Families

Prevalence
Currently, 12 patients with DENNED are known reported with biallelic variants of ZNF526although some data from the previous cases are incomplete. To date, phenotypic details have been reported for only seven patients with ZNF526variants.

Main clinical features
The patients with DENNED presented with developmental delay, microcephaly (ranging from -2 SD to -8 SD), abnormal brain imaging, and seizures.

All patients showed a severe to profound developmental delay and severe intellectual disability which did not allow to perform a formal IQ testing. Language was severely impaired and no patient was able to pronounce meaningful words. Neurological examination disclosed axial hypotonia and spastic hypertonic–dystonic tetraparesis in all patients except one patient with homozygous missense variant who achieved standing and walking abilities. Epilepsy occurred in the majority of patients, including drug-resistant myoclonic seizures, infantile spasms that evolved into refractory epilepsy with distinct seizure types. Brain MRI disclosed simplified gyration, thinning of corpus callosum, full anterior horns of the ventricles, and slightly widened extracerebral spaces in the frontoparietal temporal region bilateral. One patient with homozygous variant had a normal brain MRI. No additional congenital malformations were noted.

Recurrent subtle facial features identified were mainly secondary to microcephaly, including sloping forehead, high nasal bridge and enlarged ears. Additional dysmorphisms included hypertelorism, upslanting palpebral fissures, fleshy lobules, thin upper lip, pointed chin and small widely spaced teeth.

Inheritance
The inheritance pattern is autosomal recessive. Six carried homozygous LOF variants, four had homozygous missense variants, and two had compound heterozygous variants.