Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome

J. C. Czeschik, C. Voigt, Y. Alanay, B. Albrecht, S. Avci, D. FitzPatrick, D. R. Goudie, U. Hehr, A. J. Hoogeboom, H. Kayserili, P. O. Simsek-Kiper, L. Klein-Hitpass, A. Kuechler, V. Lopez-Gonzalez, M. Martin, S. Rahmann, B. Schweiger, M. Splitt, B. Wollnik, H-J Ludecke & 2 others M. Zeschnigk, D. Wieczorek

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

    Original languageEnglish
    Pages (from-to)885-898
    Number of pages14
    JournalHuman Genetics
    Volume132
    Issue number8
    DOIs
    Publication statusPublished - 2013

    Keywords

    • ATRESIA
    • Thumb hypoplasia
    • EFTUD2
    • Exome sequencing
    • ACROFACIAL DYSOSTOSIS
    • Preaxial limb defect
    • SF3B4
    • MANDIBULOFACIAL DYSOSTOSIS
    • Acrofacial dysostosis
    • COMPONENT
    • Radial hypoplasia
    • HAPLOINSUFFICIENCY
    • TREACHER-COLLINS-SYNDROME

    Cite this

    Czeschik, J. C., Voigt, C., Alanay, Y., Albrecht, B., Avci, S., FitzPatrick, D., ... Wieczorek, D. (2013). Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Human Genetics, 132(8), 885-898. https://doi.org/10.1007/s00439-013-1295-2
    Czeschik, J. C. ; Voigt, C. ; Alanay, Y. ; Albrecht, B. ; Avci, S. ; FitzPatrick, D. ; Goudie, D. R. ; Hehr, U. ; Hoogeboom, A. J. ; Kayserili, H. ; Simsek-Kiper, P. O. ; Klein-Hitpass, L. ; Kuechler, A. ; Lopez-Gonzalez, V. ; Martin, M. ; Rahmann, S. ; Schweiger, B. ; Splitt, M. ; Wollnik, B. ; Ludecke, H-J ; Zeschnigk, M. ; Wieczorek, D. / Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. In: Human Genetics. 2013 ; Vol. 132, No. 8. pp. 885-898.
    @article{39e0eb9f9c884b05a60e9521874188ae,
    title = "Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome",
    abstract = "Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.",
    keywords = "ATRESIA, Thumb hypoplasia, EFTUD2, Exome sequencing, ACROFACIAL DYSOSTOSIS, Preaxial limb defect, SF3B4, MANDIBULOFACIAL DYSOSTOSIS, Acrofacial dysostosis, COMPONENT, Radial hypoplasia, HAPLOINSUFFICIENCY, TREACHER-COLLINS-SYNDROME",
    author = "Czeschik, {J. C.} and C. Voigt and Y. Alanay and B. Albrecht and S. Avci and D. FitzPatrick and Goudie, {D. R.} and U. Hehr and Hoogeboom, {A. J.} and H. Kayserili and Simsek-Kiper, {P. O.} and L. Klein-Hitpass and A. Kuechler and V. Lopez-Gonzalez and M. Martin and S. Rahmann and B. Schweiger and M. Splitt and B. Wollnik and H-J Ludecke and M. Zeschnigk and D. Wieczorek",
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    Czeschik, JC, Voigt, C, Alanay, Y, Albrecht, B, Avci, S, FitzPatrick, D, Goudie, DR, Hehr, U, Hoogeboom, AJ, Kayserili, H, Simsek-Kiper, PO, Klein-Hitpass, L, Kuechler, A, Lopez-Gonzalez, V, Martin, M, Rahmann, S, Schweiger, B, Splitt, M, Wollnik, B, Ludecke, H-J, Zeschnigk, M & Wieczorek, D 2013, 'Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome', Human Genetics, vol. 132, no. 8, pp. 885-898. https://doi.org/10.1007/s00439-013-1295-2

    Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. / Czeschik, J. C.; Voigt, C.; Alanay, Y.; Albrecht, B.; Avci, S.; FitzPatrick, D.; Goudie, D. R.; Hehr, U.; Hoogeboom, A. J.; Kayserili, H.; Simsek-Kiper, P. O.; Klein-Hitpass, L.; Kuechler, A.; Lopez-Gonzalez, V.; Martin, M.; Rahmann, S.; Schweiger, B.; Splitt, M.; Wollnik, B.; Ludecke, H-J; Zeschnigk, M.; Wieczorek, D.

    In: Human Genetics, Vol. 132, No. 8, 2013, p. 885-898.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome

    AU - Czeschik, J. C.

    AU - Voigt, C.

    AU - Alanay, Y.

    AU - Albrecht, B.

    AU - Avci, S.

    AU - FitzPatrick, D.

    AU - Goudie, D. R.

    AU - Hehr, U.

    AU - Hoogeboom, A. J.

    AU - Kayserili, H.

    AU - Simsek-Kiper, P. O.

    AU - Klein-Hitpass, L.

    AU - Kuechler, A.

    AU - Lopez-Gonzalez, V.

    AU - Martin, M.

    AU - Rahmann, S.

    AU - Schweiger, B.

    AU - Splitt, M.

    AU - Wollnik, B.

    AU - Ludecke, H-J

    AU - Zeschnigk, M.

    AU - Wieczorek, D.

    PY - 2013

    Y1 - 2013

    N2 - Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

    AB - Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

    KW - ATRESIA

    KW - Thumb hypoplasia

    KW - EFTUD2

    KW - Exome sequencing

    KW - ACROFACIAL DYSOSTOSIS

    KW - Preaxial limb defect

    KW - SF3B4

    KW - MANDIBULOFACIAL DYSOSTOSIS

    KW - Acrofacial dysostosis

    KW - COMPONENT

    KW - Radial hypoplasia

    KW - HAPLOINSUFFICIENCY

    KW - TREACHER-COLLINS-SYNDROME

    U2 - 10.1007/s00439-013-1295-2

    DO - 10.1007/s00439-013-1295-2

    M3 - Article

    VL - 132

    SP - 885

    EP - 898

    JO - Human Genetics

    JF - Human Genetics

    SN - 0340-6717

    IS - 8

    ER -

    Czeschik JC, Voigt C, Alanay Y, Albrecht B, Avci S, FitzPatrick D et al. Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Human Genetics. 2013;132(8):885-898. https://doi.org/10.1007/s00439-013-1295-2