Publications by authors named "Patrick Blackburn"

An amplicon-based targeted next-generation sequencing (NGS) assay for the detection of gene fusions in sarcomas was developed, validated, and implemented. This assay can detect fusions in targeted regions of 138 genes and BCOR internal tandem duplications. This study reviews our experience with testing on the first 652 patients analyzed.

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Purpose: To assess the differences in variant classifications using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines and the Bayesian point-based classification system (here referred to as the point system) in 115 hereditary cancer predisposition genes and explore variant sub-tiering by the point system.

Methods: Germline variant classifications for 721 pediatric patients from an in-house panel were retrospectively evaluated using the 2 scoring systems.

Results: A total of 2376 unique variants were identified, with ∼23.

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Article Synopsis
  • - This study examines the link between rare variants in the cullin-3 ubiquitin ligase (CUL3) gene and neurodevelopmental disorders (NDDs), gathering data from multiple centers to explore genetic mutations and their clinical impacts.
  • - Researchers identified 37 individuals with CUL3 variants, most of which result in loss-of-function (LoF), leading to intellectual disabilities and possibly autistic traits; specific mechanisms affecting protein stability were also investigated.
  • - The findings enhance the understanding of NDDs associated with CUL3 mutations, suggesting that LoF variants are the main cause, which could help inform future diagnostics and treatment strategies.
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  • Researchers identified bi-allelic disruptive variants as the cause of autosomal recessive intellectual developmental disorder type 65, while dominant variants are harder to link to specific traits due to their presence in unaffected individuals.
  • The study involved a retrospective analysis of 21 individuals with likely pathogenic variants, focusing on clinical information and molecular data from their families.
  • Key findings revealed that those with dominant disruptive variants exhibited more developmental and behavioral problems, while individuals with dominant missense variants had a higher occurrence of renal and skin anomalies, enhancing the understanding of the related neurodevelopmental disorder.
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  • Dysmorphologists face challenges due to the diverse phenotypic variability of human faces, particularly when using Next-Generation Phenotyping (NGP) tools, which are often trained on limited data.
  • To address this, the GestaltMatcher Database (GMDB) was created, compiling over 10,980 facial images from various global populations, significantly improving the representation of underrepresented ancestries, especially African and Asian patients.
  • The study found that incorporating data from non-European patients enhanced NGP accuracy by over 11% without compromising performance for European patients, highlighting the importance of diverse datasets in identifying genetic disorders.
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Erythroid sarcoma (ES) is exceedingly rare in the pediatric population with only a handful of reports of de novo cases, mostly occurring in the central nervous system (CNS) or orbit. It is clinically and pathologically challenging and can masquerade as a nonhematopoietic small round blue cell tumor. Clinical presentation of ES without bone marrow involvement makes diagnosis particularly difficult.

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Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1.

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Article Synopsis
  • The significant phenotypic variability of human faces complicates the work of dysmorphologists by challenging Next-Generation Phenotyping (NGP) tools, especially when analyzing patients from diverse genetic backgrounds.
  • The research established the GestaltMatcher Database (GMDB), which includes over 10,000 facial images from patients with rare genetic disorders worldwide, striving to improve representation of underrepresented populations, particularly Asian and African patients.
  • The analysis showed that incorporating data from non-European patients enhanced the accuracy of NGP in diagnosing facial disorders without negatively affecting performance on European patients, emphasizing the need for more diverse datasets in medical genetics.
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Purpose: variants in (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.

Methods: Genetic data and detailed clinical records were collected via multi-center collaboration.

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The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML).

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Congenital/neonatal bone neoplasms are extremely rare. We present the case of a patient with a neonatal bone tumor of the fibula that had osteoblastic differentiation and a novel PTBP1::FOSB fusion. FOSB fusions are described in several different tumor types, including osteoid osteoma and osteoblastoma; however, these tumors typically present in the second or third decade of life, with case reports as young as 4 months of age.

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Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature.

Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X-inactivation). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants.

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The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22's functions in early mitosis.

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Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher.

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Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma: WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma.

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Background: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival.

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The World Health Organization category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA rearrangements is composed of a heterogeneous group of neoplasms that can present as a myeloproliferative neoplasm, acute myeloid leukemia, myeloid sarcoma, or lymphoblastic leukemia/lymphoma. The overall outcome of these neoplasms is favorable with imatinib therapy. Herein, we describe an adult female patient with a myeloid neoplasm accompanied by eosinophilia and a novel USP25::PDGFRA gene fusion.

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Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.

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Article Synopsis
  • Detecting gene fusions, especially those involving driver oncogenes, is crucial for the clinical diagnosis and treatment of cancer, and advancements in next-generation sequencing (NGS) have improved detection methods.
  • Traditional informatics methods for detecting gene fusions in RNA sequencing face challenges, including low-quality alignments and scalability issues, highlighting the need for better solutions.
  • SeekFusion is introduced as an efficient and accurate pipeline specifically designed for detecting gene fusions in targeted PCR-based NGS, demonstrating superior performance compared to existing methods and successfully analyzing samples from 4,484 patients with neurological tumors and sarcomas.
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This study investigates the role of recursive language and working memory (WM) in second-order false belief skills in Danish-speaking children with autism spectrum disorder (ASD; n = 62; 8 females) and typical development (n = 41; 15 females), ages 6-16. Second-order false belief skills correlated with receptive grammar, vocabulary, and age; sentential complement production predicted second-order false beliefs, controlling for age, receptive grammar and WM. Regressions showed that second-order false belief was associated with age across groups, but with sentential complements in the ASD group only.

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Motivation: Genomic data are prevalent, leading to frequent encounters with uninterpreted variants or mutations with unknown mechanisms of effect. Researchers must manually aggregate data from multiple sources and across related proteins, mentally translating effects between the genome and proteome, to attempt to understand mechanisms.

Materials And Methods: PT presents diverse data and annotation types in a unified protein-centric view, facilitating the interpretation of coding variants and hypothesis generation.

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