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

Abstract

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.

CEDNIK syndrome with phenotypic variability

“…Our patients had most features of CEDNIK syndrome previously described except palmoplantar keratoderma, and the presence of verrucous venous malformation in the older sibling. Absent palmoplantar keratoderma/ichthyosis has been documented earlier in a few families with SNAP29 pathogenic variants 3–5 . Due to the lack of these features some families were not reported as CEDNIK syndrome 4,5 .…”

“…Absent palmoplantar keratoderma/ichthyosis has been documented earlier in a few families with SNAP29 pathogenic variants. [3][4][5] Due to the lack of these features some families were not reported as CEDNIK syndrome. 4,5 Based on incomplete penetrance for ichthyosis, keratoderma, neuropathy, and cerebral dysgenesis in some families,…”

“…11 homozygous or compound heterozygous pathogenic variants in SNAP29 have been reported to cause CEDNIK syndrome but no phenotypic-genotypic correlation has been observed. 3 SNAP proteins are t-SNARE proteins that must form a complex with v-SNARE proteins located on vesicle membranes for fusion and subsequent secretion of vesicle content to occur. SNAP29 deficiency in CEDNIK syndrome results in markedly impaired maturation and secretion of lamellar granules leading to mislocation of epidermal lipids and proteases, resulting in ichthyosiform skin changes.…”

“…Mah-Som et al3 propose that the patients with SNAP29 pathogenic variants irrespective of their phenotypic characteristics should be labeled as SNAP29-related disorders instead of CEDNIK syndrome. Development of palmoplantar keratoderma in the later years of age in some patients cannot be ruled out.…”

Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

“…Namely, 5 frameshifts, 2 nonsense and 3 missense ( 112 ). Mutations in SNAP29 have been linked to CEDNIK syndrome, whose clinical features include microcephaly, severe neurologic impairment, psychomotor retardation, failure to thrive, and facial dysmorphism, as well as palmoplantar keratoderma and late-onset ichthyosis ( 113 ). Global developmental delay and intellectual disability have been reported in all the affected individuals.…”