Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Katrine M Johannesen; Sumaiya Iqbal; Milena Guazzi; Nazanin A Mohammadi; Eduardo Pérez-Palma; Elise Schaefer; Anne De Saint Martin; Marie Therese Abiwarde; Amy McTague; Roser Pons; Amelie Piton; Manju A Kurian; Gautam Ambegaonkar; Helen Firth; Alba Sanchis-Juan; Marie Deprez; Katrien Jansen; Liesbeth De Waele; Eva H Briltra; Nienke E Verbeek; Marjan van Kempen; Walid Fazeli; Pasquale Striano; Federico Zara; Gerhard Visser; Hilde M H Braakman; Martin Haeusler; Miriam Elbracht; Ulvi Vaher; Thomas Smol; Johannes R Lemke; Konrad Platzer; Joanna Kennedy; Karl Martin Klein; Ping Yee Billie Au; Kimberly Smyth; Julie Kaplan; Morgan Thomas; Malin K Dewenter; Argirios Dinopoulos; Arthur J Campbell; Dennis Lal; Damien Lederer; Vivian W Y Liao; Philip K Ahring; Rikke S Møller; Elena Gardella

doi:10.1016/j.gim.2021.11.004

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Katrine M Johannesen, Sumaiya Iqbal, Milena Guazzi, Nazanin A Mohammadi, Eduardo Pérez-Palma, Elise Schaefer, Anne De Saint Martin, Marie Therese Abiwarde, Amy McTague, Roser Pons, Amelie Piton, Manju A Kurian, Gautam Ambegaonkar, Helen Firth, Alba Sanchis-Juan, Marie Deprez, Katrien Jansen, Liesbeth De Waele, Eva H Briltra, Nienke E VerbeekMarjan van Kempen, Walid Fazeli, Pasquale Striano, Federico Zara, Gerhard Visser, Hilde M H Braakman, Martin Haeusler, Miriam Elbracht, Ulvi Vaher, Thomas Smol, Johannes R Lemke, Konrad Platzer, Joanna Kennedy, Karl Martin Klein, Ping Yee Billie Au, Kimberly Smyth, Julie Kaplan, Morgan Thomas, Malin K Dewenter, Argirios Dinopoulos, Arthur J Campbell, Dennis Lal, Damien Lederer, Vivian W Y Liao, Philip K Ahring, Rikke S Møller, Elena Gardella^*

^*Corresponding author af dette arbejde

Filadelfia

Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

Abstract

PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.

METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.

RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.

CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

Originalsprog	Engelsk
Sider (fra-til)	681-693
Antal sider	13
Tidsskrift	Genetics in Medicine
Vol/bind	24
Udgave nummer	3
Tidlig onlinedato	7 dec. 2021
DOI	https://doi.org/10.1016/j.gim.2021.11.004
Status	Udgivet - mar. 2022

Bibliografisk note

Adgang til dokumentet

10.1016/j.gim.2021.11.004

Citationsformater

Johannesen, K. M., Iqbal, S., Guazzi, M., Mohammadi, N. A., Pérez-Palma, E., Schaefer, E., De Saint Martin, A., Abiwarde, M. T., McTague, A., Pons, R., Piton, A., Kurian, M. A., Ambegaonkar, G., Firth, H., Sanchis-Juan, A., Deprez, M., Jansen, K., De Waele, L., Briltra, E. H., ... Gardella, E. (2022). Structural mapping of GABRB3 variants reveals genotype-phenotype correlations. Genetics in Medicine, 24(3), 681-693. https://doi.org/10.1016/j.gim.2021.11.004

