A study has uncovered several under-recognized features of cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome, including features such as strabismus, hypomyelination, early puberty, and seizures. This may expand the genotypic and phenotypic spectrum of the disease, according to findings published in a recent edition of Neurology Genetics.
Biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29) is implicated in the rare genetic condition known as CEDNIK syndrome. Known manifestations of the syndrome include delayed development and/or intellectual disability, brain abnormalities, skin abnormalities, and failure to thrive. A total of 19 patients from 10 unrelated families with the condition have been described to date.
In this new study, researchers reported the clinical manifestations in 6 additional patients, 5 of whom had homozygous predicted loss-of-function variants in SNAP29 and 1 with compound heterozygous variants (frameshift SNAP29 variant plus 370 kb deletion on 22q11.2). The study researchers performed clinical exomes or targeted sequencing to determine the molecular genetic causative pathway in these patients.
All patients in this study showed signs of delayed development, hypotonia, as well as ichthyosis and/or palmoplantar keratoderma.
Of the 6 patients, 4 demonstrated white matter changes consistent with hypomyelination on magnetic resonance imaging. Additionally, 2 patients entered puberty early and 4 had strabismus, an ocular condition that has been rarely reported in previous patients.
Dysmorphic features, feeding difficulties, and recurrent respiratory infections were variably reported across the cohort. Overall, 2 siblings in this study had a c.2T>C variant and a milder phenotype of the condition. There was 1 patient with the most C-terminal variant yet described (homozygous c.622G>T), while 3 patients had the previously described variants c.354dupG and c.487dupA.
The study researchers concluded that “significant phenotypic variability in patients with SNAP29 variants suggests that CEDNIK syndrome should be defined genetically rather than as a specific constellation of neurologic, brain imaging, and skin findings.”
Mah-Som AY, Skrypnyk C, Guerin A, et al. New cohort of patients with cednik syndrome expands the phenotypic and genotypic spectra. Neurol Genet. 2021;7(1):e553. doi:10.1212/NXG.0000000000000553