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1. Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Author

Layo-Carris, DE, Lubin, EE, Sangree, AK, Clark, KJ, Durham, EL, Gonzalez, EM, Smith, S, Angireddy, R, Wang, XM, Weiss, E, Mendoza-Londono, R, Dupuis, L, Damseh, N, Velasco, D, Valenzuela, I, Codina-Sola, M, Ziats, C, Have, J, Clarkson, K, Steel, D, Kurian, M, Barwick, K, Carrasco, D, Dagli, AI, Nowaczyk, MJM, Hancarova, M, Bendova, S, Prchalova, D, Sedlacek, Z, Baxova, A, Nowak, CB, Douglas, J, Chung, WK, Longo, N, Platzer, K, Kloeckner, C, Averdunk, L, Wieczorek, D, Krey, I, Zweier, C, Reis, A, Balci, T, Simon, M, Kroes, HY, Wiesener, A, Vasileiou, G, Marinakis, NM, Veltra, D, Sofocleous, C, Kosma, K, Synodinos, JT, Voudris, KA, Vuillaume, M-L, Gueguen, P, Derive, N, Colin, E, Battault, C, Au, B, Delatycki, M, Wallis, M, Gallacher, L, Majdoub, F, Smal, N, Weckhuysen, S, Schoonjans, A-S, Kooy, RF, Meuwissen, M, Cocanougher, BT, Taylor, K, Pizoli, CE, McDonald, MT, James, P, Roeder, ER, Littlejohn, R, Borja, NA, Thorson, W, King, K, Stoeva, R, Suerink, M, Nibbeling, E, Baskin, S, Guyader, GLE, Kaplan, J, Muss, C, Carere, DA, Bhoj, EJK, Bryant, LM, Layo-Carris, DE, Lubin, EE, Sangree, AK, Clark, KJ, Durham, EL, Gonzalez, EM, Smith, S, Angireddy, R, Wang, XM, Weiss, E, Mendoza-Londono, R, Dupuis, L, Damseh, N, Velasco, D, Valenzuela, I, Codina-Sola, M, Ziats, C, Have, J, Clarkson, K, Steel, D, Kurian, M, Barwick, K, Carrasco, D, Dagli, AI, Nowaczyk, MJM, Hancarova, M, Bendova, S, Prchalova, D, Sedlacek, Z, Baxova, A, Nowak, CB, Douglas, J, Chung, WK, Longo, N, Platzer, K, Kloeckner, C, Averdunk, L, Wieczorek, D, Krey, I, Zweier, C, Reis, A, Balci, T, Simon, M, Kroes, HY, Wiesener, A, Vasileiou, G, Marinakis, NM, Veltra, D, Sofocleous, C, Kosma, K, Synodinos, JT, Voudris, KA, Vuillaume, M-L, Gueguen, P, Derive, N, Colin, E, Battault, C, Au, B, Delatycki, M, Wallis, M, Gallacher, L, Majdoub, F, Smal, N, Weckhuysen, S, Schoonjans, A-S, Kooy, RF, Meuwissen, M, Cocanougher, BT, Taylor, K, Pizoli, CE, McDonald, MT, James, P, Roeder, ER, Littlejohn, R, Borja, NA, Thorson, W, King, K, Stoeva, R, Suerink, M, Nibbeling, E, Baskin, S, Guyader, GLE, Kaplan, J, Muss, C, Carere, DA, Bhoj, EJK, and Bryant, LM

