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Journal of Autism and Developmental Disorders

, Volume 48, Issue 8, pp 2886–2889 | Cite as

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide the Forest?

  • Caroline Demily
  • Gaétan Lesca
  • Alice Poisson
  • Marianne Till
  • Giulia Barcia
  • Nicolas Chatron
  • Damien Sanlaville
  • Arnold Munnich
Letter to the Editor

Abstract

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

Keywords

22q11.2 duplication Incomplete penetrance Genetic counseling Autism spectrum disorders Next generation sequencing Epilepsy 

Notes

Acknowledgments

Pr Nicolas Franck for his advice and le Vinatier Hospital for its support.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Caroline Demily
    • 1
  • Gaétan Lesca
    • 2
    • 3
  • Alice Poisson
    • 1
  • Marianne Till
    • 2
  • Giulia Barcia
    • 4
  • Nicolas Chatron
    • 2
    • 3
  • Damien Sanlaville
    • 2
    • 3
  • Arnold Munnich
    • 4
  1. 1.Centre de Référence Maladies Rares GénoPsy, Centre Hospitalier le VinatierBron et UMR 5229 (CNRS & Université Lyon 1)BronFrance
  2. 2.Hospices Civils de Lyon, Centre de Référence des Anomalies du Développement, Laboratoire de CytogénétiqueGHELyonFrance
  3. 3.Centre de Recherche en Neurosciences de LyonInserm U1028, UMR CNRS 5292, Université Claude Bernard Lyon 1LyonFrance
  4. 4.Département de génétique médicale, Institut Imagine, Hôpital Necker-Enfants MaladesINSERM UMR 1163, Université Paris Descartes-SorbonneParisFrance

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