Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Sayaka Kayumi; Luis A. Pérez-Jurado; María Palomares; Sneha Rangu; Sarah E. Sheppard; Wendy K. Chung; Michael C. Kruer; Mira Kharbanda; David J. Amor; George McGillivray; Julie S. Cohen; Sixto García-Miñaúr; Clare L. van Eyk; Kelly Harper; Lachlan A. Jolly; Dani L. Webber; Christopher P. Barnett; Fernando Santos-Simarro; Marta Pacio-Míguez; Angela del Pozo; Somayeh Bakhtiari; Matthew Deardorff; Holly A. Dubbs; Kosuke Izumi; Katheryn Grand; Christopher Gray; Paul R. Mark; Elizabeth J. Bhoj; Dong Li; Xilma R. Ortiz-Gonzalez; Beth Keena; Elaine H. Zackai; Ethan M. Goldberg; Guiomar Perez de Nanclares; Arrate Pereda; Isabel Llano-Rivas; Ignacio Arroyo; María Ángeles Fernández-Cuesta; Christel Thauvin-Robinet; Laurence Faivre; Aurore Garde; Benoit Mazel; Ange Line Bruel; Michael L. Tress; Eva Brilstra; Amena Smith Fine; Kylie E. Crompton; Alexander P.A. Stegmann; Margje Sinnema; Servi C.J. Stevens; Joost Nicolai; Gaetan Lesca; Laurence Lion-François; Damien Haye; Nicolas Chatron; Amelie Piton; Mathilde Nizon; Benjamin Cogne; Siddharth Srivastava; Jennifer Bassetti; Candace Muss; Karen W. Gripp; Rebecca A. Procopio; Francisca Millan; Michelle M. Morrow; Melissa Assaf; Andres Moreno-De-Luca; Shelagh Joss; Mark J. Hamilton; Marta Bertoli; Nicola Foulds; Shane McKee; Alastair H. MacLennan; Jozef Gecz; Mark A. Corbett

doi:10.1016/j.gim.2022.08.006

Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Sayaka Kayumi, Luis A. Pérez-Jurado, María Palomares, Sneha Rangu, Sarah E. Sheppard, Wendy K. Chung, Michael C. Kruer, Mira Kharbanda, David J. Amor, George McGillivray, Julie S. Cohen, Sixto García-Miñaúr, Clare L. van Eyk, Kelly Harper, Lachlan A. Jolly, Dani L. Webber, Christopher P. Barnett, Fernando Santos-Simarro, Marta Pacio-Míguez, Angela del PozoSomayeh Bakhtiari, Matthew Deardorff, Holly A. Dubbs, Kosuke Izumi, Katheryn Grand, Christopher Gray, Paul R. Mark, Elizabeth J. Bhoj, Dong Li, Xilma R. Ortiz-Gonzalez, Beth Keena, Elaine H. Zackai, Ethan M. Goldberg, Guiomar Perez de Nanclares, Arrate Pereda, Isabel Llano-Rivas, Ignacio Arroyo, María Ángeles Fernández-Cuesta, Christel Thauvin-Robinet, Laurence Faivre, Aurore Garde, Benoit Mazel, Ange Line Bruel, Michael L. Tress, Eva Brilstra, Amena Smith Fine, Kylie E. Crompton, Alexander P.A. Stegmann, Margje Sinnema, Servi C.J. Stevens, Joost Nicolai, Gaetan Lesca, Laurence Lion-François, Damien Haye, Nicolas Chatron, Amelie Piton, Mathilde Nizon, Benjamin Cogne, Siddharth Srivastava, Jennifer Bassetti, Candace Muss, Karen W. Gripp, Rebecca A. Procopio, Francisca Millan, Michelle M. Morrow, Melissa Assaf, Andres Moreno-De-Luca, Shelagh Joss, Mark J. Hamilton, Marta Bertoli, Nicola Foulds, Shane McKee, Alastair H. MacLennan, Jozef Gecz, Mark A. Corbett

Kennedy Krieger Institute

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Methods: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. Results: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. Conclusion: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Original language	English (US)
Pages (from-to)	2351-2366
Number of pages	16
Journal	Genetics in Medicine
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.gim.2022.08.006
State	Published - Nov 2022

Keywords

Autism
Cerebral palsy
Familial exudative vitreoretinopathy
Microcephaly
Wnt beta catenin signaling pathway

