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BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only eight 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: To provide a comprehensive overview of the clinical and immunological findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting using kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, two clinically diagnosed patients, and two asymptomatic siblings. All had severely reduced CD19+ B-cells (< 0.1×109/L) on first evaluation, yet subsequent follow-ups indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with immunoglobulin G substitution. Two patients successfully discontinued substitution without developing susceptibility to infections and maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100´000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.
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Craniosynostosis constitutes one of the most common congenital cranial malformations, affecting approximately 6/10,0000 live births. A genetic etiology has long been known for several forms of syndromic craniosynostosis, including pathogenic variants in TWIST1 and FGFR3 in children with Saethre-Chotzen and Muenke syndrome. Over the last decade, reports of genetic aberrations in TCF12 in children with craniosynostosis have emerged, in particular in cases with premature closure of the coronal suture(s). In this study, we, therefore, systematically reviewed the rapidly growing knowledge of TCF12-related coronal craniosynostosis, clearly illustrating its high degree of genotype and phenotype variability. With the two novel cases presented, at least 113 cases of TCF12-related coronal craniosynostosis have currently been reported. By pooling data from several prospectively collected undifferentiated craniosynostosis cohorts (ntotal = 770), we estimate a prevalence of pathogenic TCF12 variants of at least 2%. Overall, pathogenic germline variants in TCF12 are relatively frequent in children with coronal craniosynostosis, accounting for â¼10-20% of TWIST1- and FGFR1/2/3-negative cases, with even higher rates for bicoronal and syndromic cases. Genetic counseling is recommended for all children with craniosynostosis, and involvement of the coronal suture(s) should precipitate TCF12 testing.
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Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.
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Neoplasias , Adulto , Humanos , Criança , Neoplasias/genética , Predisposição Genética para Doença , Pool Gênico , Mutação , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
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Síndrome de Beckwith-Wiedemann , Neoplasias Renais , Tumor de Wilms , Masculino , Feminino , Humanos , Proteína 7 com Repetições F-Box-WD/genética , Macrossomia Fetal/genética , Impressão Genômica , Tumor de Wilms/genética , Genótipo , Síndrome de Beckwith-Wiedemann/patologia , Metilação de DNA/genética , Suscetibilidade a Doenças , Neoplasias Renais/genética , Células Germinativas/patologiaRESUMO
BACKGROUND: Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. METHODS: We developed double batched sequencing where DNA samples are batch-sequenced twice - directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. RESULTS: We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91-1.00 and 95% CI, 0.98-1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. CONCLUSIONS: Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.
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Predisposição Genética para Doença , Neoplasias , Criança , Recém-Nascido , Humanos , Testes Genéticos/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Mutação em Linhagem Germinativa , Fatores de Risco , Sequenciamento de Nucleotídeos em Larga Escala , DNARESUMO
BACKGROUND: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. METHODS: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. RESULTS: Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). CONCLUSIONS: In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
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Astrocitoma , Glioma , RNA Longo não Codificante , Humanos , Criança , Estudo de Associação Genômica Ampla , Glioma/genética , Genótipo , Predisposição Genética para Doença , Astrocitoma/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Reliable prediction of free energy changes upon amino acid substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein-protein interaction. Advances in experimental mutational scans allow high-throughput studies thanks to multiplex techniques. On the other hand, genomics initiatives provide a large amount of data on disease-related variants that can benefit from analyses with structure-based methods. Therefore, the computational field should keep the same pace and provide new tools for fast and accurate high-throughput ΔΔG calculations. In this context, the Rosetta modeling suite implements effective approaches to predict folding/unfolding ΔΔGs in a protein monomer upon amino acid substitutions and calculate the changes in binding free energy in protein complexes. However, their application can be challenging to users without extensive experience with Rosetta. Furthermore, Rosetta protocols for ΔΔG prediction are designed considering one variant at a time, making the setup of high-throughput screenings cumbersome. For these reasons, we devised RosettaDDGPrediction, a customizable Python wrapper designed to run free energy calculations on a set of amino acid substitutions using Rosetta protocols with little intervention from the user. Moreover, RosettaDDGPrediction assists with checking completed runs and aggregates raw data for multiple variants, as well as generates publication-ready graphics. We showed the potential of the tool in four case studies, including variants of uncertain significance in childhood cancer, proteins with known experimental unfolding ΔΔGs values, interactions between target proteins and disordered motifs, and phosphomimetics. RosettaDDGPrediction is available, free of charge and under GNU General Public License v3.0, at https://github.com/ELELAB/RosettaDDGPrediction.
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Proteínas , Software , Proteínas/química , Mutação , Entropia , Estabilidade ProteicaRESUMO
BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected. CONCLUSIONS: Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.
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Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Glioma , Adulto , Criança , Humanos , Predisposição Genética para Doença , Estudos Prospectivos , Neoplasias do Sistema Nervoso Central/patologia , Glioma/genética , Neoplasias Cerebelares/genéticaRESUMO
Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.
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Ependimoma , Criança , Ependimoma/diagnóstico , Ependimoma/genética , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Humanos , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Historically, few pediatric central nervous system (CNS) tumors were thought to result from genetic predisposition. However, within the last decade, new DNA sequencing methods have led to an increased recognition of high-risk cancer predisposition syndromes in children with CNS tumors. Thus, genetic predisposition is increasingly impacting clinical pediatric neuro-oncology. METHODS: In this narrative review, we discuss the current understanding of genetic predisposition to childhood CNS tumors and provide a general overview of involved research methodologies and terminology. Moreover, we consider how germline genetics may influence neurosurgical practice. RESULTS: Introduction of next-generation DNA sequencing has greatly increased our understanding of genetic predisposition to pediatric CNS tumors by enabling whole-exome/-genome sequencing of large cohorts. To date, the scientific literature has reported germline sequencing findings for more than 2000 children with CNS tumors. Although varying between tumor types, at least 10% of childhood CNS tumors can currently be explained by rare pathogenic germline variants in known cancer-related genes. Novel methodologies continue to uncover new mechanisms, suggesting that a much higher proportion of children with CNS tumors have underlying genetic causes. Understanding how genetic predisposition influences tumor biology and the clinical course in a given patient may mandate adjustments to neurosurgical treatment. CONCLUSION: Germline genetics is becoming increasingly important to clinicians, including neurosurgeons. This review provides an updated overview of genetic predisposition to childhood CNS tumors with focus on aspects relevant to pediatric neurosurgeons.
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Neoplasias do Sistema Nervoso Central , Predisposição Genética para Doença , Criança , Humanos , Predisposição Genética para Doença/genética , Neurocirurgiões , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/cirurgia , SíndromeRESUMO
Germ line mutations causing paediatric cancer predisposition syndromes (PCPSs) are more common than previously anticipated and are now recognised as a significant contributor to the incidence of childhood cancer. Advances in and increased clinical application of next-generation sequencing technologies have led to a rise in paediatric patients undergoing whole genome sequencing (WGS). This review focuses on the potential syndromes/diagnoses, which WGS may reveal in patients with childhood cancers, and highlights the clinical and psychosocial impact of PCPSs.
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Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias/genética , Adolescente , Criança , Humanos , Neoplasias/diagnóstico , Síndrome , Sequenciamento Completo do GenomaRESUMO
During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.