Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.

PURPOSE: Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing. METHODS: Family-based exome sequencing included whole-exome sequencing followed by family inheritance-based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes. RESULTS: A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy. CONCLUSION: Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.

Activity-dependent inhibitory gating in molecular signaling cascades induces a novel form of intermediate-term synaptic facilitation in Aplysia californica.

Mechanistically distinct forms of long-lasting plasticity and memory can be induced by a variety of different training patterns. Although several studies have identified distinct molecular pathways that are engaged during these different training patterns, relatively little work has explored potential interactions between pathways when they are simultaneously engaged in the same neurons and circuits during memory formation. Aplysia californica exhibits two forms of intermediate-term synaptic facilitation (ITF) in response to two different training patterns: (1) repeated trial (RT) ITF (induced by repeated tail nerve shocks [TNSs] or repeated serotonin [5HT] application) and (2) activity-dependent (AD) ITF (induced by sensory neuron activation paired with a single TNS or 5HT pulse). RT-ITF requires PKA activation and de novo protein synthesis, while AD-ITF requires PKC activation and has no requirement for protein synthesis. Here, we explored how these distinct molecular pathways underlying ITF interact when both training patterns occur in temporal register (an "Interactive" training pattern). We found that (1) RT, AD, and Interactive training all induce ITF; (2) Interactive ITF requires PKC activity but not de novo protein synthesis; and (3), surprisingly, Interactive training blocks persistent PKA activity 1 h after training, and this block is PKC-independent. These data support the hypothesis that sensory neuron activity coincident with the last RT training trial is sufficient to convert the molecular signaling already established by RT training into an AD-like molecular phenotype.

MicroRNAs in memory processing.

MicroRNAs are a class of small RNA molecules that regulate the expression of a wide variety of genes. In this issue of Neuron, Rajasethupathy and colleagues identify 170 distinct microRNAs in Aplysia, including one, miR-124, that plays a critical role in the regulation of signaling molecules underlying synaptic plasticity and memory.