Identification of a novel variant of FOXP3 resulting in severe immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome highlights potential pitfalls of molecular testing.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genetic disorder that typically presents in the first year of life with severe diarrhea, autoimmune endocrine disorder, and inflammatory dermatitis, most commonly an eczematous dermatitis. IPEX syndrome is caused by variants in the FOXP3 gene leading to dysregulation of T-regulatory (Treg) cells and an aberrant immune response. Here, we present a case of severe IPEX syndrome diagnosed following whole genome sequencing (WGS) in a 2-week-old boy with bloody mucoid diarrhea, failure to thrive, and a diffuse eczematous dermatitis. As multiple variants of interest were identified with WGS, this case highlights the importance of relating the clinical symptoms to the genetic results.

Parental attitudes regarding the need for genetic services in a pediatric brain tumor survivorship program.

Pediatric brain tumor survivorship populations have not been typically offered genetic services as part of routine care. Genetic services can be defined as family history collection, genetic risk assessment for a patient and family members, and coordination of genetic testing. Prior research has focused on the integration of genetic services in the general pediatric oncology survivorship population and found a need for these services to be implemented. Gathering a family history and providing a genetic risk assessment have previously been determined to be an integral step in determining if an individual's cancer was due to a hereditary predisposition. The purpose of this study was to examine parental attitudes regarding the need for genetic services in their child's pediatric brain tumor survivorship clinic. Twelve semi-structured interviews were conducted with parents participating in the Brain STAR (Survivors Taking Action and Responsibility) program at Ann and Robert H. Lurie Children's Hospital of Chicago. A grounded theory approach was used to code and analyze the results thematically. Five key themes were identified: participants' perceived benefits and barriers regarding receiving genetic services, desirable time for implementation of these services, relevance of family history, and their thoughts regarding reproductive risk. These results provide insight for genetics professionals regarding the need for genetic services in this population, and how to best implement them.

A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.