Minjie Luo

CMIP, a c-maf inducing protein that plays a key role in cytoskeletal remodeling, neuronal migration and synaptic formation, was first associated with specific language impairment and autism through the identification of a deletion in a single patient in 2012. Since then, only two additional individuals with CMIP deletions have been reported, both sharing features of autism and gastrointestinal features. However, a firm causal relationship between variants in CMIP and neurodevelopmental disorders has not yet been established. In this multicentre cohort study, we identified 25 individuals, from 17 unrelated families, with CMIP-related neurodevelopmental disorders, 22 of whom have not been previously reported. Of these, seven individuals carried heterozygous loss-of-function CMIP single-nucleotide variants, while the other 18 individuals had a complete or partial deletion of CMIP, some involving adjacent genes. The clinical phenotype was variable with a high prevalence of developmental delay (20/25), autism spectrum disorder features (13/25), attention-deficit/hyperactivity disorder features (11/25) and other psychiatric disorders (15/25). Epilepsy was present in nine individuals (9/25), of whom three had therapy-resistant seizures. To study the pathogenicity of CMIP variants, a cmip mutant zebrafish model carrying a premature stop codon was investigated. These mutants showed temperature-dependent altered locomotor activity suggestive of seizure-like behavior, which was confirmed by spontaneous epileptiform discharges in cmip^+/- mutant zebrafish larvae. Our patient cohort and the zebrafish data establish CMIP as a gene implicated in neurodevelopmental and neuropsychiatric disorders. We recommend inclusion of CMIP in the genetic work-up of neurodevelopmental delay, with or without autism or psychiatric disorders and epilepsy.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance ( P < 5 × 10 ⁻⁸ ) after meta-analysis. Two loci were established trans-ancestral susceptibility regions ( IKZF1 , ARID5B ), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10 ⁻³ ). Novel risk variants were also associated with subtype-specific disease ( P < 0.05), including higher susceptibility for a subtype overrepresented in African American children ( TCF3-PBX1 ) and lower susceptibility for a subtype with excellent prognosis ( ETV6-RUNX1 ). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity ( P < 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.

To determine the cellular and molecular basis of Castleman Disease (CD), we analyze the spatial proteome and transcriptome from a discovery (n = 9 cases) and validation (n = 13 cases) cohort of Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD shows increased stromal cells that form unique microenvironments. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation. CXCL13+ FDCs, PDGFRA + T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were the predominant source of increased VEGF expression and IL-6 signaling. MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC). VEGF expression by FDCs is associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activates JAK-STAT, TGFβ, and MAPK pathways via specific ligand-receptor interactions. Here, we show that stromal-cell activation and associated B cell activation and differentiation, neovascularization and stromal remodeling underlie CD.

HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant

TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for patient management. We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified following published guidelines. In 248 tumors from 222 patients, 284 Tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 73.9% of 142 unique variants were pathogenic/likely pathogenic (P/LP). Confirmatory testing on 118 patients revealed germline TP53 variants in 28 patients (23 P/LP and 5 uncertain significance), suggesting a minimum Li-Fraumeni syndrome (LFS) incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant-carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet LFS diagnostic/testing criteria while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction (VAF). However, somatic evidence including low VAF correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants. The high incidence and variable phenotype of LFS in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.