Clinical and molecular characterization of patients with YWHAG-related epilepsy

Valentina Cetica; Tiziana Pisano; Gaetan Lesca; Dana Marafi; Laura Licchetta; Florence Riccardi; Davide Mei; Hon yin B. Chung; Allan Bayat; Meena Balasubramanian; Daniel H. Lowenstein; Milda Endzinienė; Maha Alotaibi; Nathalie Villeneuve; Julia Jacobs; Bertrand Isidor; Roberta Solazzi; Nicolette S. den Hollander; Dragan Marjanovic; Christelle Rougeot-Jung; Julien Jung; Marion Lesieur-Sebellin; Andrea Accogli; Vincenzo Salpietro; Nebal W. Saadi; Eleni Panagiotakaki; Thomas Foiadelli; Sylvia Redon; Meng Han Tsai; Francesca Bisulli; Trine B. Hammer; James R. Lupski; Elena Parrini; Renzo Guerrini

doi:10.1111/epi.17939

Clinical and molecular characterization of patients with YWHAG-related epilepsy

Valentina Cetica, Tiziana Pisano, Gaetan Lesca, Dana Marafi, Laura Licchetta, Florence Riccardi, Davide Mei, Hon yin B. Chung, Allan Bayat, Meena Balasubramanian, Daniel H. Lowenstein, Milda Endzinienė, Maha Alotaibi, Nathalie Villeneuve, Julia Jacobs, Bertrand Isidor, Roberta Solazzi, Nicolette S. den Hollander, Dragan Marjanovic, Christelle Rougeot-JungJulien Jung, Marion Lesieur-Sebellin, Andrea Accogli, Vincenzo Salpietro, Nebal W. Saadi, Eleni Panagiotakaki, Thomas Foiadelli, Sylvia Redon, Meng Han Tsai, Francesca Bisulli, Trine B. Hammer, James R. Lupski, Elena Parrini, Renzo Guerrini^*

^*Corresponding author for this work

School of Medicine

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

3 Scopus citations

Abstract

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy.

METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.

RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).

SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Original language	English
Pages (from-to)	1439-1450
Number of pages	12
Journal	Epilepsia
Volume	65
Issue number	5
DOIs	https://doi.org/10.1111/epi.17939
State	Published - 05 2024

Bibliographical note

Keywords

epilepsy
genotype–phenotype correlation
YWHAG
Genetic Association Studies
Humans
Child, Preschool
Epilepsy/diagnostic imaging
Infant
Male
Electroencephalography
Developmental Disabilities/genetics
Young Adult
Intellectual Disability/genetics
Magnetic Resonance Imaging
Phenotype
Adolescent
Adult
Female
Child
Cohort Studies

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Cetica, V., Pisano, T., Lesca, G., Marafi, D., Licchetta, L., Riccardi, F., Mei, D., Chung, H. Y. B., Bayat, A., Balasubramanian, M., Lowenstein, D. H., Endzinienė, M., Alotaibi, M., Villeneuve, N., Jacobs, J., Isidor, B., Solazzi, R., den Hollander, N. S., Marjanovic, D., ... Guerrini, R. (2024). Clinical and molecular characterization of patients with YWHAG-related epilepsy. Epilepsia, 65(5), 1439-1450. https://doi.org/10.1111/epi.17939

@article{9893b051e31440fe82e8b9f17987e2e3,

title = "Clinical and molecular characterization of patients with YWHAG-related epilepsy",

abstract = "OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy.METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.",

keywords = "epilepsy, genotype–phenotype correlation, YWHAG, Genetic Association Studies, Humans, Child, Preschool, Epilepsy/diagnostic imaging, Infant, Male, Electroencephalography, Developmental Disabilities/genetics, Young Adult, Intellectual Disability/genetics, Magnetic Resonance Imaging, Phenotype, Adolescent, Adult, Female, Child, Cohort Studies",

