Understanding and interpretation of a variant of uncertain significance (VUS) genetic test result by pediatric providers who do not specialize in genetics

Menke, Chelsea; Nagaraj, Chinmayee B.; Dawson, Brian; He, Hua; Tawde, Sanjukta; Wakefield, Emily

doi:10.1002/jgc4.1422

Cited by 9 publications

(5 citation statements)

References 15 publications

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“…This may indicate that while GCs perceive limitations in the current skills of NGHPs in interpreting results, they believe this to be the most critical area of genetics/genomics knowledge for NGHPs if they are providing genetic services to patients in the future. Limited experimental and anecdotal data have shown that results interpretation, particularly with variants of uncertain significance, are challenging for providers without formal genetics/genomics training, which can lead to misinterpretation (Donohue et al, 2021; Menke et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Critical components of genomic medicine practice for non‐genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education

Coleman

Bensend

Mills

et al. 2023

Journal of Genetic Counseling

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Genetic services are increasingly provided by non‐genetics healthcare professionals (NGHPs) with minimal formal training in genetics/genomics. Research demonstrates gaps in knowledge and clinical practices in genetics/genomics among NGHPs, but there is a lack of consensus on the specific knowledge needed by NGHPs to effectively provide genetic services. As clinical genetics professionals, genetic counselors (GCs) have insight into the critical components of genetics/genomics knowledge and practices needed by NGHPs. This study explored GCs' beliefs regarding whether NGHPs should provide genetic services and identified GCs' perceptions of the components of knowledge and clinical practice in genetics/genomics that are most critical for NGHPs providing genetic services. Two hundred and forty GCs completed an online quantitative survey with 17 participating in a follow‐up qualitative interview. Descriptive statistics and cross‐comparisons were generated for survey data. Interview data were analyzed using an inductive qualitative method for cross‐case analysis. Most GCs disagreed with NGHPs providing genetic services, but beliefs varied widely, ranging from disagreement due to perceived gaps in knowledge or clinical skills to acceptance of NGHPs providing genetic services due to limited access to genetics professionals. Across survey and interview data, GCs endorsed the interpretation of genetic test results, understanding implications of results, collaboration with genetics professionals, knowledge of the risks and benefits to testing, and recognizing indications for genetic testing as critical components of knowledge and clinical practice for NGHPs. Several recommendations for improving the provision of genetic services were provided by respondents including educating NGHPs to provide genetic services through case‐based continuing medical education and increasing collaboration between NGHPs and genetics professionals. As GCs are healthcare providers with experience and vested interests in educating NGHPs, their perspectives can help inform the creation of continuing medical education to ensure patients' access to high‐quality genomic medicine care from providers of varying backgrounds.

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Section: Discussionmentioning

confidence: 99%

Critical components of genomic medicine practice for non‐genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education

Coleman

Bensend

Mills

et al. 2023

Journal of Genetic Counseling

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“…Variant classification still remains a nuanced art, rather than a precise science [ 40 ]. Fully informed genetic counselling is required to guide families through the diagnostic limitations and uncertainties inherent in genetic testing for neurodevelopmental conditions [ 41 ]. Several research priorities remain.…”

Section: Discussionmentioning

confidence: 99%

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

et al. 2022

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Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

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“…VUS necessitate HCPs provide the carrier with a nuanced explanation as to why the variant is considered uncertain and clarify implications for the individual and their family members [7]. The lack of formal genetics training among many HCPs complicates their capacity to interpret and convey these findings [8–10]. Even amongst genetic counsellors (GCs), clinical practices of returning VUS results to probands, or of recommending changes in their clinical care, vary based on individual HCP factors, such as their self-perception of their role, confidence in their skills, and practice setting [11].…”

Section: Introductionmentioning

confidence: 99%

Enhancing Variant of Uncertain Significance (VUS) Interpretation in Neurogenetics: Collaborative Experiences from a Tertiary Care Centre

Horowitz,

Fotopoulos,

Mistry

et al. 2024

Preprint

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Background:The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.Methods:VUS Rounds brought together genetic counsellors, molecular geneticists, and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification "VUS Hot", "True VUS", or "VUS Cold", corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions, and discuss nuances of VUS result communication.Results:In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritization of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. Herein, we thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.Conclusions:The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices, ensures equitable knowledge dissemination amongst HCPs and effective incorporation of uncertain genetic results into patient care.

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Understanding and interpretation of a variant of uncertain significance (VUS) genetic test result by pediatric providers who do not specialize in genetics

Cited by 9 publications

References 15 publications

Critical components of genomic medicine practice for non‐genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education

Critical components of genomic medicine practice for non‐genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Enhancing Variant of Uncertain Significance (VUS) Interpretation in Neurogenetics: Collaborative Experiences from a Tertiary Care Centre

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