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  • Springer Science and Business Media LLC  (4)
  • Ashley, Euan A.  (4)
  • 1
    Online Resource
    Online Resource
    Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment
    Springer Science and Business Media LLC ; 2023
    In:  npj Genomic Medicine Vol. 8, No. 1 ( 2023-02-10)
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    In: npj Genomic Medicine, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2023-02-10)
    Abstract: Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D , encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or “primed” by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.
    Type of Medium: Online Resource
    ISSN: 2056-7944
    URL: Article
    DOI: 10.1038/s41525-022-00343-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2813848-X
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  • 2
    Online Resource
    Online Resource
    Participation in a national diagnostic research study: assessing the patient experience
    Springer Science and Business Media LLC ; 2023
    In:  Orphanet Journal of Rare Diseases Vol. 18, No. 1 ( 2023-04-10)
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    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2023-04-10)
    Abstract: The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience. Methods We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach. Results The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation. Conclusion Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-023-02695-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2225857-7
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  • 3
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    Continuing a search for a diagnosis: the impact of adolescence and family dynamics
    Springer Science and Business Media LLC ; 2023
    In:  Orphanet Journal of Rare Diseases Vol. 18, No. 1 ( 2023-01-09)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2023-01-09)
    Abstract: The “diagnostic odyssey” describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family’s decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475–491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child’s age was 11 years (range 3–18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-022-02598-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2225857-7
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  • 4
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    Online Resource
    LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants
    Springer Science and Business Media LLC ; 2024
    In:  BMC Genomics Vol. 25, No. 1 ( 2024-01-26)
    Details
    In: BMC Genomics, Springer Science and Business Media LLC, Vol. 25, No. 1 ( 2024-01-26)
    Abstract: Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. Results Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. Conclusions LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.
    Type of Medium: Online Resource
    ISSN: 1471-2164
    URL: Article
    DOI: 10.1186/s12864-023-09935-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
    detail.hit.zdb_id: 2041499-7
    SSG: 12
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