De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

Incomplete follow-up of hemoglobinopathy carriers identified by newborn screening despite reporting in electronic medical records.

OBJECTIVE: Has the recent availability of newborn hemoglobinopathy screening results within patient electronic medical records (EMR) of birth hospitals facilitated follow-up by primary care pediatric providers? METHODS: An online survey of all 137 primary care pediatric providers at a New York City academic medical center was conducted in 2008-2009 to assess practices for hemoglobin-apathy trait follow-up. Physicians were resurveyed 1 year later, following educational outreach and a letter of instruction underscoring the availability of screening results in the EMR. All 62 primary care pediatricians were surveyed at a nearby city hospital for comparison. RESULTS: Overall response rate for the initial survey at the teaching hospital was 58% for pediatricians (N = 57) and family physicians (N = 23), and 50% for pediatricians at the city hospital (N = 31). Despite high prevalence of hemoglobinopathies in the population served and screening results in EMRs, only 46.2% of providers surveyed at the academic center reported routinely checking results of their infant patients: 38.6% of pediatricians and 66.7% of family practitioners. Some respondents were unaware that results are available in the EMR. The proportion of providers checking screening results was not significantly affected by educational intervention (N = 40). Provision of recommended follow-up for a positive trait result was modestly improved, especially in referring families for genetic counseling (25% to 50%, p<.01). In contrast, most pediatricians (83%) at the city hospital routinely check and perform follow-up. CONCLUSION: Despite access to results in the EMR and targeted educational outreach, follow-up of hemoglobinopathy screening by primary care varies widely across clinical sites.

De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity.

Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of unknown significance (c.1554 G > T (p.(K518N)), c.1967A > C (p.(E656A)), and c.3476 A > G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. Our data suggest that the BK channel may represent a drug target for the treatment of epilepsy. Our data highlight the importance of functional electrophysiological studies of BK channel variants in distinguishing whether a genomic variant of unknown significance is a disease-causing variant or a benign variant.