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Background There is a gap in the literature regarding genetic underpinnings of pediatric autoimmune CNS diseases. This study explored rare gene variants implicated in immune dysregulation within these disorders. Methods This was a single-center observational study of children with inflammatory CNS disorder who had genetic testing through next generation focused exome sequencing targeting 155 genes associated with innate or adaptive immunity. For in silico prediction of functional effects of single-nucleotide variants, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant were used, and Combined Annotation Dependent Depletion (CADD) scores were calculated. Identified genes were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results Of 54 patients, 42 (77.8%) carried variant(s), among which 12 (22.2%) had 3-8 variants. Eighty-eight unique singlenucleotide variants of 55 genes were identified. The most variants were detected in UNC13D, LRBA, LYST, NOD2, DOCK8, RNASEH2A, STAT5B, and AIRE. The majority of variants (62, 70.4%) had CADD > 10. KEGG pathway analysis revealed seven genes associated with primary immunodeficiency (Benjamini 1.40E − 06), six genes with NOD-like receptor signaling (Benjamini 4.10E − 04), five genes with Inflammatory Bowel Disease (Benjamini 9.80E − 03), and five genes with NF-kappa B signaling pathway (Benjamini 1.90E − 02). Discussion We observed a high rate of identification of rare and low-frequency variants in immune regulatory genes in pediatric neuroinflammatory CNS disorders. We identified 88 unique single-nucleotide variants of 55 genes with pathway analysis revealing an enrichment of NOD2-receptor signaling, consistent with involvement of the pathway within other autoinflammatory conditions and warranting further investigation.

Down syndrome (DS) and Marfan syndrome (MFS) are two unique genetic disorders that share limited phenotypic overlap. There are very few reported cases in the existing literature on overlapping DS and MFS. Although these two disorders are phenotypically unique, features present in these cases are variable, resulting in mixed and dominant expressions of particular features. We present the first adolescent case of trisomy 21 associated DS and fibrillin-1 gene associated MFS in the literature who had a height at 90th percentile for an 11-year old boy and discuss the implications of this case in terms of future medical care when these two genetic syndromes are present in the same individual. Understanding of certain features of the ‘non-dominating’ syndrome is crucial for clinicians to recognise when DS co-occurs with MFS. Close monitoring of the cardiovascular, ophthalmologic and musculoskeletal systems is recommended if both syndromes are diagnosed given that both can be independently associated with disorders in these organ systems.

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