Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the <i>MEF2C</i> gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without <i>MEF2C</i> involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve <i>MEF2C</i> but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a <i>TBX22</i> gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

RPP25 as a Prognostic-Related Biomarker That Correlates With Tumor Metabolism in Glioblastoma

RPP25, a 25 kDa protein subunit of ribonuclease P (RNase P), is a protein-coding gene. Disorders associated with RPP25 include chromosome 15Q24 deletion syndrome and diffuse scleroderma, while systemic sclerosis can be complicated by malignancy. However, the functional role of RPP25 expression in glioblastoma multiforme (GBM) is unclear. In this study, comprehensive bioinformatics analysis was used to evaluate the impact of RPP25 on GBM occurrence and prognosis. Differential analysis of multiple databases showed that RPP25 was commonly highly expressed in multiple cancers but lowly expressed in GBM. Survival prognostic results showed that RPP25 was prognostically relevant in six tumors (CESC, GBM, LAML, LUAD, SKCM, and UVM), but high RPP25 expression was significantly associated with poor patient prognosis except for CESC. Analysis of RPP25 expression in GBM alone revealed that RPP25 was significantly downregulated in GBM compared with normal tissue. Receiver operating characteristic (ROC) combined with Kaplan-Meier (KM) analysis and Cox regression analysis showed that high RPP25 expression was a prognostic risk factor for GBM and had a predictive value for the 1-year, 2-year, and 3-year survival of GBM patients. In addition, the expression of RPP25 was correlated with the level of immune cell infiltration. The gene set enrichment analysis (GSEA) results showed that RPP25 was mainly associated with signalling pathways related to tumor progression and tumor metabolism.

Characterizing Daily-Life Social Interactions in Adolescents and Young Adults with Neurodevelopmental Disorders: A Comparison Between Individuals with Autism Spectrum Disorders and 22q11.2 Deletion Syndrome

Social impairments are common features of 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). The Ecological Momentary Assessment (EMA) allowed access to daily-life information in order to explore the phenomenology of social interactions. 32 individuals with 22q11DS, 26 individuals with ASD and 44 typically developing peers (TD) aged 12–30 were assessed during 6 days 8 times a day using a mobile app. Participants with 22q11DS and ASD did not spend more time alone but showed distinct implication in the social sphere than TD. Distinct profiles emerged between the two conditions regarding the subjective experience of aloneness and the subjective experience of social interactions. This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD that points towards different therapeutic targets.

The TBX1/miR-193a-3p/TGF-β2 Axis Mediates CHD by Promoting Ferroptosis

Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-β2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-β2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-β2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-β2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-β2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-β2 may be a target gene for CHD diagnosis and treatment in children.

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.