ASJC Scopus subject areas

Genetics(clinical)

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10.1016/j.gim.2022.08.006

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Kayumi, S., Pérez-Jurado, L. A., Palomares, M., Rangu, S., Sheppard, S. E., Chung, W. K., Kruer, M. C., Kharbanda, M., Amor, D. J., McGillivray, G., Cohen, J. S., García-Miñaúr, S., van Eyk, C. L., Harper, K., Jolly, L. A., Webber, D. L., Barnett, C. P., Santos-Simarro, F., Pacio-Míguez, M., ... Corbett, M. A. (2022). Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genetics in Medicine, 24(11), 2351-2366. https://doi.org/10.1016/j.gim.2022.08.006

Kayumi, S, Pérez-Jurado, LA, Palomares, M, Rangu, S, Sheppard, SE, Chung, WK, Kruer, MC, Kharbanda, M, Amor, DJ, McGillivray, G, Cohen, JS, García-Miñaúr, S, van Eyk, CL, Harper, K, Jolly, LA, Webber, DL, Barnett, CP, Santos-Simarro, F, Pacio-Míguez, M, Pozo, AD, Bakhtiari, S, Deardorff, M, Dubbs, HA, Izumi, K, Grand, K, Gray, C, Mark, PR, Bhoj, EJ, Li, D, Ortiz-Gonzalez, XR, Keena, B, Zackai, EH, Goldberg, EM, Perez de Nanclares, G, Pereda, A, Llano-Rivas, I, Arroyo, I, Fernández-Cuesta, MÁ, Thauvin-Robinet, C, Faivre, L, Garde, A, Mazel, B, Bruel, AL, Tress, ML, Brilstra, E, Fine, AS, Crompton, KE, Stegmann, APA, Sinnema, M, Stevens, SCJ, Nicolai, J, Lesca, G, Lion-François, L, Haye, D, Chatron, N, Piton, A, Nizon, M, Cogne, B, Srivastava, S, Bassetti, J, Muss, C, Gripp, KW, Procopio, RA, Millan, F, Morrow, MM, Assaf, M, Moreno-De-Luca, A, Joss, S, Hamilton, MJ, Bertoli, M, Foulds, N, McKee, S, MacLennan, AH, Gecz, J & Corbett, MA 2022, 'Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants', Genetics in Medicine, vol. 24, no. 11, pp. 2351-2366. https://doi.org/10.1016/j.gim.2022.08.006

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title = "Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants",

abstract = "Purpose: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Methods: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. Results: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. Conclusion: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.",

keywords = "Autism, Cerebral palsy, Familial exudative vitreoretinopathy, Microcephaly, Wnt beta catenin signaling pathway",

author = "Sayaka Kayumi and P{\'e}rez-Jurado, {Luis A.} and Mar{\'i}a Palomares and Sneha Rangu and Sheppard, {Sarah E.} and Chung, {Wendy K.} and Kruer, {Michael C.} and Mira Kharbanda and Amor, {David J.} and George McGillivray and Cohen, {Julie S.} and Sixto Garc{\'i}a-Mi{\~n}a{\'u}r and {van Eyk}, {Clare L.} and Kelly Harper and Jolly, {Lachlan A.} and Webber, {Dani L.} and Barnett, {Christopher P.} and Fernando Santos-Simarro and Marta Pacio-M{\'i}guez and Pozo, {Angela del} and Somayeh Bakhtiari and Matthew Deardorff and Dubbs, {Holly A.} and Kosuke Izumi and Katheryn Grand and Christopher Gray and Mark, {Paul R.} and Bhoj, {Elizabeth J.} and Dong Li and Ortiz-Gonzalez, {Xilma R.} and Beth Keena and Zackai, {Elaine H.} and Goldberg, {Ethan M.} and {Perez de Nanclares}, Guiomar and Arrate Pereda and Isabel Llano-Rivas and Ignacio Arroyo and Fern{\'a}ndez-Cuesta, {Mar{\'i}a {\'A}ngeles} and Christel Thauvin-Robinet and Laurence Faivre and Aurore Garde and Benoit Mazel and Bruel, {Ange Line} and Tress, {Michael L.} and Eva Brilstra and Fine, {Amena Smith} and Crompton, {Kylie E.} and Stegmann, {Alexander P.A.} and Margje Sinnema and Stevens, {Servi C.J.} and Joost Nicolai and Gaetan Lesca and Laurence Lion-Fran{\c c}ois and Damien Haye and Nicolas Chatron and Amelie Piton and Mathilde Nizon and Benjamin Cogne and Siddharth Srivastava and Jennifer Bassetti and Candace Muss and Gripp, {Karen W.} and Procopio, {Rebecca A.} and Francisca Millan and Morrow, {Michelle M.} and Melissa Assaf and Andres Moreno-De-Luca and Shelagh Joss and Hamilton, {Mark J.} and Marta Bertoli and Nicola Foulds and Shane McKee and MacLennan, {Alastair H.} and Jozef Gecz and Corbett, {Mark A.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

