The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Fanny Kortüm, Soma Das, Max Flindt, Deborah J. Morris-Rosendahl, Irina Stefanova, Amy Goldstein, Denise Horn, Eva Klopocki, Gerhard Kluger, Peter Martin, Anita Rauch, Agathe Roumer, Sulagna Saitta, Larry Walsh, Dagmar Wieczorek, Gökhan Uyanik, Kerstin Kutsche, William B. Dobyns

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions: These findings have significantly expanded the number of FOXG1mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

Original languageEnglish
Pages (from-to)396-406
Number of pages11
JournalJournal of Medical Genetics
Volume48
Issue number6
DOIs
StatePublished - Jun 2011

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Agenesis of Corpus Callosum
Microcephaly
Dyskinesias
Intellectual Disability
Language
Phenotype
Mutation
Rett Syndrome
Crying
Chromosome Deletion
Language Development
Comparative Genomic Hybridization
Cytogenetic Analysis
Frontal Lobe
Autistic Disorder
Gastroesophageal Reflux
Fluorescence In Situ Hybridization
Neuroimaging
Epilepsy
Sleep

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. / Kortüm, Fanny; Das, Soma; Flindt, Max; Morris-Rosendahl, Deborah J.; Stefanova, Irina; Goldstein, Amy; Horn, Denise; Klopocki, Eva; Kluger, Gerhard; Martin, Peter; Rauch, Anita; Roumer, Agathe; Saitta, Sulagna; Walsh, Larry; Wieczorek, Dagmar; Uyanik, Gökhan; Kutsche, Kerstin; Dobyns, William B.

In: Journal of Medical Genetics, Vol. 48, No. 6, 06.2011, p. 396-406.

Research output: Contribution to journalArticle

Kortüm, F, Das, S, Flindt, M, Morris-Rosendahl, DJ, Stefanova, I, Goldstein, A, Horn, D, Klopocki, E, Kluger, G, Martin, P, Rauch, A, Roumer, A, Saitta, S, Walsh, L, Wieczorek, D, Uyanik, G, Kutsche, K & Dobyns, WB 2011, 'The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis', Journal of Medical Genetics, vol. 48, no. 6, pp. 396-406. https://doi.org/10.1136/jmg.2010.087528
Kortüm, Fanny ; Das, Soma ; Flindt, Max ; Morris-Rosendahl, Deborah J. ; Stefanova, Irina ; Goldstein, Amy ; Horn, Denise ; Klopocki, Eva ; Kluger, Gerhard ; Martin, Peter ; Rauch, Anita ; Roumer, Agathe ; Saitta, Sulagna ; Walsh, Larry ; Wieczorek, Dagmar ; Uyanik, Gökhan ; Kutsche, Kerstin ; Dobyns, William B. / The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. In: Journal of Medical Genetics. 2011 ; Vol. 48, No. 6. pp. 396-406.
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abstract = "Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions: These findings have significantly expanded the number of FOXG1mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.",
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T1 - The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

AU - Kortüm, Fanny

AU - Das, Soma

AU - Flindt, Max

AU - Morris-Rosendahl, Deborah J.

AU - Stefanova, Irina

AU - Goldstein, Amy

AU - Horn, Denise

AU - Klopocki, Eva

AU - Kluger, Gerhard

AU - Martin, Peter

AU - Rauch, Anita

AU - Roumer, Agathe

AU - Saitta, Sulagna

AU - Walsh, Larry

AU - Wieczorek, Dagmar

AU - Uyanik, Gökhan

AU - Kutsche, Kerstin

AU - Dobyns, William B.

PY - 2011/6

Y1 - 2011/6

N2 - Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions: These findings have significantly expanded the number of FOXG1mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

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