NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Hannah Stamberger; Trine B Hammer; Elena Gardella; Danique R M Vlaskamp; Birgitte Bertelsen; Simone Mandelstam; Iris de Lange; Jing Zhang; Candace T Myers; Christina Fenger; Zaid Afawi; Edith P Almanza Fuerte; Danielle M Andrade; Yunus Balcik; Bruria Ben Zeev; Mark F Bennett; Samuel F Berkovic; Bertrand Isidor; Arjan Bouman; Eva Brilstra; Øyvind L Busk; Anita Cairns; Roseline Caumes; Nicolas Chatron; Russell C Dale; Christa de Geus; Patrick Edery; Deepak Gill; Jakob Bie Granild-Jensen; Lauren Gunderson; Boudewijn Gunning; Gali Heimer; Johan R Helle; Michael S Hildebrand; Georgie Hollingsworth; Volodymyr Kharytonov; Eric W Klee; Bobby P C Koeleman; David A Koolen; Christian Korff; Sébastien Küry; Gaetan Lesca; Dorit Lev; Richard J Leventer; Mark T Mackay; Erica L Macke; Meriel McEntagart; Shekeeb S Mohammad; Pauline Monin; Martino Montomoli; Eva Morava; Sebastien Moutton; Alison M Muir; Elena Parrini; Peter Procopis; Emmanuelle Ranza; Laura Reed; Philipp S Reif; Felix Rosenow; Massimiliano Rossi; Lynette G Sadleir; Tara Sadoway; Helenius J Schelhaas; Amy L Schneider; Krati Shah; Ruth Shalev; Sanjay M Sisodiya; Thomas Smol; Connie T R M Stumpel; Kyra Stuurman; Joseph D Symonds; Frederic Tran Mau-Them; Nienke Verbeek; Judith S Verhoeven; Geoffrey Wallace; Keren Yosovich; Yuri A Zarate; Ayelet Zerem; Sameer M Zuberi; Renzo Guerrini; Heather C Mefford; Chirag Patel; Yue-Hua Zhang; Rikke S Møller; Ingrid E Scheffer

doi:10.1038/s41436-020-00988-9

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Hannah Stamberger, Trine B Hammer, Elena Gardella, Danique R M Vlaskamp, Birgitte Bertelsen, Simone Mandelstam, Iris de Lange, Jing Zhang, Candace T Myers, Christina Fenger, Zaid Afawi, Edith P Almanza Fuerte, Danielle M Andrade, Yunus Balcik, Bruria Ben Zeev, Mark F Bennett, Samuel F Berkovic, Bertrand Isidor, Arjan Bouman, Eva BrilstraØyvind L Busk, Anita Cairns, Roseline Caumes, Nicolas Chatron, Russell C Dale, Christa de Geus, Patrick Edery, Deepak Gill, Jakob Bie Granild-Jensen, Lauren Gunderson, Boudewijn Gunning, Gali Heimer, Johan R Helle, Michael S Hildebrand, Georgie Hollingsworth, Volodymyr Kharytonov, Eric W Klee, Bobby P C Koeleman, David A Koolen, Christian Korff, Sébastien Küry, Gaetan Lesca, Dorit Lev, Richard J Leventer, Mark T Mackay, Erica L Macke, Meriel McEntagart, Shekeeb S Mohammad, Pauline Monin, Martino Montomoli, Eva Morava, Sebastien Moutton, Alison M Muir, Elena Parrini, Peter Procopis, Emmanuelle Ranza, Laura Reed, Philipp S Reif, Felix Rosenow, Massimiliano Rossi, Lynette G Sadleir, Tara Sadoway, Helenius J Schelhaas, Amy L Schneider, Krati Shah, Ruth Shalev, Sanjay M Sisodiya, Thomas Smol, Connie T R M Stumpel, Kyra Stuurman, Joseph D Symonds, Frederic Tran Mau-Them, Nienke Verbeek, Judith S Verhoeven, Geoffrey Wallace, Keren Yosovich, Yuri A Zarate, Ayelet Zerem, Sameer M Zuberi, Renzo Guerrini, Heather C Mefford, Chirag Patel, Yue-Hua Zhang, Rikke S Møller, Ingrid E Scheffer

Department of Clinical Medicine - Børneafdeling, Randers

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

41 Citations (Scopus)

Abstract

PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Original language	English
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	23
Issue	2
Pages (from-to)	363-373
Number of pages	11
ISSN	1098-3600
DOIs	https://doi.org/10.1038/s41436-020-00988-9
Publication status	Published - Feb 2021

Keywords

Autism Spectrum Disorder/genetics
Brain Diseases/genetics
Epilepsy/genetics
Female
Genes, X-Linked/genetics
Humans
Male
Nerve Tissue Proteins
Seizures/genetics

