Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Silvestre Cuinat; Mathilde Nizon; Bertrand Isidor; Alexander Stegmann; Richard H van Jaarsveld; Koen L van Gassen; Jasper J van der Smagt; Catharina M L Volker-Touw; Sjoerd J B Holwerda; Paulien A Terhal; Sarah Schuhmann; Georgia Vasileiou; Mohamed Khalifa; Alaa A Nugud; Hemad Yasaei; Lilian Bomme Ousager; Charlotte Brasch-Andersen; Wallid Deb; Thomas Besnard; Marleen E H Simon; Karin Huijsdens-van Amsterdam; Nienke E Verbeek; Dena Matalon; Natalie Dykzeul; Shana White; Elizabeth Spiteri; Koen Devriendt; Anneleen Boogaerts; Marjolein Willemsen; Han G Brunner; Margje Sinnema; Bert B A De Vries; Erica H Gerkes; Rolph Pfundt; Kosuke Izumi; Ian D Krantz; Zhou L Xu; Jill R Murrell; Irene Valenzuela; Ivon Cusco; Eulàlia Rovira-Moreno; Yaping Yang; Varoona Bizaoui; Olivier Patat; Laurence Faivre; Frederic Tran-Mau-Them; Antonio Vitobello; Anne-Sophie Denommé-Pichon; Christophe Philippe; Stéphane Bezieau; Benjamin Cogné

doi:10.1016/j.gim.2022.04.011

Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Silvestre Cuinat^*, Mathilde Nizon, Bertrand Isidor, Alexander Stegmann, Richard H van Jaarsveld, Koen L van Gassen, Jasper J van der Smagt, Catharina M L Volker-Touw, Sjoerd J B Holwerda, Paulien A Terhal, Sarah Schuhmann, Georgia Vasileiou, Mohamed Khalifa, Alaa A Nugud, Hemad Yasaei, Lilian Bomme Ousager, Charlotte Brasch-Andersen, Wallid Deb, Thomas Besnard, Marleen E H SimonKarin Huijsdens-van Amsterdam, Nienke E Verbeek, Dena Matalon, Natalie Dykzeul, Shana White, Elizabeth Spiteri, Koen Devriendt, Anneleen Boogaerts, Marjolein Willemsen, Han G Brunner, Margje Sinnema, Bert B A De Vries, Erica H Gerkes, Rolph Pfundt, Kosuke Izumi, Ian D Krantz, Zhou L Xu, Jill R Murrell, Irene Valenzuela, Ivon Cusco, Eulàlia Rovira-Moreno, Yaping Yang, Varoona Bizaoui, Olivier Patat, Laurence Faivre, Frederic Tran-Mau-Them, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Christophe Philippe, Stéphane Bezieau, Benjamin Cogné^*

^*Corresponding author for this work

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

Abstract

PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.

METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.

RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.

CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

Original language	English
Pages (from-to)	1774-1780
Number of pages	7
Journal	Genetics in Medicine
Volume	24
Issue number	8
Early online date	13 May 2022
DOIs	https://doi.org/10.1016/j.gim.2022.04.011
Publication status	Published - Aug 2022

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Cuinat, S., Nizon, M., Isidor, B., Stegmann, A., van Jaarsveld, R. H., van Gassen, K. L., van der Smagt, J. J., Volker-Touw, C. M. L., Holwerda, S. J. B., Terhal, P. A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A. A., Yasaei, H., Ousager, L. B., Brasch-Andersen, C., Deb, W., Besnard, T., ... Cogné, B. (2022). Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder. Genetics in Medicine, 24(8), 1774-1780. https://doi.org/10.1016/j.gim.2022.04.011

