Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a “double duplication” (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

T h e m e d i a of representative marnrnalian cell lines were s u p p l e m e n t e d with low levels of selenium in t h e form of sodium selenite in order to investigate t h e effects of selenium on rnammafian cells.Following incubation In 30 nM sodium selenite, these cells were assayed for changes in glutathione peroxidase (GPx) activity. The cells examined included NIH 3T3 mouse fibroblasts, PC12 rat sympathetic precursor cells, cells. AA8 cells w e r e selected to e v a l u a t e whether selenium S u p p l e m e n t a t i o n was radioprotective against 60cobalt gamma irradiation.Protection against radiation-induced mutation was measured by evaluating mutation frequency at the hprt locus. In this assay, pre- Se-dependent glutathione peroxidases (SeGPx) represent a family of related enzymes which are generally believed to constitute a major defense system against toxic peroxides and oxygen free radicals f113. Given the role of SeGPx in anti-oxidant defense, one might speculate that some of the bioprotective effects of selenium, at kast in part, would be due to this enzyme activity. This is generally not believed to be the case as several older studies have indicated that chernoprotective doses of selenium did not result in significant increases in SeGPx activity in experimental animats [I 2,131. In this manuscript, it was examined whether the supplementation of culture media with low levels of sodium selenite would have on effect on GPx activity and report that this activity was stimulated in several mammalian cell lines. A represenlive cell line, CHO AA8 cells, were further examined and shown to be protected from radiation-induced mutation. The irnpiicatioris of this data are discussed reyarding the mechanisms by which selenium may provide its bioprotectivt? role. likely to be by mechanisms independent of effects on GPx activity [12,13,24,25]. The results with CHO AA8 cells indicated that the same dose of selenium that resulted in a better than 4 fold increase in GPx activity significantly protected these cells from radiation-induced mutation. This data cannot distinguish between GPx-dependent vs. -independent mechanisms of protection. Future studies using GPx expression constructs to genetically increase GPx activity independent of selenium status will be required to establish the protective role of this enzyme.Acknowledgement: This work was sapported by Grant ## CN-I33 from the American Cancer Society (to A.M.D.).

Background and ObjectivesTo date, all reports of pathogenic variants affecting the GTPase domain of the DNM1 gene have a clinically severe neurodevelopmental phenotype, including severe delays or intractable epilepsy. We describe a case with moderate developmental delays and self-resolved epilepsy.MethodsThe patient was followed by our neurology and genetics teams. After clinical examination and EEG to characterize the patient's presentation, we conducted etiologic workup including brain MRI, chromosomal microarray, genetic and metabolic investigations, and nerve conduction studies. Subsequently, we arranged an Intellectual Disability Plus Trio Panel.ResultsOur patient presented with seizures at 2 days old, requiring phenobarbital. She also had hypotonia, mild dysmorphic features, and mild ataxia. Although initial workup returned unremarkable, the trio gene panel identified a de novo heterozygous pathogenic missense variant in the DNM1 GTPase domain. Now 4 years old, she has been seizure-free for 3 years without ongoing treatment and has nonsevere developmental delays (e.g., ambulates independently and speaks 2-word phrases).DiscussionOur case confirms that not all individuals with DNM1 pathogenic variants, even affecting the GTPase domain, will present with intractable epilepsy or severe delays. Expanding the known clinical spectrum of dynamin-related neurodevelopmental disorder is crucial for patient prognostication and counseling.

TCF20-associated neurodevelopmental disorder (TAND) is a rare and phenotypically variable genetic condition. Common features include intellectual disability, neurobehavioural concerns, postnatal tall stature and hypotonia.Two unrelated early adolescent males were referred to genetics for assessment of developmental delay. The first male of Caucasian descent had a history of autism spectrum disorder (ASD), mitral valve prolapse and subtle craniofacial dysmorphisms. The second male of Somali descent had a history of intellectual disability, thick corpus callosum and ASD. Whole-exome sequencing revealed a pathogenic variant inTCF20in both individuals. Further testing revealed that the former individual’s mother was mosaic for theTCF20 pathogenic variant.We report two individuals withTCF20pathogenic variants presenting with unique findings, including thick corpus callosum, family history of mosaicism and cardiac anomalies. These examples expand the TAND phenotype, describe associated dysmorphism in a minority group and highlight the importance of rare disease research.