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10.1038/s41436-020-00988-9

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Stamberger, H., Hammer, T. B., Gardella, E., Vlaskamp, D. R. M., Bertelsen, B., Mandelstam, S., de Lange, I., Zhang, J., Myers, C. T., Fenger, C., Afawi, Z., Almanza Fuerte, E. P., Andrade, D. M., Balcik, Y., Ben Zeev, B., Bennett, M. F., Berkovic, S. F., Isidor, B., Bouman, A., ... Scheffer, I. E. (2021). NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genetics in medicine : official journal of the American College of Medical Genetics, 23(2), 363-373. https://doi.org/10.1038/s41436-020-00988-9

@article{e11315320dbb452bb498161c14d65f97,

title = "NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns",

abstract = "PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.",

keywords = "Autism Spectrum Disorder/genetics, Brain Diseases/genetics, Epilepsy/genetics, Female, Genes, X-Linked/genetics, Humans, Male, Nerve Tissue Proteins, Seizures/genetics",

author = "Hannah Stamberger and Hammer, {Trine B} and Elena Gardella and Vlaskamp, {Danique R M} and Birgitte Bertelsen and Simone Mandelstam and {de Lange}, Iris and Jing Zhang and Myers, {Candace T} and Christina Fenger and Zaid Afawi and {Almanza Fuerte}, {Edith P} and Andrade, {Danielle M} and Yunus Balcik and {Ben Zeev}, Bruria and Bennett, {Mark F} and Berkovic, {Samuel F} and Bertrand Isidor and Arjan Bouman and Eva Brilstra and Busk, {{\O}yvind L} and Anita Cairns and Roseline Caumes and Nicolas Chatron and Dale, {Russell C} and {de Geus}, Christa and Patrick Edery and Deepak Gill and Granild-Jensen, {Jakob Bie} and Lauren Gunderson and Boudewijn Gunning and Gali Heimer and Helle, {Johan R} and Hildebrand, {Michael S} and Georgie Hollingsworth and Volodymyr Kharytonov and Klee, {Eric W} and Koeleman, {Bobby P C} and Koolen, {David A} and Christian Korff and S{\'e}bastien K{\"u}ry and Gaetan Lesca and Dorit Lev and Leventer, {Richard J} and Mackay, {Mark T} and Macke, {Erica L} and Meriel McEntagart and Mohammad, {Shekeeb S} and Pauline Monin and Martino Montomoli and Eva Morava and Sebastien Moutton and Muir, {Alison M} and Elena Parrini and Peter Procopis and Emmanuelle Ranza and Laura Reed and Reif, {Philipp S} and Felix Rosenow and Massimiliano Rossi and Sadleir, {Lynette G} and Tara Sadoway and Schelhaas, {Helenius J} and Schneider, {Amy L} and Krati Shah and Ruth Shalev and Sisodiya, {Sanjay M} and Thomas Smol and Stumpel, {Connie T R M} and Kyra Stuurman and Symonds, {Joseph D} and Mau-Them, {Frederic Tran} and Nienke Verbeek and Verhoeven, {Judith S} and Geoffrey Wallace and Keren Yosovich and Zarate, {Yuri A} and Ayelet Zerem and Zuberi, {Sameer M} and Renzo Guerrini and Mefford, {Heather C} and Chirag Patel and Yue-Hua Zhang and M{\o}ller, {Rikke S} and Scheffer, {Ingrid E}",

year = "2021",

month = feb,

doi = "10.1038/s41436-020-00988-9",

language = "English",

volume = "23",

pages = "363--373",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier B.V.",

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Stamberger, H, Hammer, TB, Gardella, E, Vlaskamp, DRM, Bertelsen, B, Mandelstam, S, de Lange, I, Zhang, J, Myers, CT, Fenger, C, Afawi, Z, Almanza Fuerte, EP, Andrade, DM, Balcik, Y, Ben Zeev, B, Bennett, MF, Berkovic, SF, Isidor, B, Bouman, A, Brilstra, E, Busk, ØL, Cairns, A, Caumes, R, Chatron, N, Dale, RC, de Geus, C, Edery, P, Gill, D, Granild-Jensen, JB, Gunderson, L, Gunning, B, Heimer, G, Helle, JR, Hildebrand, MS, Hollingsworth, G, Kharytonov, V, Klee, EW, Koeleman, BPC, Koolen, DA, Korff, C, Küry, S, Lesca, G, Lev, D, Leventer, RJ, Mackay, MT, Macke, EL, McEntagart, M, Mohammad, SS, Monin, P, Montomoli, M, Morava, E, Moutton, S, Muir, AM, Parrini, E, Procopis, P, Ranza, E, Reed, L, Reif, PS, Rosenow, F, Rossi, M, Sadleir, LG, Sadoway, T, Schelhaas, HJ, Schneider, AL, Shah, K, Shalev, R, Sisodiya, SM, Smol, T, Stumpel, CTRM, Stuurman, K, Symonds, JD, Mau-Them, FT, Verbeek, N, Verhoeven, JS, Wallace, G, Yosovich, K, Zarate, YA, Zerem, A, Zuberi, SM, Guerrini, R, Mefford, HC, Patel, C, Zhang, Y-H, Møller, RS & Scheffer, IE 2021, 'NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 23, no. 2, pp. 363-373. https://doi.org/10.1038/s41436-020-00988-9

