BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

Camille Engel; Stéphanie Valence; Geoffroy Delplancq; Reza Maroofian; Andrea Accogli; Emanuele Agolini; Fowzan S. Alkuraya; Valentina Baglioni; Irene Bagnasco; Mathilde Becmeur-Lefebvre; Enrico Bertini; Ingo Borggraefe; Elise Brischoux-Boucher; Ange Line Bruel; Alfredo Brusco; Dalal K. Bubshait; Christelle Cabrol; Maria Roberta Cilio; Marie Coralie Cornet; Christine Coubes; Olivier Danhaive; Valérie Delague; Anne Sophie Denommé-Pichon; Marilena Carmela Di Giacomo; Martine Doco-Fenzy; Hartmut Engels; Kirsten Cremer; Marion Gérard; Joseph G. Gleeson; Delphine Heron; Joanna Goffeney; Anne Guimier; Frederike L. Harms; Henry Houlden; Michele Iacomino; Rauan Kaiyrzhanov; Benjamin Kamien; Ehsan Ghayoor Karimiani; Dror Kraus; Paul Kuentz; Kerstin Kutsche; Damien Lederer; Lauren Massingham; Cyril Mignot; Déborah Morris-Rosendahl; Lakshmi Nagarajan; Sylvie Odent; Clothilde Ormières; Jennifer Neil Partlow; Laurent Pasquier; Lynette Penney; Christophe Philippe; Gianluca Piccolo; Cathryn Poulton; Audrey Putoux; Marlène Rio; Christelle Rougeot; Vincenzo Salpietro; Ingrid Scheffer; Amy Schneider; Siddharth Srivastava; Rachel Straussberg; Pasquale Striano; Enza Maria Valente; Perrine Venot; Laurent Villard; Antonio Vitobello; Johanna Wagner; Matias Wagner; Maha S. Zaki; Federizo Zara; Gaetan Lesca; Vahid Reza Yassaee; Mohammad Miryounesi; Farzad Hashemi-Gorji; Mehran Beiraghi; Farah Ashrafzadeh; Hamid Galehdari; Christopher Walsh; Antonio Novelli; Moritz Tacke; Dinara Sadykova; Yerdan Maidyrov; Kairgali Koneev; Chingiz Shashkin; Valeria Capra; Mina Zamani; Lionel Van Maldergem; Lydie Burglen; Juliette Piard

doi:10.1038/s41431-023-01410-z

BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

Camille Engel^*, Stéphanie Valence, Geoffroy Delplancq, Reza Maroofian, Andrea Accogli, Emanuele Agolini, Fowzan S. Alkuraya, Valentina Baglioni, Irene Bagnasco, Mathilde Becmeur-Lefebvre, Enrico Bertini, Ingo Borggraefe, Elise Brischoux-Boucher, Ange Line Bruel, Alfredo Brusco, Dalal K. Bubshait, Christelle Cabrol, Maria Roberta Cilio, Marie Coralie Cornet, Christine CoubesOlivier Danhaive, Valérie Delague, Anne Sophie Denommé-Pichon, Marilena Carmela Di Giacomo, Martine Doco-Fenzy, Hartmut Engels, Kirsten Cremer, Marion Gérard, Joseph G. Gleeson, Delphine Heron, Joanna Goffeney, Anne Guimier, Frederike L. Harms, Henry Houlden, Michele Iacomino, Rauan Kaiyrzhanov, Benjamin Kamien, Ehsan Ghayoor Karimiani, Dror Kraus, Paul Kuentz, Kerstin Kutsche, Damien Lederer, Lauren Massingham, Cyril Mignot, Déborah Morris-Rosendahl, Lakshmi Nagarajan, Sylvie Odent, Clothilde Ormières, Jennifer Neil Partlow, Laurent Pasquier, Lynette Penney, Christophe Philippe, Gianluca Piccolo, Cathryn Poulton, Audrey Putoux, Marlène Rio, Christelle Rougeot, Vincenzo Salpietro, Ingrid Scheffer, Amy Schneider, Siddharth Srivastava, Rachel Straussberg, Pasquale Striano, Enza Maria Valente, Perrine Venot, Laurent Villard, Antonio Vitobello, Johanna Wagner, Matias Wagner, Maha S. Zaki, Federizo Zara, Gaetan Lesca, Vahid Reza Yassaee, Mohammad Miryounesi, Farzad Hashemi-Gorji, Mehran Beiraghi, Farah Ashrafzadeh, Hamid Galehdari, Christopher Walsh, Antonio Novelli, Moritz Tacke, Dinara Sadykova, Yerdan Maidyrov, Kairgali Koneev, Chingiz Shashkin, Valeria Capra, Mina Zamani, Lionel Van Maldergem, Lydie Burglen, Juliette Piard

