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Human Genetics

, Volume 138, Issue 11–12, pp 1409–1417 | Cite as

Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD)

  • Lorida Llaci
  • Keri Ramsey
  • Newell Belnap
  • Ana M. Claasen
  • Chris D. Balak
  • Szabolcs Szelinger
  • Wayne M. Jepsen
  • Ashley L. Siniard
  • Ryan Richholt
  • Tyler Izat
  • Marcus Naymik
  • Matt De Both
  • Ignazio S. Piras
  • David W. Craig
  • Matthew J. Huentelman
  • Vinodh Narayanan
  • Isabelle SchrauwenEmail author
  • Sampathkumar RangasamyEmail author
Original Investigation

Abstract

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient’s blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.

Notes

Acknowledgements

The authors thank the family for participating in this study and all the previous members of the C4RCD research group not included in the author list.

Funding

This work was supported by the TGen Foundation funding to Center for Rare Childhood Disorders (C4RCD).

Compliance with ethical standards

Conflict of interest

The authors have no competing interests to disclose.

Informed consent

Written informed consent for publication of clinical details and clinical images was obtained from the legally authorized representative and the patient’s family. The study protocol and consent procedure was approved by the Western Institutional Review Board (WIRB; study number 20120789). 

Supplementary material

439_2019_2077_MOESM1_ESM.tiff (77 kb)
List of genes known to cause Pelizaeus-Merzbacher-like disease (TIFF 76 kb)
439_2019_2077_MOESM2_ESM.tiff (94 kb)
A list of variants of unknown significance (VUS) found by WES in our patient. Maximum MAF cut-off is 0.001 (ExAC, ESP, 1000G). Listed are also number of homozygotes, heterozygotes or hemizygotes found in the gnomAD database (TIFF 94 kb)
439_2019_2077_MOESM3_ESM.tif (1 mb)
Images of the patient at 12 years of age, showing acne in the Front chest (A), Back (B), Hand (C), and Leg (D) (TIFF 1051 kb)
439_2019_2077_MOESM4_ESM.tif (331 kb)
Heatmap of expression of the significantly dysregulated genes between the patient and unaffected age-matched controls (DeSeq 2; PAdj < 0.05). Expression values are plotted as Rlog (counts) (TIFF 331 kb)

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Copyright information

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

Authors and Affiliations

  • Lorida Llaci
    • 1
    • 2
  • Keri Ramsey
    • 1
    • 2
  • Newell Belnap
    • 1
    • 2
  • Ana M. Claasen
    • 1
    • 2
  • Chris D. Balak
    • 1
    • 2
  • Szabolcs Szelinger
    • 1
    • 2
  • Wayne M. Jepsen
    • 1
    • 2
  • Ashley L. Siniard
    • 1
    • 2
  • Ryan Richholt
    • 1
    • 2
  • Tyler Izat
    • 1
  • Marcus Naymik
    • 1
    • 2
  • Matt De Both
    • 1
    • 2
  • Ignazio S. Piras
    • 1
    • 2
  • David W. Craig
    • 1
    • 2
    • 3
  • Matthew J. Huentelman
    • 1
    • 2
  • Vinodh Narayanan
    • 1
    • 2
  • Isabelle Schrauwen
    • 1
    • 2
    • 4
    Email author
  • Sampathkumar Rangasamy
    • 1
    • 2
    Email author
  1. 1.Center for Rare Childhood Disorders, Translational Genomics Research InstitutePhoenixUSA
  2. 2.Neurogenomics DivisionTranslational Genomics Research InstitutePhoenixUSA
  3. 3.Department of Translational GenomicsUniversity of Southern CaliforniaLos AngelesUSA
  4. 4.Center for Statistical Genetics, Department of Neurology, Gertrude H. Sergievsky CenterColumbia University Medical CenterNew YorkUSA

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