A number sign (#) is used with this entry because of evidence that White-Kernohan syndrome (WHIKERS) is caused by heterozygous mutation in the DDB1 gene (600045) on chromosome 11q12.

White-Kernohan syndrome (WHIKERS) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, hypotonia, and characteristic facial features. Some patients may have abnormalities of other systems, including genitourinary and skeletal (summary by White et al., 2021).

White et al. (2021) reported 8 unrelated patients, ranging in age from 1 to 17 years, with a similar neurodevelopmental disorder. The patients were ascertained through the GeneMatcher program after undergoing exome sequencing; the phenotypes were assessed as a cohort. All patients had global developmental delay with mildly delayed walking by 2 to 3 years of age, speech and language delay, and variably impaired intellectual development. About half had neonatal complications, such as poor feeding, hypoglycemia, and hypotonia. Some patients were able to understand or speak more than one language and attend special education schools. One patient had an IQ of 69, and another patient had hearing loss. Other variable features included nystagmus, joint laxity, and distal anomalies of the hands and feet, such as brachydactyly, clinodactyly, proximally placed thumbs, and cutaneous syndactyly of the toes. Three of the older patients were obese. All patients had some characteristic facial features, including full cheeks, maxillary hypoplasia, retrognathia, epicanthal folds, telecanthus, deep-set eyes, lateral extension of palpebral fissures, abnormally long or short palpebral fissures, short nose with hypoplastic alae nasi, depressed nasal bridge, large and fleshy low-set ears, strabismus, horizontal straight eyebrows with synophrys, hirsutism, thin and tented upper lip, and short neck. Four patients had genitourinary or gastrointestinal defects, including horseshoe kidney, vesicoureteral reflux, hydronephrosis, bicornuate uterus, anterior anus, rectovaginal fistula, and gastroesophageal reflux. Brain imaging, performed in 5 patients, showed nonspecific abnormalities, including enlarged ventricles, thin corpus callosum, and delayed myelination.

The heterozygous mutations in the DDB1 gene that were identified in patients with WHIKERS by White et al. (2021) occurred de novo.

In 8 unrelated patients with WHIKERS, White et al. (2021) identified 5 different de novo heterozygous mutations in the DDB1 gene (600045.0001-600045.0005). The mutations were found by exome sequencing, and the patients were ascertained through the Matchmaker Exchange Program. There was 1 in-frame deletion and 4 missense mutations; all occurred in the conserved MSS1 domain. Lymphoblasts derived from 2 patients (P2 and P4), who had missense mutations, showed normal DDB1 mRNA and protein levels. In vitro functional studies of these patient cells demonstrated altered DNA damage signaling responses and changes in histone methylation following UV-induced DNA damage compared to controls. The authors suggested either a dominant-negative or gain-of-function effect of the mutations, although a loss-of-function effect could not be excluded.