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. / Stamberger, Hannah; Hammer, Trine B; Gardella, Elena et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 23, No. 2, 02.2021, p. 363-373.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - NEXMIF encephalopathy

T2 - an X-linked disorder with male and female phenotypic patterns

AU - Stamberger, Hannah

AU - Hammer, Trine B

AU - Gardella, Elena

AU - Vlaskamp, Danique R M

AU - Bertelsen, Birgitte

AU - Mandelstam, Simone

AU - de Lange, Iris

AU - Zhang, Jing

AU - Myers, Candace T

AU - Fenger, Christina

AU - Afawi, Zaid

AU - Almanza Fuerte, Edith P

AU - Andrade, Danielle M

AU - Balcik, Yunus

AU - Ben Zeev, Bruria

AU - Bennett, Mark F

AU - Berkovic, Samuel F

AU - Isidor, Bertrand

AU - Bouman, Arjan

AU - Brilstra, Eva

AU - Busk, Øyvind L

AU - Cairns, Anita

AU - Caumes, Roseline

AU - Chatron, Nicolas

AU - Dale, Russell C

AU - de Geus, Christa

AU - Edery, Patrick

AU - Gill, Deepak

AU - Granild-Jensen, Jakob Bie

AU - Gunderson, Lauren

AU - Gunning, Boudewijn

AU - Heimer, Gali

AU - Helle, Johan R

AU - Hildebrand, Michael S

AU - Hollingsworth, Georgie

AU - Kharytonov, Volodymyr

AU - Klee, Eric W

AU - Koeleman, Bobby P C

AU - Koolen, David A

AU - Korff, Christian

AU - Küry, Sébastien

AU - Lesca, Gaetan

AU - Lev, Dorit

AU - Leventer, Richard J

AU - Mackay, Mark T

AU - Macke, Erica L

AU - McEntagart, Meriel

AU - Mohammad, Shekeeb S

AU - Monin, Pauline

AU - Montomoli, Martino

AU - Morava, Eva

AU - Moutton, Sebastien

AU - Muir, Alison M

AU - Parrini, Elena

AU - Procopis, Peter

AU - Ranza, Emmanuelle

AU - Reed, Laura

AU - Reif, Philipp S

AU - Rosenow, Felix

AU - Rossi, Massimiliano

AU - Sadleir, Lynette G

AU - Sadoway, Tara

AU - Schelhaas, Helenius J

AU - Schneider, Amy L

AU - Shah, Krati

AU - Shalev, Ruth

AU - Sisodiya, Sanjay M

AU - Smol, Thomas

AU - Stumpel, Connie T R M

AU - Stuurman, Kyra

AU - Symonds, Joseph D

AU - Mau-Them, Frederic Tran

AU - Verbeek, Nienke

AU - Verhoeven, Judith S

AU - Wallace, Geoffrey

AU - Yosovich, Keren

AU - Zarate, Yuri A

AU - Zerem, Ayelet

AU - Zuberi, Sameer M

AU - Guerrini, Renzo

AU - Mefford, Heather C

AU - Patel, Chirag

AU - Zhang, Yue-Hua

AU - Møller, Rikke S

AU - Scheffer, Ingrid E

PY - 2021/2

Y1 - 2021/2

N2 - PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

AB - PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

KW - Autism Spectrum Disorder/genetics

KW - Brain Diseases/genetics

KW - Epilepsy/genetics

KW - Female

KW - Genes, X-Linked/genetics

KW - Humans

KW - Male

KW - Nerve Tissue Proteins

KW - Seizures/genetics

UR - http://www.scopus.com/inward/record.url?scp=85094911047&partnerID=8YFLogxK

U2 - 10.1038/s41436-020-00988-9

DO - 10.1038/s41436-020-00988-9

M3 - Journal article

C2 - 33144681

SN - 1098-3600

VL - 23

SP - 363

EP - 373

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 2

ER -

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

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