^*Corresponding author for this work

Pediatrics

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

7 Scopus citations

Abstract

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Original language	English
Pages (from-to)	1023-1031
Number of pages	9
Journal	European Journal of Human Genetics
Volume	31
Issue number	9
DOIs	https://doi.org/10.1038/s41431-023-01410-z
State	Published - Sep 2023

Funding

Funders	Funder number
National Institutes of Health
National Institute of Neurological Disorders and Stroke	K23NS119666
King Salman Center for Disability Research	RG-2022-011

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10.1038/s41431-023-01410-z

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Engel, C., Valence, S., Delplancq, G., Maroofian, R., Accogli, A., Agolini, E., Alkuraya, F. S., Baglioni, V., Bagnasco, I., Becmeur-Lefebvre, M., Bertini, E., Borggraefe, I., Brischoux-Boucher, E., Bruel, A. L., Brusco, A., Bubshait, D. K., Cabrol, C., Cilio, M. R., Cornet, M. C., ... Piard, J. (2023). BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients. European Journal of Human Genetics, 31(9), 1023-1031. https://doi.org/10.1038/s41431-023-01410-z

@article{95ad03a25f324592a8d27a4e62de54bb,

title = "BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients",

abstract = "BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).",

author = "Camille Engel and St{\'e}phanie Valence and Geoffroy Delplancq and Reza Maroofian and Andrea Accogli and Emanuele Agolini and Alkuraya, {Fowzan S.} and Valentina Baglioni and Irene Bagnasco and Mathilde Becmeur-Lefebvre and Enrico Bertini and Ingo Borggraefe and Elise Brischoux-Boucher and Bruel, {Ange Line} and Alfredo Brusco and Bubshait, {Dalal K.} and Christelle Cabrol and Cilio, {Maria Roberta} and Cornet, {Marie Coralie} and Christine Coubes and Olivier Danhaive and Val{\'e}rie Delague and Denomm{\'e}-Pichon, {Anne Sophie} and {Di Giacomo}, {Marilena Carmela} and Martine Doco-Fenzy and Hartmut Engels and Kirsten Cremer and Marion G{\'e}rard and Gleeson, {Joseph G.} and Delphine Heron and Joanna Goffeney and Anne Guimier and Harms, {Frederike L.} and Henry Houlden and Michele Iacomino and Rauan Kaiyrzhanov and Benjamin Kamien and Karimiani, {Ehsan Ghayoor} and Dror Kraus and Paul Kuentz and Kerstin Kutsche and Damien Lederer and Lauren Massingham and Cyril Mignot and D{\'e}borah Morris-Rosendahl and Lakshmi Nagarajan and Sylvie Odent and Clothilde Ormi{\`e}res and Partlow, {Jennifer Neil} and Laurent Pasquier and Lynette Penney and Christophe Philippe and Gianluca Piccolo and Cathryn Poulton and Audrey Putoux and Marl{\`e}ne Rio and Christelle Rougeot and Vincenzo Salpietro and Ingrid Scheffer and Amy Schneider and Siddharth Srivastava and Rachel Straussberg and Pasquale Striano and Valente, {Enza Maria} and Perrine Venot and Laurent Villard and Antonio Vitobello and Johanna Wagner and Matias Wagner and Zaki, {Maha S.} and Federizo Zara and Gaetan Lesca and Yassaee, {Vahid Reza} and Mohammad Miryounesi and Farzad Hashemi-Gorji and Mehran Beiraghi and Farah Ashrafzadeh and Hamid Galehdari and Christopher Walsh and Antonio Novelli and Moritz Tacke and Dinara Sadykova and Yerdan Maidyrov and Kairgali Koneev and Chingiz Shashkin and Valeria Capra and Mina Zamani and {Van Maldergem}, Lionel and Lydie Burglen and Juliette Piard",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to European Society of Human Genetics.",

