A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electro-clinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with generalized epilepsy, behavioral issues, and various degrees of intellectual disability. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioral issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electro-clinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor over-activity is observed in a broader range of patients with neurodevelopmental disorders, since SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, since a substantial portion of available anti-seizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

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Background and Hypothesis:Thymic Epithelial Tumors are uncommon tumors of the anterior mediastinum composed ofthymomas and thymic carcinomas (TC). TC’s are known to have worse disease outcomes andlower rates of survival in comparison to thymomas and are suspected to have lower responserates to chemotherapy as well. As these tumors are rare, little data exists assessing the trueefficacy of chemotherapeutic regimens for TC patients. Due to this lack of data, and that theIndiana University Health Simon Cancer Center treats a high percentage of TET patients, adatabase of these patients covering a variety different disease characteristics and treatmentshas been established. We hypothesize, upon evaluation of this database, response rates toanthracycline based regimens (PAC) will be superior to non-anthracycline based regimens (i.e.,PE, Carbo/Taxol) for TC patients. Methods:In this project, a collection of patients seen by Dr. Patrick Loehrer and/or Dr. Kenneth Keslerwas acquired, and a database was created using these patients in RedCap. Once established,we evaluated patient medical records in Cerner and entered data related to diseasecharacteristics and treatments. These patients were then analyzed accordingly to evaluatechemotherapy response rates. Results:The database yielded 123 instances of chemotherapy treatment for TC. Of which, the mostpopular treatments were PAC and Carbo/Taxol. The data suggests that PAC generates a higherresponse rate (65.5%) than other therapies (Carbo/Taxol: 27.6%, PE: 58.3%, etc.). Therefore,there is evidence that anthracycline based regimens may be more effective at generatingresponse rates in comparison to non-anthracycline based regimens. Conclusion and Potential Impact:This project will help elucidate the effectiveness of recommended systemic therapies for thymiccarcinoma patients from one of the largest TET databases constructed. Ultimately, we hope thatwith clarity of the effectiveness of treatment, this can serve as a reliable reference for evidencebasedmedicine for the care of TC patients.

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