Skraban-Deardorff Syndrome

A number sign (#) is used with this entry because of evidence that Skraban-Deardorff syndrome (SKDEAS) is caused by heterozygous mutation in the WDR26 gene (617424) on chromosome 1q42.

Description

Skraban-Deardorff syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development with variable intellectual disability, early-onset seizures, and characteristic dysmorphic facial features comprising coarse facies with a prominent maxilla and upper lip revealing the upper gingiva, widely-spaced teeth, and a broad nasal tip (summary by Skraban et al., 2017).

Clinical Features

Skraban et al. (2017) reported 15 unrelated individuals, ranging in age from 24 months to 34 years, with a syndromic form of intellectual disability apparent since infancy. All patients had global developmental delay that varied in severity from mild to severe, and all had some form of speech delay, including several with absent speech between 4 and 8 years of age. Motor delay was common, with delayed sitting, crawling, and walking, and 9 patients had mild hypotonia. Walking was acquired between 17 months and 3 years, although most had an abnormal spastic, stiff, or wide-based gait. All patients had onset of seizures in infancy or in childhood, although the seizure type varied and included febrile, nonfebrile, tonic-clonic, absence, and Rolandic seizures. Nine patients had minor variable structural brain abnormalities, including dilated ventricles, thin corpus callosum, white matter volume loss, and pineal cysts; opercular dysplasia and pachygyria was found in 1 patient. However, several patients had normal brain imaging. The patients had a distinctive gestalt with coarse facial features and common abnormalities, including prominent maxilla and upper lip (13 patients), wide mouth (10), abnormal gingiva (9), widely spaced teeth (13), full cheeks in childhood (11), large irises with rounded palpebral fissures (10), strabismus and/or amblyopia (9), broad or full nasal tip (11), and cupid bow of the lip (11). Less common features included anteverted nares (8), depressed nasal bridge (5), sparse lateral eyebrows (6), and mild micrognathia (5). Many patients had nonspecific gastrointestinal abnormalities, mainly constipation, gastric reflux, or poor feeding, and several had recurrent otitis media in the absence of an immune disorder. Rare features included cardiac defects and minor skeletal anomalies. The patients had a happy demeanor overall; some had repetitive behaviors or autistic features. Skraban et al. (2017) noted that the phenotype in these patients showed overlap with that of chromosome 1q41-q42 deletion syndrome (612530).

Molecular Genetics

In 15 unrelated patients with Skraban-Deardorff syndrome, Skraban et al. (2017) identified 15 different de novo heterozygous mutations in the WDR26 gene (see, e.g., 617424.0001-617424.0006). There were 5 frameshift, 5 nonsense, 1 splice site, and 4 missense mutations. Analysis of patient cells from 3 patients, including 2 with truncating mutations (617424.0002 and 617424.0004) and 1 with a missense mutation (D284N; 617424.0005), showed that the truncating mutations resulted in significantly decreased mRNA and protein levels and the missense mutation resulted in slightly decreased mRNA and protein levels, suggesting haploinsufficiency as the pathogenic mechanism. Further functional studies and studies of the other variants were not performed. Skraban et al. (2017) postulated that reduced expression of WDR26 may alter multiple signaling pathways and cellular mechanisms. The patients, all of whom were of European descent or from the United States, were ascertained from several different large patient cohorts and gene repository databases; all mutations were found by trio-based exome sequencing. The frequency of WDR26 mutations was about 1 in 2,000 for all exome analyses and about 1 in 1,500 for individuals with intellectual disability, suggesting that this disorder may not be uncommon. Skraban et al. (2017) suggested that WDR26 may be the likely candidate gene whose haploinsufficiency is the cause of 1q41-q42 deletion syndrome, as it lies within the deleted region in most of those patients.