year = "2023",

month = sep,

doi = "10.1038/s41431-023-01410-z",

language = "אנגלית",

volume = "31",

pages = "1023--1031",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "9",

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Engel, C, Valence, S, Delplancq, G, Maroofian, R, Accogli, A, Agolini, E, Alkuraya, FS, Baglioni, V, Bagnasco, I, Becmeur-Lefebvre, M, Bertini, E, Borggraefe, I, Brischoux-Boucher, E, Bruel, AL, Brusco, A, Bubshait, DK, Cabrol, C, Cilio, MR, Cornet, MC, Coubes, C, Danhaive, O, Delague, V, Denommé-Pichon, AS, Di Giacomo, MC, Doco-Fenzy, M, Engels, H, Cremer, K, Gérard, M, Gleeson, JG, Heron, D, Goffeney, J, Guimier, A, Harms, FL, Houlden, H, Iacomino, M, Kaiyrzhanov, R, Kamien, B, Karimiani, EG, Kraus, D, Kuentz, P, Kutsche, K, Lederer, D, Massingham, L, Mignot, C, Morris-Rosendahl, D, Nagarajan, L, Odent, S, Ormières, C, Partlow, JN, Pasquier, L, Penney, L, Philippe, C, Piccolo, G, Poulton, C, Putoux, A, Rio, M, Rougeot, C, Salpietro, V, Scheffer, I, Schneider, A, Srivastava, S, Straussberg, R, Striano, P, Valente, EM, Venot, P, Villard, L, Vitobello, A, Wagner, J, Wagner, M, Zaki, MS, Zara, F, Lesca, G, Yassaee, VR, Miryounesi, M, Hashemi-Gorji, F, Beiraghi, M, Ashrafzadeh, F, Galehdari, H, Walsh, C, Novelli, A, Tacke, M, Sadykova, D, Maidyrov, Y, Koneev, K, Shashkin, C, Capra, V, Zamani, M, Van Maldergem, L, Burglen, L & Piard, J 2023, 'BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients', European Journal of Human Genetics, vol. 31, no. 9, pp. 1023-1031. https://doi.org/10.1038/s41431-023-01410-z

TY - JOUR

T1 - BRAT1–related disorders

T2 - phenotypic spectrum and phenotype-genotype correlations from 97 patients

AU - Engel, Camille

AU - Valence, Stéphanie

AU - Delplancq, Geoffroy

AU - Maroofian, Reza

AU - Accogli, Andrea

AU - Agolini, Emanuele

AU - Alkuraya, Fowzan S.

AU - Baglioni, Valentina

AU - Bagnasco, Irene

AU - Becmeur-Lefebvre, Mathilde

AU - Bertini, Enrico

AU - Borggraefe, Ingo

AU - Brischoux-Boucher, Elise

AU - Bruel, Ange Line

AU - Brusco, Alfredo

AU - Bubshait, Dalal K.

AU - Cabrol, Christelle

AU - Cilio, Maria Roberta

AU - Cornet, Marie Coralie

AU - Coubes, Christine

AU - Danhaive, Olivier

AU - Delague, Valérie

AU - Denommé-Pichon, Anne Sophie

AU - Di Giacomo, Marilena Carmela

AU - Doco-Fenzy, Martine

AU - Engels, Hartmut

AU - Cremer, Kirsten

AU - Gérard, Marion

AU - Gleeson, Joseph G.

AU - Heron, Delphine

AU - Goffeney, Joanna

AU - Guimier, Anne

AU - Harms, Frederike L.

AU - Houlden, Henry

AU - Iacomino, Michele

AU - Kaiyrzhanov, Rauan

AU - Kamien, Benjamin

AU - Karimiani, Ehsan Ghayoor

AU - Kraus, Dror

AU - Kuentz, Paul

AU - Kutsche, Kerstin

AU - Lederer, Damien

AU - Massingham, Lauren

AU - Mignot, Cyril

AU - Morris-Rosendahl, Déborah

AU - Nagarajan, Lakshmi

AU - Odent, Sylvie

AU - Ormières, Clothilde

AU - Partlow, Jennifer Neil

AU - Pasquier, Laurent

AU - Penney, Lynette

AU - Philippe, Christophe

AU - Piccolo, Gianluca

AU - Poulton, Cathryn

AU - Putoux, Audrey

AU - Rio, Marlène

AU - Rougeot, Christelle

AU - Salpietro, Vincenzo

AU - Scheffer, Ingrid

AU - Schneider, Amy

AU - Srivastava, Siddharth

AU - Straussberg, Rachel

AU - Striano, Pasquale

AU - Valente, Enza Maria

AU - Venot, Perrine

AU - Villard, Laurent

AU - Vitobello, Antonio

AU - Wagner, Johanna

AU - Wagner, Matias

AU - Zaki, Maha S.

AU - Zara, Federizo

AU - Lesca, Gaetan

AU - Yassaee, Vahid Reza

AU - Miryounesi, Mohammad

AU - Hashemi-Gorji, Farzad

AU - Beiraghi, Mehran

AU - Ashrafzadeh, Farah

AU - Galehdari, Hamid

AU - Walsh, Christopher

AU - Novelli, Antonio

AU - Tacke, Moritz

AU - Sadykova, Dinara

AU - Maidyrov, Yerdan

AU - Koneev, Kairgali

AU - Shashkin, Chingiz

AU - Capra, Valeria

AU - Zamani, Mina

AU - Van Maldergem, Lionel

AU - Burglen, Lydie

AU - Piard, Juliette

PY - 2023/9

Y1 - 2023/9

N2 - BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

AB - BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

UR - http://www.scopus.com/inward/record.url?scp=85163032567&partnerID=8YFLogxK

U2 - 10.1038/s41431-023-01410-z

DO - 10.1038/s41431-023-01410-z

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 37344571

AN - SCOPUS:85163032567

SN - 1018-4813

VL - 31

SP - 1023

EP - 1031

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 9

ER -

BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

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