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Human Genetics

, Volume 136, Issue 4, pp 409–420 | Cite as

Exome analysis of Smith–Magenis-like syndrome cohort identifies de novo likely pathogenic variants

  • Seth I. Berger
  • Carla Ciccone
  • Karen L. Simon
  • May Christine Malicdan
  • Thierry Vilboux
  • Charles Billington
  • Roxanne Fischer
  • Wendy J. Introne
  • Andrea Gropman
  • Jan K. Blancato
  • James C. Mullikin
  • NISC Comparative Sequencing Program
  • William A. Gahl
  • Marjan Huizing
  • Ann C. M. SmithEmail author
Original Investigation

Abstract

Smith–Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader–Willi Syndrome (PWS) region. This can help clarify NDN’s role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.

Keywords

Intellectual Disability Intellectual Disability Exome Sequencing Missense Variant Exome Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank the SMS-like patients and their families for participating in this study. The authors appreciate the support of Settara C Chandrasekharappa, Ph.D., and the Genomics Core of the National Human Genome Research Institute, NIH. This study was partially supported by an NIH Bench to Bedside award (to ACM Smith) and by the Intramural Research Program of the National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethics standards.

Supplementary material

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Supplementary material 1 (DOCX 13 kb)
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Supplementary material 2 (JPEG 834 kb)
439_2017_1767_MOESM3_ESM.xlsx (770 kb)
Supplementary material 3 (XLSX 770 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2017

Authors and Affiliations

  • Seth I. Berger
    • 1
  • Carla Ciccone
    • 1
  • Karen L. Simon
    • 1
  • May Christine Malicdan
    • 1
  • Thierry Vilboux
    • 1
    • 5
  • Charles Billington
    • 1
  • Roxanne Fischer
    • 1
  • Wendy J. Introne
    • 2
  • Andrea Gropman
    • 3
  • Jan K. Blancato
    • 4
  • James C. Mullikin
    • 6
  • NISC Comparative Sequencing Program
    • 6
  • William A. Gahl
    • 1
    • 2
  • Marjan Huizing
    • 1
  • Ann C. M. Smith
    • 2
    Email author
  1. 1.Medical Genetics Branch, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Office of Clinical Director, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Children’s National Medical CenterWashingtonUSA
  4. 4.Department of OncologyGeorgetown University Medical CenterWashingtonUSA
  5. 5.Division of Medical GenomicsInova Translational Medicine InstituteFalls ChurchUSA
  6. 6.NIH Intramural Sequencing Center (NISC), National Human Genome Research InstituteNational Institutes of HealthRockvilleUSA

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