Publications by authors named "Kristen J Rasmussen"

Article Synopsis
  • - Variants of Uncertain Significance (VUS) are frequent outcomes of genetic testing and can lead to misinterpretation and unnecessary costs for clinicians.
  • - A study analyzed over 1.5 million genetic test results, revealing that exome and genome sequencing had a lower rate of inconclusive results (22.5%) compared to multi-gene panels (32.6%).
  • - The findings suggest a need to reevaluate how VUS are reported and propose strategies to lower VUS rates while ensuring clinicians focus on significant cases.
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Genome sequencing (GS) is a powerful clinical tool used for the comprehensive diagnosis of germline disorders. GS library preparation typically involves mechanical DNA fragmentation, end repair, and bead-based library size selection followed by adapter ligation, which can require a large amount of input genomic DNA. Tagmentation using bead-linked transposomes can simplify the library preparation process and reduce the DNA input requirement.

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Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome.

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Article Synopsis
  • Adaptor protein complexes play a key role in the transportation of proteins within neurons and are linked to various human disorders, including intellectual disabilities.
  • This study identifies specific variants in the AP1G1 gene, which are associated with neurodevelopmental disorders characterized by issues like intellectual disabilities and epilepsy across eleven diverse families.
  • Experimental evidence shows that these variants affect the protein's structure and functionality, impacting cellular processes and leading to severe developmental defects in model organisms like zebrafish.
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Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

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There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain.

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DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958).

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