doi = "10.1016/j.gim.2022.08.006",

language = "English (US)",

volume = "24",

pages = "2351--2366",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "11",

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TY - JOUR

T1 - Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

AU - Kayumi, Sayaka

AU - Pérez-Jurado, Luis A.

AU - Palomares, María

AU - Rangu, Sneha

AU - Sheppard, Sarah E.

AU - Chung, Wendy K.

AU - Kruer, Michael C.

AU - Kharbanda, Mira

AU - Amor, David J.

AU - McGillivray, George

AU - Cohen, Julie S.

AU - García-Miñaúr, Sixto

AU - van Eyk, Clare L.

AU - Harper, Kelly

AU - Jolly, Lachlan A.

AU - Webber, Dani L.

AU - Barnett, Christopher P.

AU - Santos-Simarro, Fernando

AU - Pacio-Míguez, Marta

AU - Pozo, Angela del

AU - Bakhtiari, Somayeh

AU - Deardorff, Matthew

AU - Dubbs, Holly A.

AU - Izumi, Kosuke

AU - Grand, Katheryn

AU - Gray, Christopher

AU - Mark, Paul R.

AU - Bhoj, Elizabeth J.

AU - Li, Dong

AU - Ortiz-Gonzalez, Xilma R.

AU - Keena, Beth

AU - Zackai, Elaine H.

AU - Goldberg, Ethan M.

AU - Perez de Nanclares, Guiomar

AU - Pereda, Arrate

AU - Llano-Rivas, Isabel

AU - Arroyo, Ignacio

AU - Fernández-Cuesta, María Ángeles

AU - Thauvin-Robinet, Christel

AU - Faivre, Laurence

AU - Garde, Aurore

AU - Mazel, Benoit

AU - Bruel, Ange Line

AU - Tress, Michael L.

AU - Brilstra, Eva

AU - Fine, Amena Smith

AU - Crompton, Kylie E.

AU - Stegmann, Alexander P.A.

AU - Sinnema, Margje

AU - Stevens, Servi C.J.

AU - Nicolai, Joost

AU - Lesca, Gaetan

AU - Lion-François, Laurence

AU - Haye, Damien

AU - Chatron, Nicolas

AU - Piton, Amelie

AU - Nizon, Mathilde

AU - Cogne, Benjamin

AU - Srivastava, Siddharth

AU - Bassetti, Jennifer

AU - Muss, Candace

AU - Gripp, Karen W.

AU - Procopio, Rebecca A.

AU - Millan, Francisca

AU - Morrow, Michelle M.

AU - Assaf, Melissa

AU - Moreno-De-Luca, Andres

AU - Joss, Shelagh

AU - Hamilton, Mark J.

AU - Bertoli, Marta

AU - Foulds, Nicola

AU - McKee, Shane

AU - MacLennan, Alastair H.

AU - Gecz, Jozef

AU - Corbett, Mark A.

PY - 2022/11

Y1 - 2022/11

N2 - Purpose: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Methods: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. Results: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. Conclusion: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

AB - Purpose: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Methods: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. Results: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. Conclusion: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

KW - Autism

KW - Cerebral palsy

KW - Familial exudative vitreoretinopathy

KW - Microcephaly

KW - Wnt beta catenin signaling pathway

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U2 - 10.1016/j.gim.2022.08.006

DO - 10.1016/j.gim.2022.08.006

M3 - Article

C2 - 36083290

AN - SCOPUS:85140454140

SN - 1098-3600

VL - 24

SP - 2351

EP - 2366

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

ER -

Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

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