tezcan K, Schaefer GB, Danylchuk NR, Asamoah A, Jackson KE, Yachelevich N, Au M, Pérez-Jurado LA, Kleefstra T, Penzes P, Wood SA, Burne T, Pierson TM, Piper M, Gécz J, and Jolly LA
- Subjects
- Animals, Female, Haploinsufficiency, Humans, Male, Mice, Phenotype, Signal Transduction, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Developmental Disabilities genetics, Intellectual Disability genetics, Transforming Growth Factor beta
- Abstract
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 β 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 β signaling and hippocampal function., (Copyright © 2019 Society of Biological Psychiatry. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.