Abstract

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

Published
2024

2. Correction: Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals (vol 3, 2024, 59)

Author

Layo-Carris, DE, Lubin, EE, Sangree, AK, Clark, KJ, Durham, EL, Gonzalez, EM, Smith, S, Angireddy, R, Wang, XM, Weiss, E, Toutain, A, Mendoza-Londono, R, Dupuis, L, Damseh, N, Velasco, D, Valenzuela, I, Codina-Sola, M, Ziats, C, Have, J, Clarkson, K, Steel, D, Kurian, M, Barwick, K, Carrasco, D, Dagli, AI, Nowaczyk, MJM, Hancarova, M, Bendova, S, Prchalova, D, Sedlacek, Z, Baxova, A, Nowak, CB, Douglas, J, Chung, WK, Longo, N, Platzer, K, Klockner, C, Averdunk, L, Wieczorek, D, Krey, I, Zweier, C, Reis, A, Balci, T, Simon, M, Kroes, HY, Wiesener, A, Vasileiou, G, Marinakis, NM, Veltra, D, Sofocleous, C, Kosma, K, Synodinos, JT, Voudris, KA, Vuillaume, M-L, Gueguen, P, Derive, N, Colin, E, Battault, C, Au, B, Delatycki, M, Wallis, M, Gallacher, L, Majdoub, F, Smal, N, Weckhuysen, S, Schoonjans, A-S, Kooy, RF, Meuwissen, M, Cocanougher, BT, Taylor, K, Pizoli, CE, Mcdonald, MT, James, P, Roeder, ER, Littlejohn, R, Borja, NA, Thorson, W, King, K, Stoeva, R, Suerink, M, Nibbeling, E, Baskin, S, Guyader, GLE, Kaplan, J, Muss, C, Carere, DA, Bhoj, EJK, Bryant, LM, Layo-Carris, DE, Lubin, EE, Sangree, AK, Clark, KJ, Durham, EL, Gonzalez, EM, Smith, S, Angireddy, R, Wang, XM, Weiss, E, Toutain, A, Mendoza-Londono, R, Dupuis, L, Damseh, N, Velasco, D, Valenzuela, I, Codina-Sola, M, Ziats, C, Have, J, Clarkson, K, Steel, D, Kurian, M, Barwick, K, Carrasco, D, Dagli, AI, Nowaczyk, MJM, Hancarova, M, Bendova, S, Prchalova, D, Sedlacek, Z, Baxova, A, Nowak, CB, Douglas, J, Chung, WK, Longo, N, Platzer, K, Klockner, C, Averdunk, L, Wieczorek, D, Krey, I, Zweier, C, Reis, A, Balci, T, Simon, M, Kroes, HY, Wiesener, A, Vasileiou, G, Marinakis, NM, Veltra, D, Sofocleous, C, Kosma, K, Synodinos, JT, Voudris, KA, Vuillaume, M-L, Gueguen, P, Derive, N, Colin, E, Battault, C, Au, B, Delatycki, M, Wallis, M, Gallacher, L, Majdoub, F, Smal, N, Weckhuysen, S, Schoonjans, A-S, Kooy, RF, Meuwissen, M, Cocanougher, BT, Taylor, K, Pizoli, CE, Mcdonald, MT, James, P, Roeder, ER, Littlejohn, R, Borja, NA, Thorson, W, King, K, Stoeva, R, Suerink, M, Nibbeling, E, Baskin, S, Guyader, GLE, Kaplan, J, Muss, C, Carere, DA, Bhoj, EJK, and Bryant, LM

Published
2024

3. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., Vasileiou G., Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., and Vasileiou G.

Abstract

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non -truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.(c) 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2023

5. KAT6A Syndrome

Author

Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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7. Correction: Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.

