New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

ObjectiveTo report 6 new patients with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome.MethodsClinical exome or targeted sequencing were performed to elucidate the molecular genetic cause in patients with neurocognitive abnormalities and brain imaging findings.ResultsCEDNIK syndrome is a rare genetic condition caused by biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29), which encodes a vesicular membrane fusion protein. Clinical manifestations include significant developmental delay/intellectual disability (DD/ID), brain abnormalities, failure to thrive, and skin abnormalities. To date, 19 patients from 10 unrelated families with CEDNIK syndrome have been reported. We report 5 additional patients with homozygous predicted loss-of-function variants in SNAP29 and one with compound heterozygous variants: a frameshift SNAP29 variant and a 370 kb deletion on 22q11.2. All patients exhibit DD/ID, ichthyosis and/or palmoplantar keratoderma, and hypotonia. Four of 6 subjects had hypomyelinated white matter on MRI, 2 of 6 had early puberty, and 4 of 6 had strabismus, which were previously rarely reported. Other phenotypes were variably present, including dysmorphic features, feeding difficulties, and recurrent respiratory infections. The cohort includes 2 siblings with a c.2T>C variant who have a relatively milder phenotype, a patient with the most C-terminal variant yet described (c.622G>T), and 3 patients with previously described variants (c.354dupG, c.487dupA).ConclusionsThis cohort of 6 additional patients expands the genotypic and phenotypic spectrum of CEDNIK syndrome, highlighting previously under-recognized features such as hypomyelination, seizures, and early puberty. Owing to reduced penetrance of the skin phenotype, cerebral dysgenesis, and neuropathy, we propose renaming this syndrome SNAP29-related disorder.