FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants

Diana Mitter; Milka Pringsheim; Marc Kaulisch; Kim Sarah Plümacher; Simone Schröder; Rita Warthemann; Rami Abou Jamra; Martina Baethmann; Thomas Bast; Hans Martin Büttel; Julie S. Cohen; Elizabeth Conover; Carolina Courage; Angelika Eger; Ali Fatemi; Theresa A. Grebe; Natalie S. Hauser; Wolfram Heinritz; Katherine L. Helbig; Marion Heruth; Dagmar Huhle; Karen Höft; Stephanie Karch; Gerhard Kluger; G. Christoph Korenke; Johannes R. Lemke; Richard E. Lutz; Steffi Patzer; Isabelle Prehl; Konstanze Hoertnagel; Keri Ramsey; Tina Rating; Angelika Rieß; Luis Rohena; Mareike Schimmel; Rachel Westman; Frank Martin Zech; Barbara Zoll; Dörthe Malzahn; Birgit Zirn; Knut Brockmann

doi:10.1038/gim.2017.75

FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants

Diana Mitter, Milka Pringsheim, Marc Kaulisch, Kim Sarah Plümacher, Simone Schröder, Rita Warthemann, Rami Abou Jamra, Martina Baethmann, Thomas Bast, Hans Martin Büttel, Julie S. Cohen, Elizabeth Conover, Carolina Courage, Angelika Eger, Ali Fatemi, Theresa A. Grebe, Natalie S. Hauser, Wolfram Heinritz, Katherine L. Helbig, Marion HeruthDagmar Huhle, Karen Höft, Stephanie Karch, Gerhard Kluger, G. Christoph Korenke, Johannes R. Lemke, Richard E. Lutz, Steffi Patzer, Isabelle Prehl, Konstanze Hoertnagel, Keri Ramsey, Tina Rating, Angelika Rieß, Luis Rohena, Mareike Schimmel, Rachel Westman, Frank Martin Zech, Barbara Zoll, Dörthe Malzahn, Birgit Zirn, Knut Brockmann

Kennedy Krieger Institute

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

Abstract

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

Original language	English (US)
Pages (from-to)	98-108
Number of pages	11
Journal	Genetics in Medicine
Volume	20
Issue number	1
DOIs	https://doi.org/10.1038/gim.2017.75
State	Published - Jan 1 2018

Keywords

FOXG1 phenotypic spectrum
FOXG1 variants
congenital variant of Rett syndrome
genotype-phenotype association

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/gim.2017.75

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Mitter, D., Pringsheim, M., Kaulisch, M., Plümacher, K. S., Schröder, S., Warthemann, R., Abou Jamra, R., Baethmann, M., Bast, T., Büttel, H. M., Cohen, J. S., Conover, E., Courage, C., Eger, A., Fatemi, A., Grebe, T. A., Hauser, N. S., Heinritz, W., Helbig, K. L., ... Brockmann, K. (2018). FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants. Genetics in Medicine, 20(1), 98-108. https://doi.org/10.1038/gim.2017.75

Mitter, D, Pringsheim, M, Kaulisch, M, Plümacher, KS, Schröder, S, Warthemann, R, Abou Jamra, R, Baethmann, M, Bast, T, Büttel, HM, Cohen, JS, Conover, E, Courage, C, Eger, A, Fatemi, A, Grebe, TA, Hauser, NS, Heinritz, W, Helbig, KL, Heruth, M, Huhle, D, Höft, K, Karch, S, Kluger, G, Korenke, GC, Lemke, JR, Lutz, RE, Patzer, S, Prehl, I, Hoertnagel, K, Ramsey, K, Rating, T, Rieß, A, Rohena, L, Schimmel, M, Westman, R, Zech, FM, Zoll, B, Malzahn, D, Zirn, B & Brockmann, K 2018, 'FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants', Genetics in Medicine, vol. 20, no. 1, pp. 98-108. https://doi.org/10.1038/gim.2017.75

@article{d6af3b3a79b340ceb8a6d6c78456842a,

title = "FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants",

abstract = "PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.",

keywords = "FOXG1 phenotypic spectrum, FOXG1 variants, congenital variant of Rett syndrome, genotype-phenotype association",

author = "Diana Mitter and Milka Pringsheim and Marc Kaulisch and Pl{\"u}macher, {Kim Sarah} and Simone Schr{\"o}der and Rita Warthemann and {Abou Jamra}, Rami and Martina Baethmann and Thomas Bast and B{\"u}ttel, {Hans Martin} and Cohen, {Julie S.} and Elizabeth Conover and Carolina Courage and Angelika Eger and Ali Fatemi and Grebe, {Theresa A.} and Hauser, {Natalie S.} and Wolfram Heinritz and Helbig, {Katherine L.} and Marion Heruth and Dagmar Huhle and Karen H{\"o}ft and Stephanie Karch and Gerhard Kluger and Korenke, {G. Christoph} and Lemke, {Johannes R.} and Lutz, {Richard E.} and Steffi Patzer and Isabelle Prehl and Konstanze Hoertnagel and Keri Ramsey and Tina Rating and Angelika Rie{\ss} and Luis Rohena and Mareike Schimmel and Rachel Westman and Zech, {Frank Martin} and Barbara Zoll and D{\"o}rthe Malzahn and Birgit Zirn and Knut Brockmann",

note = "Publisher Copyright: {\textcopyright} American College of Medical Genetics and Genomics.",

year = "2018",

month = jan,

day = "1",

doi = "10.1038/gim.2017.75",

language = "English (US)",

volume = "20",

pages = "98--108",

journal = "Genetics in Medicine",

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TY - JOUR

T1 - FOXG1 syndrome

T2 - Genotype-phenotype association in 83 patients with FOXG1 variants

AU - Mitter, Diana

AU - Pringsheim, Milka

AU - Kaulisch, Marc

AU - Plümacher, Kim Sarah

AU - Schröder, Simone

AU - Warthemann, Rita

AU - Abou Jamra, Rami

AU - Baethmann, Martina

AU - Bast, Thomas

AU - Büttel, Hans Martin

AU - Cohen, Julie S.

AU - Conover, Elizabeth

AU - Courage, Carolina

AU - Eger, Angelika

AU - Fatemi, Ali

AU - Grebe, Theresa A.

AU - Hauser, Natalie S.

AU - Heinritz, Wolfram

AU - Helbig, Katherine L.

AU - Heruth, Marion

AU - Huhle, Dagmar

AU - Höft, Karen

AU - Karch, Stephanie

AU - Kluger, Gerhard

AU - Korenke, G. Christoph

AU - Lemke, Johannes R.

AU - Lutz, Richard E.

AU - Patzer, Steffi

AU - Prehl, Isabelle

AU - Hoertnagel, Konstanze

AU - Ramsey, Keri

AU - Rating, Tina

AU - Rieß, Angelika

AU - Rohena, Luis

AU - Schimmel, Mareike

AU - Westman, Rachel

AU - Zech, Frank Martin

AU - Zoll, Barbara

AU - Malzahn, Dörthe

AU - Zirn, Birgit

AU - Brockmann, Knut

PY - 2018/1/1

Y1 - 2018/1/1

N2 - PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

AB - PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

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KW - FOXG1 variants

KW - congenital variant of Rett syndrome

KW - genotype-phenotype association

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FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants

Abstract

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