A number sign (#) is used with this entry because of evidence that DeSanto-Shinawi syndrome (DESSH) is caused by heterozygous mutation in the WAC gene (615049) on chromosome 10p11.
Some patients with an overlapping phenotype have a deletion at chromosome 10p12-p11 encompassing several genes and consistent with a contiguous gene deletion syndrome.
DeSanto et al. (2015) reported 6 children, including 2 sibs, of various ethnic origins, with global developmental delay noted in the first year of life and dysmorphic features. The patients ranged from 15 months to 11 years in age at the time of the report. Two patients were non-verbal, and the others showed delayed language acquisition. Behavioral abnormalities were variable but common, and included aggression, anxiety, and attention deficit-hyperactivity disorder, and autistic features. All had hypotonia and gastrointestinal difficulties, mainly feeding difficulties and constipation. Dysmorphic features included broad, prominent forehead, flat nasal bridge with bulbous tip and flaring nostrils, hypertelorism, synophrys, and strabismus. More variable dysmorphic features included brachycephaly, deep-set eyes, posteriorly rotated and/or simple ears, thin upper lip, downturned mouth, inverted nipples. Three patients had myopia and astigmatism, and an unrelated patient had sensorineural hearing loss.
Wentzel et al. (2011) reported 6 unrelated children with developmental delay and common dysmorphic features associated with a heterozygous de novo deletion of chromosome 10p12-p11. All of the deletions had different breakpoints and ranged in size from 1 to 10 Mb with a common overlap of 360 kb, including the WAC gene. Most patients also had speech delay and hyperactive, aggressive, and/or autistic behavior. Visual abnormalities, such as hyperopia, strabismus, astigmatism, and myopia, were common, as were variable cardiac malformations, such as patent ductus arteriosus, septal defects, pulmonary valvular stenosis, and coarctation of the aorta. Two patients had seizures. Common dysmorphic features included deep-set eyes, downslanting or short palpebral fissures, synophrys, low-set eyebrows, dysplastic ears, bulbous nasal tip, thin upper lip, full cheeks, and short neck. Wentzel et al. (2011) noted the phenotypic similarities to a patient reported by Shahdadpuri et al. (2008) who also had a de novo heterozygous 10-Mb deletion of chromosome 10p12.1-p11.21, containing over 50 genes. The patient reported by Shahdadpuri et al. (2008) also had pseudoarthrosis of the clavicle, thin corpus callosum, and a 'beaten copper' appearance of the cranium without craniosynostosis (see 118980).
Okamoto et al. (2012) reported 2 unrelated Japanese children with developmental delay and common maxillofacial abnormalities associated with a heterozygous deletion at chromosome 10p12-p11. The deletions overlapped for 957 kb and included 4 genes: ARMC4 (615408), MPP7 (610973), WAC, and BAMBI (604444). Both children had frontal bossing, midface retrusion, coarse face, downslanting palpebral fissures, synophrys, deep-set eyes, epicanthus, wide nasal bridge, wide mouth, absent Cupid bow, downturned corners of the mouth, and large tongue. One also had malformed auricles, congenital cardiac anomalies, and short fingers with camptodactyly. The other child had a bulbous nose, deafness, and short stature with growth hormone deficiency. Brain imaging in both children was normal. The deletion was confirmed to be de novo in 1 of the patients.
In 6 children, including 2 sibs, with DeSanto-Shinawi syndrome, DeSanto et al. (2015) identified 5 different heterozygous truncating mutations in the WAC gene (615049.0002-615049.0006). The mutation in the sibs was postulated to have resulted from germline mosaicism in 1 of the parents; the remaining mutations occurred de novo. The mutations were found by whole-exome sequencing; functional studies were not performed, but all were predicted to result in a loss of function.
DeSanto et al. (2015) noted that Hamdan et al. (2014) had identified a de novo heterozygous truncating mutation in the WAC gene (615049.0001) in a woman with moderate intellectual disability. That patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.