Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

Accidental injuries are more common in children with attention deficit hyperactivity disorder compared with their non-affected siblings.

BACKGROUND: Accidental injuries are a leading cause of paediatric morbidity and mortality. We hypothesized that attention deficit hyperactivity disorder (ADHD), a common childhood disorder characterized by behaviours such as hyperactivity and impulsivity, is a risk factor for accidental injuries. Previous retrospective studies suggested that children with ADHD have an increased injury rate, but controlled prospective studies are lacking. METHODS: We conducted a prospective case-control study of 29 school-aged children with ADHD and their same-sex, similarly aged, non-ADHD-affected siblings. All diagnoses were made by a paediatric neurologist according to DSM-IV criteria and the children and their parents underwent a structured psychiatric interview and a battery of complementary assessments including: Child Behavior Checklist (CBCL), ADHD Rating scale and Developmental Coordination Disorder Questionnaire (DCDQ). The parents were contacted by telephone every 3 months during a 9-month follow-up period and all injuries requiring medical attention were recorded. Incidence of injuries was compared between the pairs of siblings. RESULTS: During the follow-up period, a total of 13 injuries in 13 children with ADHD were reported, compared with six injuries in six children from the control group (Z=-2.11, P < 0.05). ADHD severity and subtype, CBCL, DCDQ and IQ scores were not predictive of injury risk. CONCLUSIONS: School-aged children with ADHD are at higher risk of accidental injuries than their non-ADHD siblings, regardless of ADHD subtype, co-morbid psychiatric conditions, developmental co-ordination problems and environmental/familial conditions. Awareness and adequate education of parents and caregivers of children with ADHD concerning the increased injury risks are thus warranted.