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Human Genetics

, Volume 138, Issue 2, pp 187–198 | Cite as

Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy

  • Marco FicheraEmail author
  • Pinella Failla
  • Lucia Saccuzzo
  • Martina Miceli
  • Eliana Salvo
  • Lucia Castiglia
  • Ornella Galesi
  • Lucia Grillo
  • Francesco Calì
  • Donatella Greco
  • Carmelo Amato
  • Corrado Romano
  • Maurizio Elia
Original Investigation
  • 120 Downloads

Abstract

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene–disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.

Notes

Acknowledgements

We thank the probands and their families for the participation in this study. For technical support, we acknowledge the participation of Drs. Silvestra Amata, Angela Spalletta, Maurizio Sturnio, and Pietro Schinocca from the Laboratory of Medical Genetics, Oasi Research Institute—IRCCS, Troina (Italy). We also thank Dr. Anthony Charles for the English language editing. This work was funded by Grant RF-2011-02350693 from the Italian Ministry of Health to Marco Fichera.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Financial disclosures

The authors report no disclosures relevant to the manuscript.

Supplementary material

439_2019_1972_MOESM1_ESM.docx (3.2 mb)
Supplementary material 1 (DOCX 3307 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Marco Fichera
    • 1
    • 2
    Email author
  • Pinella Failla
    • 2
  • Lucia Saccuzzo
    • 1
  • Martina Miceli
    • 1
  • Eliana Salvo
    • 1
  • Lucia Castiglia
    • 2
  • Ornella Galesi
    • 2
  • Lucia Grillo
    • 2
  • Francesco Calì
    • 2
  • Donatella Greco
    • 2
  • Carmelo Amato
    • 2
  • Corrado Romano
    • 2
  • Maurizio Elia
    • 2
  1. 1.Medical Genetics, Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  2. 2.Oasi Research Institute-IRCCSTroinaItaly

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