Author

Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, Smith S, Angireddy R, Wang XM, Weiss E, Toutain A, Mendoza-Londono R, Dupuis L, Damseh N, Velasco D, Valenzuela I, Codina-Solà M, Ziats C, Have J, Clarkson K, Steel D, Kurian M, Barwick K, Carrasco D, Dagli AI, Nowaczyk MJM, Hančárová M, Bendová Š, Prchalova D, Sedláček Z, Baxová A, Nowak CB, Douglas J, Chung WK, Longo N, Platzer K, Klöckner C, Averdunk L, Wieczorek D, Krey I, Zweier C, Reis A, Balci T, Simon M, Kroes HY, Wiesener A, Vasileiou G, Marinakis NM, Veltra D, Sofocleous C, Kosma K, Synodinos JT, Voudris KA, Vuillaume ML, Gueguen P, Derive N, Colin E, Battault C, Au B, Delatycki M, Wallis M, Gallacher L, Majdoub F, Smal N, Weckhuysen S, Schoonjans AS, Kooy RF, Meuwissen M, Cocanougher BT, Taylor K, Pizoli CE, McDonald MT, James P, Roeder ER, Littlejohn R, Borja NA, Thorson W, King K, Stoeva R, Suerink M, Nibbeling E, Baskin S, Guyader GLE, Kaplan J, Muss C, Carere DA, Bhoj EJK, and Bryant LM

Published
2024
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8. Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.

Author

Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, Smith S, Angireddy R, Wang XM, Weiss E, Toutain A, Mendoza-Londono R, Dupuis L, Damseh N, Velasco D, Valenzuela I, Codina-Solà M, Ziats C, Have J, Clarkson K, Steel D, Kurian M, Barwick K, Carrasco D, Dagli AI, Nowaczyk MJM, Hančárová M, Bendová Š, Prchalova D, Sedláček Z, Baxová A, Nowak CB, Douglas J, Chung WK, Longo N, Platzer K, Klöckner C, Averdunk L, Wieczorek D, Krey I, Zweier C, Reis A, Balci T, Simon M, Kroes HY, Wiesener A, Vasileiou G, Marinakis NM, Veltra D, Sofocleous C, Kosma K, Traeger Synodinos J, Voudris KA, Vuillaume ML, Gueguen P, Derive N, Colin E, Battault C, Au B, Delatycki M, Wallis M, Gallacher L, Majdoub F, Smal N, Weckhuysen S, Schoonjans AS, Kooy RF, Meuwissen M, Cocanougher BT, Taylor K, Pizoli CE, McDonald MT, James P, Roeder ER, Littlejohn R, Borja NA, Thorson W, King K, Stoeva R, Suerink M, Nibbeling E, Baskin S, L E Guyader G, Kaplan J, Muss C, Carere DA, Bhoj EJK, and Bryant LM

Subjects
Humans, Male, Female, Child, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Child, Preschool, Adolescent, Adult, Intellectual Disability genetics, Intellectual Disability pathology, Phenotype, Histones genetics
Abstract

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research., (© 2024. The Author(s).)

Published
2024
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9. Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.

Author

Levitin MO, Rawlins LE, Sanchez-Andrade G, Arshad OA, Collins SC, Sawiak SJ, Iffland PH 2nd, Andersson MHL, Bupp C, Cambridge EL, Coomber EL, Ellis I, Herkert JC, Ironfield H, Jory L, Kretz PF, Kant SG, Neaverson A, Nibbeling E, Rowley C, Relton E, Sanderson M, Scott EM, Stewart H, Shuen AY, Schreiber J, Tuck L, Tonks J, Terkelsen T, van Ravenswaaij-Arts C, Vasudevan P, Wenger O, Wright M, Day A, Hunter A, Patel M, Lelliott CJ, Crino PB, Yalcin B, Crosby AH, Baple EL, Logan DW, Hurles ME, and Gerety SS

Subjects
Humans, Animals, Mice, Brain metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Cognition, Microfilament Proteins genetics, Signal Transduction genetics, TOR Serine-Threonine Kinases metabolism
Abstract

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2023
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10. Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