@article{fbb48740f5584d08922f1fe38981b712,

title = "Structural mapping of GABRB3 variants reveals genotype-phenotype correlations",

abstract = "PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.",

author = "Johannesen, {Katrine M} and Sumaiya Iqbal and Milena Guazzi and Mohammadi, {Nazanin A} and Eduardo P{\'e}rez-Palma and Elise Schaefer and {De Saint Martin}, Anne and Abiwarde, {Marie Therese} and Amy McTague and Roser Pons and Amelie Piton and Kurian, {Manju A} and Gautam Ambegaonkar and Helen Firth and Alba Sanchis-Juan and Marie Deprez and Katrien Jansen and {De Waele}, Liesbeth and Briltra, {Eva H} and Verbeek, {Nienke E} and {van Kempen}, Marjan and Walid Fazeli and Pasquale Striano and Federico Zara and Gerhard Visser and Braakman, {Hilde M H} and Martin Haeusler and Miriam Elbracht and Ulvi Vaher and Thomas Smol and Lemke, {Johannes R} and Konrad Platzer and Joanna Kennedy and Klein, {Karl Martin} and Au, {Ping Yee Billie} and Kimberly Smyth and Julie Kaplan and Morgan Thomas and Dewenter, {Malin K} and Argirios Dinopoulos and Campbell, {Arthur J} and Dennis Lal and Damien Lederer and Liao, {Vivian W Y} and Ahring, {Philip K} and M{\o}ller, {Rikke S} and Elena Gardella",

year = "2022",

month = mar,

doi = "10.1016/j.gim.2021.11.004",

language = "English",

volume = "24",

pages = "681--693",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "3",

}

Johannesen, KM, Iqbal, S, Guazzi, M, Mohammadi, NA, Pérez-Palma, E, Schaefer, E, De Saint Martin, A, Abiwarde, MT, McTague, A, Pons, R, Piton, A, Kurian, MA, Ambegaonkar, G, Firth, H, Sanchis-Juan, A, Deprez, M, Jansen, K, De Waele, L, Briltra, EH, Verbeek, NE, van Kempen, M, Fazeli, W, Striano, P, Zara, F, Visser, G, Braakman, HMH, Haeusler, M, Elbracht, M, Vaher, U, Smol, T, Lemke, JR, Platzer, K, Kennedy, J, Klein, KM, Au, PYB, Smyth, K, Kaplan, J, Thomas, M, Dewenter, MK, Dinopoulos, A, Campbell, AJ, Lal, D, Lederer, D, Liao, VWY, Ahring, PK, Møller, RS & Gardella, E 2022, 'Structural mapping of GABRB3 variants reveals genotype-phenotype correlations', Genetics in Medicine, bind 24, nr. 3, s. 681-693. https://doi.org/10.1016/j.gim.2021.11.004

TY - JOUR

T1 - Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

AU - Johannesen, Katrine M

AU - Iqbal, Sumaiya

AU - Guazzi, Milena

AU - Mohammadi, Nazanin A

AU - Pérez-Palma, Eduardo

AU - Schaefer, Elise

AU - De Saint Martin, Anne

AU - Abiwarde, Marie Therese

AU - McTague, Amy

AU - Pons, Roser

AU - Piton, Amelie

AU - Kurian, Manju A

AU - Ambegaonkar, Gautam

AU - Firth, Helen

AU - Sanchis-Juan, Alba

AU - Deprez, Marie

AU - Jansen, Katrien

AU - De Waele, Liesbeth

AU - Briltra, Eva H

AU - Verbeek, Nienke E

AU - van Kempen, Marjan

AU - Fazeli, Walid

AU - Striano, Pasquale

AU - Zara, Federico

AU - Visser, Gerhard

AU - Braakman, Hilde M H

AU - Haeusler, Martin

AU - Elbracht, Miriam

AU - Vaher, Ulvi

AU - Smol, Thomas

AU - Lemke, Johannes R

AU - Platzer, Konrad

AU - Kennedy, Joanna

AU - Klein, Karl Martin

AU - Au, Ping Yee Billie

AU - Smyth, Kimberly

AU - Kaplan, Julie

AU - Thomas, Morgan

AU - Dewenter, Malin K

AU - Dinopoulos, Argirios

AU - Campbell, Arthur J

AU - Lal, Dennis

AU - Lederer, Damien

AU - Liao, Vivian W Y

AU - Ahring, Philip K

AU - Møller, Rikke S

AU - Gardella, Elena

PY - 2022/3

Y1 - 2022/3

N2 - PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

AB - PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

U2 - 10.1016/j.gim.2021.11.004

DO - 10.1016/j.gim.2021.11.004

M3 - Article

C2 - 34906499

SN - 1098-3600

VL - 24

SP - 681

EP - 693

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 3

ER -

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

Abstract

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