author = "Valentina Cetica and Tiziana Pisano and Gaetan Lesca and Dana Marafi and Laura Licchetta and Florence Riccardi and Davide Mei and Chung, {Hon yin B.} and Allan Bayat and Meena Balasubramanian and Lowenstein, {Daniel H.} and Milda Endzinienė and Maha Alotaibi and Nathalie Villeneuve and Julia Jacobs and Bertrand Isidor and Roberta Solazzi and {den Hollander}, {Nicolette S.} and Dragan Marjanovic and Christelle Rougeot-Jung and Julien Jung and Marion Lesieur-Sebellin and Andrea Accogli and Vincenzo Salpietro and Saadi, {Nebal W.} and Eleni Panagiotakaki and Thomas Foiadelli and Sylvia Redon and Tsai, {Meng Han} and Francesca Bisulli and Hammer, {Trine B.} and Lupski, {James R.} and Elena Parrini and Renzo Guerrini",

note = "{\textcopyright} 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",

year = "2024",

month = may,

doi = "10.1111/epi.17939",

language = "英语",

volume = "65",

pages = "1439--1450",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

Cetica, V, Pisano, T, Lesca, G, Marafi, D, Licchetta, L, Riccardi, F, Mei, D, Chung, HYB, Bayat, A, Balasubramanian, M, Lowenstein, DH, Endzinienė, M, Alotaibi, M, Villeneuve, N, Jacobs, J, Isidor, B, Solazzi, R, den Hollander, NS, Marjanovic, D, Rougeot-Jung, C, Jung, J, Lesieur-Sebellin, M, Accogli, A, Salpietro, V, Saadi, NW, Panagiotakaki, E, Foiadelli, T, Redon, S, Tsai, MH, Bisulli, F, Hammer, TB, Lupski, JR, Parrini, E & Guerrini, R 2024, 'Clinical and molecular characterization of patients with YWHAG-related epilepsy', Epilepsia, vol. 65, no. 5, pp. 1439-1450. https://doi.org/10.1111/epi.17939

TY - JOUR

T1 - Clinical and molecular characterization of patients with YWHAG-related epilepsy

AU - Cetica, Valentina

AU - Pisano, Tiziana

AU - Lesca, Gaetan

AU - Marafi, Dana

AU - Licchetta, Laura

AU - Riccardi, Florence

AU - Mei, Davide

AU - Chung, Hon yin B.

AU - Bayat, Allan

AU - Balasubramanian, Meena

AU - Lowenstein, Daniel H.

AU - Endzinienė, Milda

AU - Alotaibi, Maha

AU - Villeneuve, Nathalie

AU - Jacobs, Julia

AU - Isidor, Bertrand

AU - Solazzi, Roberta

AU - den Hollander, Nicolette S.

AU - Marjanovic, Dragan

AU - Rougeot-Jung, Christelle

AU - Jung, Julien

AU - Lesieur-Sebellin, Marion

AU - Accogli, Andrea

AU - Salpietro, Vincenzo

AU - Saadi, Nebal W.

AU - Panagiotakaki, Eleni

AU - Foiadelli, Thomas

AU - Redon, Sylvia

AU - Tsai, Meng Han

AU - Bisulli, Francesca

AU - Hammer, Trine B.

AU - Lupski, James R.

AU - Parrini, Elena

AU - Guerrini, Renzo

PY - 2024/5

Y1 - 2024/5

N2 - OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy.METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

AB - OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy.METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

KW - epilepsy

KW - genotype–phenotype correlation

KW - YWHAG

KW - Genetic Association Studies

KW - Humans

KW - Child, Preschool

KW - Epilepsy/diagnostic imaging

KW - Infant

KW - Male

KW - Electroencephalography

KW - Developmental Disabilities/genetics

KW - Young Adult

KW - Intellectual Disability/genetics

KW - Magnetic Resonance Imaging

KW - Phenotype

KW - Adolescent

KW - Adult

KW - Female

KW - Child

KW - Cohort Studies

UR - http://www.scopus.com/inward/record.url?scp=85188435645&partnerID=8YFLogxK

U2 - 10.1111/epi.17939

DO - 10.1111/epi.17939

M3 - 文章

C2 - 38491959

AN - SCOPUS:85188435645

SN - 0013-9580

VL - 65

SP - 1439

EP - 1450

JO - Epilepsia

JF - Epilepsia

IS - 5

ER -

Clinical and molecular characterization of patients with YWHAG-related epilepsy

Abstract

Bibliographical note

Keywords

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