RT Journal Article SR Electronic T1 WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 754 OP 761 DO 10.1136/jmedgenet-2015-103069 VO 52 IS 11 A1 DeSanto, Cori A1 D'Aco, Kristin A1 Araujo, Gabriel C A1 Shannon, Nora A1 Study, DDD A1 Vernon, Hilary A1 Rahrig, April A1 Monaghan, Kristin G A1 Niu, Zhiyv A1 Vitazka, Patrik A1 Dodd, Jonathan A1 Tang, Sha A1 Manwaring, Linda A1 Martir-Negron, Arelis A1 Schnur, Rhonda E A1 Juusola, Jane A1 Schroeder, Audrey A1 Pan, Vivian A1 Helbig, Katherine L A1 Friedman, Bethany A1 Shinawi, Marwan YR 2015 UL http://jmg.bmj.com/content/52/11/754.abstract AB Background Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype–phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described.Methods Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation.Results Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted.Conclusions Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.