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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2024)

As genomic sequencing is increasingly used as a first-tier diagnostic test, more patients will receive secondary findings. Secondary findings, sometimes referred to as incidental findings, are results from genomic testing that are not related to the clinical indication for testing but have medical utility. The American College of Medical Genetics (ACMG) currently recommends 81 genes that should be offered to be analyzed for all patients undergoing genomic sequencing. Only pathogenic and likely pathogenic variants are considered positive results. Variants of uncertain significance (VUS) are not reported to patients. Since VUS are more common in individuals of non-European ancestry due to lack of diversity in genetic databases, our hypothesis is that patients with ancestry other than European are less likely to receive positive secondary findings results. A retrospective analysis was performed of positive and VUS rates among patients and family members who underwent exome sequencing at Ambry Genetics (n = 11,185 families). The results from this study suggest disparate levels of positive secondary findings rates among different racial and ethnic groups. Overall, White/Ashkenazi Jewish families were significantly more likely to receive positive secondary findings results than non-White families (p=0.034). Black/African American/African families had the highest VUS rate (69%), and Hispanic/Latino families and Ashkenazi Jewish families had the lowest VUS rates (42% and 45%, respectively) (p<0.001). The results of this study outline how lack of diversity in genetic databases is currently affecting patient results and highlights the importance of diverse ascertainment in genetics research and clinical settings.

    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2023)
    BACKGROUND AND OBJECTIVES: Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown. METHODS: This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup. RESULTS: In total, 15 of 44 patients received a diagnosis through genomic testing explaining their calcifications, and 2 more received a diagnosis that has not been previously associated with EICs. Six of the 15 were found to have one of the 4 genes (PDGFB, PDGFRB, SLC20A2, and XPR1) conventionally associated with the phenotypic term idiopathic basal ganglia calcifications. DISCUSSION: These findings support the use of genomic testing for symptomatic patients with EICs.
      Cover page: Genomic Diagnoses for Ectopic Intracerebral Calcifications.
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2024)
      Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
        Cover page: De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2022)
        The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.
          Cover page: Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome (NODRS)
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2022)

          Purpose

          Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).

          Methods

          Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.

          Results

          DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.

          Conclusion

          We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
            Cover page: A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder
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