Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia.

Background: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.

Objective: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1.

Germline landscape of variants in pediatric malignancies: identification of as a novel cancer predisposition candidate gene.

Replication Protein A (RPA) is single-strand DNA binding protein that plays a key role in the replication and repair of DNA. RPA is a heterotrimer made of 3 subunits - RPA1, RPA2, and RPA3. Germline pathogenic variants affecting were recently described in patients with Telomere Biology Disorders (TBD), also known as dyskeratosis congenita or short telomere syndrome.

ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice.

ETS variant 6 (ETV6) encodes a transcriptional repressor expressed in hematopoietic stem and progenitor cells (HSPCs), where it is required for adult hematopoiesis. Heterozygous pathogenic germline ETV6 variants are associated with thrombocytopenia 5 (T5), a poorly understood genetic condition resulting in thrombocytopenia and predisposition to hematologic malignancies. To elucidate how germline ETV6 variants affect HSPCs and contribute to disease, we generated a mouse model harboring an Etv6R355X loss-of-function variant, equivalent to the T5-associated variant ETV6R359X.

Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis.

Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (-/-) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation.

The Genetic and Epigenetic Features of Bilateral Wilms Tumor Predisposition: A Report from the Children's Oncology Group AREN18B5-Q Study.

This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group.

Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.

Purpose: Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.

Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma.

Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged <21 years, with the median age at diagnosis of 21.

Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice.

Unlabelled: Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens.

Ancestry-specific predisposing germline variants in cancer.

Background: Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of diverse populations.

Methods: We conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas.

Recent advances in Wilms' tumor predisposition.

Wilms' tumor (WT), the most common childhood kidney cancer, develops in association with an underlying germline predisposition in up to 15% of cases. Germline alterations affecting the WT1 gene and epigenetic alterations affecting the 11p15 locus are associated with a selective increase in WT risk. Nevertheless, WT also occurs in the context of more pleiotropic cancer predispositions, such as DICER1, Li-Fraumeni and Bloom syndrome, as well as Fanconi anemia.

Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes.

Enrichment of heterozygous germline loss-of-function variants in pediatric osteosarcoma.

Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in , the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund-Thomson syndrome (RTS), are associated with increased risk for childhood cancer.

Framework for microRNA variant annotation and prioritization using human population and disease datasets.

MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE, which combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes).

Insights from the 2018 Biology of Genomes meeting.

A report on the Cold Spring Harbor Laboratory 31 annual meeting on the Biology of Genomes, held at Cold Spring Harbor, New York, USA, 8-12 May, 2018.The 2018 Biology of Genomes meeting at Cold Spring Harbor Laboratories covered a wide range of topics with research relevant to many aspects of genomics. Here we highlight two areas of research where multiple talks provided new insights.

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events.

Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines.

Background: The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants.

Integrated genomics approach to identify biologically relevant alterations in fewer samples.

Background: Several statistical tools have been developed to identify genes mutated at rates significantly higher than background, indicative of positive selection, involving large sample cohort studies. However, studies involving smaller sample sizes are inherently restrictive due to their limited statistical power to identify low frequency genetic variations.

Results: We performed an integrated characterization of copy number, mutation and expression analyses of four head and neck cancer cell lines - NT8e, OT9, AW13516 and AW8507 - by applying a filtering strategy to prioritize for genes affected by two or more alterations within or across the cell lines.

Identification of ligand binding pockets on nuclear receptors by machine learning methods.

Nuclear receptors constitute a super family of protein hormones that serve as transcription factors. They typically reside in the cytosol and, after ligand binding, migrate to the nucleus to exert their biological action. Ligands are lipophilic, small molecules including retinoids, steroids, thyroxine, and vitamin D.