Author

Kennedy J, Goudie D, Blair E, Chandler K, Joss S, McKay V, Green A, Armstrong R, Lees M, Kamien B, Hopper B, Tan TY, Yap P, Stark Z, Okamoto N, Miyake N, Matsumoto N, Macnamara E, Murphy JL, McCormick E, Hakonarson H, Falk MJ, Li D, Blackburn P, Klee E, Babovic-Vuksanovic D, Schelley S, Hudgins L, Kant S, Isidor B, Cogne B, Bradbury K, Williams M, Patel C, Heussler H, Duff-Farrier C, Lakeman P, Scurr I, Kini U, Elting M, Reijnders M, Schuurs-Hoeijmakers J, Wafik M, Blomhoff A, Ruivenkamp CAL, Nibbeling E, Dingemans AJM, Douine ED, Nelson SF, Hempel M, Bierhals T, Lessel D, Johannsen J, Arboleda VA, and Newbury-Ecob R

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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11. KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

Author

Kennedy J, Goudie D, Blair E, Chandler K, Joss S, McKay V, Green A, Armstrong R, Lees M, Kamien B, Hopper B, Tan TY, Yap P, Stark Z, Okamoto N, Miyake N, Matsumoto N, Macnamara E, Murphy JL, McCormick E, Hakonarson H, Falk MJ, Li D, Blackburn P, Klee E, Babovic-Vuksanovic D, Schelley S, Hudgins L, Kant S, Isidor B, Cogne B, Bradbury K, Williams M, Patel C, Heussler H, Duff-Farrier C, Lakeman P, Scurr I, Kini U, Elting M, Reijnders M, Schuurs-Hoeijmakers J, Wafik M, Blomhoff A, Ruivenkamp CAL, Nibbeling E, Dingemans AJM, Douine ED, Nelson SF, Hempel M, Bierhals T, Lessel D, Johannsen J, Arboleda VA, and Newbury-Ecob R

Subjects
Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Developmental Disabilities physiopathology, Exome genetics, Female, Genetic Association Studies, Genotype, Humans, Infant, Intellectual Disability physiopathology, Male, Microcephaly genetics, Microcephaly physiopathology, Mutation, Phenotype, Protein Isoforms genetics, Young Adult, Developmental Disabilities genetics, Histone Acetyltransferases genetics, Intellectual Disability genetics
Abstract

Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported., Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review., Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction., Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Published
2019
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12. Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia.

Author

Nibbeling E, Schaake S, Tijssen MA, Weissbach A, Groen JL, Altenmüller E, Verbeek DS, and Lohmann K

Subjects
Databases, Factual statistics & numerical data, Female, Genome-Wide Association Study, Germany, Humans, Male, Netherlands, Arylsulfatases genetics, Dystonic Disorders genetics, Polymorphism, Single Nucleotide genetics
Abstract

Musician's dystonia and writer's cramp are examples of task-specific dystonia. Recently, the arylsulfatase G (ARSG) locus was suggested to be associated with musician's dystonia and writer's cramp by a genome-wide association study. To test for the presence of causal variants, the entire coding region and exon-intron boundaries of ARSG were sequenced in DNA samples from 158 musician's dystonia patients which were collected at the University of Music, Drama, and Media (Hanover, Germany), and 72 patients with writer's cramp which were recruited at the Academic Medical Centers in Amsterdam and Groningen, the Netherlands. The frequency of variants within ARSG was compared to publically available data at the exome variant server (EVS) from the NHLBI GO Exome Sequencing Project. We identified 11 single nucleotide variants (SNVs) in the patients including eight non-synonymous substitutions. All variants have previously been reported at EVS including two SNVs with a reported minor allele frequency <1%. One rare missense variant, rs61999318 (p.I493T), was significantly enriched in the group of writer's cramp patients compared to European Americans in EVS database (p = 0.0013). In patients with writer's cramp, there was an overall enrichment for rare, protein-changing variants compared to controls (p < 0.01). In conclusion, we did not detect any conclusive mutation in ARSG. However, we showed an association with rs61999318 in patients with writer's cramp that contributed to an overall enrichment for rare, protein-changing variants in these patients. Thus, our data provide further support for a role of ARSG variants in task-specific dystonia, especially writer's cramp.

Published
2015
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