@article{40da9a50b6d14326b6d6a0240ffd802d,

title = "Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder",

abstract = "PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.",

author = "Silvestre Cuinat and Mathilde Nizon and Bertrand Isidor and Alexander Stegmann and {van Jaarsveld}, {Richard H} and {van Gassen}, {Koen L} and {van der Smagt}, {Jasper J} and Volker-Touw, {Catharina M L} and Holwerda, {Sjoerd J B} and Terhal, {Paulien A} and Sarah Schuhmann and Georgia Vasileiou and Mohamed Khalifa and Nugud, {Alaa A} and Hemad Yasaei and Ousager, {Lilian Bomme} and Charlotte Brasch-Andersen and Wallid Deb and Thomas Besnard and Simon, {Marleen E H} and Amsterdam, {Karin Huijsdens-van} and Verbeek, {Nienke E} and Dena Matalon and Natalie Dykzeul and Shana White and Elizabeth Spiteri and Koen Devriendt and Anneleen Boogaerts and Marjolein Willemsen and Brunner, {Han G} and Margje Sinnema and {De Vries}, {Bert B A} and Gerkes, {Erica H} and Rolph Pfundt and Kosuke Izumi and Krantz, {Ian D} and Xu, {Zhou L} and Murrell, {Jill R} and Irene Valenzuela and Ivon Cusco and Eul{\`a}lia Rovira-Moreno and Yaping Yang and Varoona Bizaoui and Olivier Patat and Laurence Faivre and Frederic Tran-Mau-Them and Antonio Vitobello and Anne-Sophie Denomm{\'e}-Pichon and Christophe Philippe and St{\'e}phane Bezieau and Benjamin Cogn{\'e}",

year = "2022",

month = aug,

doi = "10.1016/j.gim.2022.04.011",

language = "English",

volume = "24",

pages = "1774--1780",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "8",

}

Cuinat, S, Nizon, M, Isidor, B, Stegmann, A, van Jaarsveld, RH, van Gassen, KL, van der Smagt, JJ, Volker-Touw, CML, Holwerda, SJB, Terhal, PA, Schuhmann, S, Vasileiou, G, Khalifa, M, Nugud, AA, Yasaei, H, Ousager, LB, Brasch-Andersen, C, Deb, W, Besnard, T, Simon, MEH, Amsterdam, KH, Verbeek, NE, Matalon, D, Dykzeul, N, White, S, Spiteri, E, Devriendt, K, Boogaerts, A, Willemsen, M, Brunner, HG , Sinnema, M, De Vries, BBA, Gerkes, EH, Pfundt, R, Izumi, K, Krantz, ID, Xu, ZL, Murrell, JR, Valenzuela, I, Cusco, I, Rovira-Moreno, E, Yang, Y, Bizaoui, V, Patat, O, Faivre, L, Tran-Mau-Them, F, Vitobello, A, Denommé-Pichon, A-S, Philippe, C, Bezieau, S & Cogné, B 2022, 'Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder', Genetics in Medicine, vol. 24, no. 8, pp. 1774-1780. https://doi.org/10.1016/j.gim.2022.04.011

TY - JOUR

T1 - Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

AU - Cuinat, Silvestre

AU - Nizon, Mathilde

AU - Isidor, Bertrand

AU - Stegmann, Alexander

AU - van Jaarsveld, Richard H

AU - van Gassen, Koen L

AU - van der Smagt, Jasper J

AU - Volker-Touw, Catharina M L

AU - Holwerda, Sjoerd J B

AU - Terhal, Paulien A

AU - Schuhmann, Sarah

AU - Vasileiou, Georgia

AU - Khalifa, Mohamed

AU - Nugud, Alaa A

AU - Yasaei, Hemad

AU - Ousager, Lilian Bomme

AU - Brasch-Andersen, Charlotte

AU - Deb, Wallid

AU - Besnard, Thomas

AU - Simon, Marleen E H

AU - Amsterdam, Karin Huijsdens-van

AU - Verbeek, Nienke E

AU - Matalon, Dena

AU - Dykzeul, Natalie

AU - White, Shana

AU - Spiteri, Elizabeth

AU - Devriendt, Koen

AU - Boogaerts, Anneleen

AU - Willemsen, Marjolein

AU - Brunner, Han G

AU - Sinnema, Margje

AU - De Vries, Bert B A

AU - Gerkes, Erica H

AU - Pfundt, Rolph

AU - Izumi, Kosuke

AU - Krantz, Ian D

AU - Xu, Zhou L

AU - Murrell, Jill R

AU - Valenzuela, Irene

AU - Cusco, Ivon

AU - Rovira-Moreno, Eulàlia

AU - Yang, Yaping

AU - Bizaoui, Varoona

AU - Patat, Olivier

AU - Faivre, Laurence

AU - Tran-Mau-Them, Frederic

AU - Vitobello, Antonio

AU - Denommé-Pichon, Anne-Sophie

AU - Philippe, Christophe

AU - Bezieau, Stéphane

AU - Cogné, Benjamin

PY - 2022/8

Y1 - 2022/8

N2 - PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

AB - PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

U2 - 10.1016/j.gim.2022.04.011

DO - 10.1016/j.gim.2022.04.011

M3 - Article

C2 - 35567594

SN - 1098-3600

VL - 24

SP - 1774

EP - 1780

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 8

ER -