Vol.:(0123456789) 1 3 Human Genetics https://doi.org/10.1007/s00439-019-02077-7 ORIGINAL INVESTIGATION Compound heterozygous mutations in SNAP29 is associated with Pelizaeus‑Merzbacher‑like disorder (PMLD) 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  · Sampathkumar Rangasamy 1,2 Received: 28 July 2019 / Accepted: 22 October 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clini- cally 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 kerato- derma, 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. Introduction Pelizaeus-Merzbacher disease (PMD; MIM #312080) is a rare, X-linked recessive hypomyelinating leukodystrophy with prevalence among males of 1:200,000–1:500,000. PMD is a prototypic hypomyelinating leukodystrophy (HLD) with classic clinical features including congenital nystagmus, developmental delay, ataxia, progressive spasticity, and dif- fuse abnormality of the white matter on brain magnetic reso- nance imaging (MRI). PMD is caused by mutations in PLP1, encoding for myelin proteolipid protein, a major protein component of central nervous system myelin (Madry et al. 2010). The clinically similar disease, Pelizaeus-Merzbacher- like disease (PMLD; MIM #608804), shares several features of PMD; however, patients with PMLD typically possess better cognitive and motor function. In addition, PMLD is usually inherited in an autosomal recessive manner in both males and females (Biancheri et al. 2013) and exhibits Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-019-02077-7) contains supplementary material, which is available to authorized users. * Isabelle Schrauwen isabelle.schrauwen@gmail.com * Sampathkumar Rangasamy srangasamy@tgen.org 1 Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA 2 Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA 3 Present Address: Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA 4 Present Address: Center for Statistical Genetics, Department of Neurology, Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA