Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing

Reuter, Chloe; Kohler, Jennefer N.; Bonner, Devon; Zastrow, Diane B.; Fernández, Liliana; Dries, Annika M.; Marwaha, Shruti; Davidson, Jean M.; Brokamp, Elly; Herzog, Matthew; Hong, Joyce; Macnamara, Ellen; Rosenfeld, Jill A.; Schoch, Kelly; Spillmann, Rebecca C.; Loscalzo, Joseph; Krier, Joel B.; Stoler, Joan M.; Sweetser, David A.; Palmer, Christina G.S.; Phillips, John A.; Shashi, Vandana; Adams, David; Yang, Yaping; Ashley, Euan A.; Fisher, Paul G.; Mulvihill, John J.; Bernstein, Jonathan A.; Wheeler, Matthew T.

doi:10.1002/jgc4.1161

Cited by 51 publications

(50 citation statements)

References 36 publications

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“…The lack of knowledge parents perceived by insurance representatives led to greater frustrations when payors did not consider the medical bene ts and long-term cost savings of access to equipment, therapy, and diagnostics. This is consistent with studies that have indicated barriers to diagnosis and diagnostic testing for rare diseases (7,45). Parents in this study expressed frustration that insurance…”

Section: Discussionsupporting

confidence: 91%

Navigating the U.S. Health Insurance Landscape for Children with Rare Diseases: A Qualitative Study of Parents’ Experiences.

Pasquini

Goff

Whitehill

2020

Preprint

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Background: Parents of children with rare diseases often face uncertainty about diagnosis, treatment, and costs associated with healthcare for their child. Health insurance status impacts each of these areas, but no U.S. study has explored parents’ perceptions of the health insurance impacts on their child’s care. This study aimed to qualitatively explore how these parents navigate the complex health insurance system for their children and their experiences in doing so.Methods: Semi-structured interviews were conducted with parents of children with metachromatic leukodystrophy (MLD) and spinal muscular atrophy (SMA), chosen for specific disease characteristics and orphan drug status. Participants were recruited via e-mail through patient advocacy organizations between September and December 2018. Interviews were conducted via Skype, were recorded, and professionally transcribed. Grounded theory was utilized as a methodology to analyze transcripts in an iterative process to determine themes and sub-themes based on participant described experiences.Results: Major themes and subthemes that emerged across the 15 interviews included: 1) difficulties obtaining secondary insurance based on state eligibility criteria; 2) difficulty accessing needed healthcare services; and 3) need for repeated interactions with insurance representatives. The absence of clearly documented or widely recognized clinical guidelines exacerbated the difficulty accessing care identified as necessary by their healthcare team, such as therapy and equipment. An explanatory model for parent’s experiences was developed from the themes and subthemes. The model includes the cyclical nature of interacting with insurance for redundant reauthorizations and the outside support and financial assistance that is often necessary to address their child’s healthcare needs.Conclusions: With complex health conditions, small setbacks can become costly and disruptive to the health of the child and the life of the family. This study suggests that patients with rare diseases may benefit from time limits for processing coverage decisions, increasing transparency in the claims and preauthorization processes, and more expansive authorizations for on-going needs. Additional studies are needed to understand the full scope of barriers and to inform policies that can facilitate better access for families living with rare diseases.

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Section: Discussionsupporting

confidence: 91%

Navigating the U.S. Health Insurance Landscape for Children with Rare Diseases: A Qualitative Study of Parents’ Experiences.

Pasquini

Goff

Whitehill

2020

Preprint

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“…Notably, the UDN has a mandate to accept individuals without regard to their insurance or financial status; therefore geographic and financial barriers are minimized beyond what can be achieved in clinical practice, to improve equity in access to those with the most diagnostically intractable diseases. As a result, individuals who have no access to clinical ES or are denied ES coverage by insurance continue to be accepted by the network, 38 leading to some diagnoses that could be tractable in a clinical setting. This number is declining as clinical reimbursement for ES increases, although unlikely to ever become zero.…”

Section: Discussionmentioning

confidence: 99%

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Schoch

Esteves

Bican

et al. 2021

Genetics in Medicine

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Purpose: The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods: We analyzed retrospective data from four UDN clinical sites, from July 2015-September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results: Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior non-diagnostic exome sequencing and 45 diagnoses (19%) that were non-genetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants and collaborative science for functional assays and animal modeling. Conclusion: Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries and delineation of novel disorders represent a model for genomic medicine and science.

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“…Clinical whole-exome sequencing (WES) has a reported diagnostic rate of 25%-30% (Yang et al 2013;Lazaridis et al 2016;Retterer et al 2016;Reuter et al 2019). Here we used research-based WES followed by clinical confirmation of the variants to diagnose a proband presenting with a history of multiple melanomas.…”

Section: Discussionmentioning

confidence: 99%

A novel missense variant and multiexon deletion causing a delayed presentation of xeroderma pigmentosum, group C

Macke

Morales‐Rosado

Gupta

et al. 2020

Cold Spring Harb Mol Case Stud

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Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor (XPC) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14-15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics. Prior to age 36, she had more than 60 skin biopsies that showed dysplastic nevi, many of which had atypia. At age 36 she presented with her first melanoma in situ, and since then has had more than 10 melanomas. The proband underwent research whole-exome sequencing (WES) through the Mayo Clinic's Center for Individualized Medicine and a novel heterozygous variant of uncertain significance (VUS) in XPC (c.1709T > G, p.Val570Gly) was identified. Clinical confirmation pursued via XPC gene sequencing and deletion/duplication analysis of XPC revealed a pathogenic heterozygous deletion of ∼1 kb within XPC, including exons 14 and 15. Research studies determined the alterations to be in trans. Although variants in XPC generally result in early-onset skin cancer in childhood, the proband is atypical in that she did not present with her first melanoma until age 36. Review of the patient's clinical, pathological, and genetic findings points to a diagnosis of delayed presentation of xeroderma pigmentosum.

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Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing

Cited by 51 publications

References 36 publications

Navigating the U.S. Health Insurance Landscape for Children with Rare Diseases: A Qualitative Study of Parents’ Experiences.

Navigating the U.S. Health Insurance Landscape for Children with Rare Diseases: A Qualitative Study of Parents’ Experiences.

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

A novel missense variant and multiexon deletion causing a delayed presentation of xeroderma pigmentosum, group C

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