Correction: Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Nykamp, Keith; Anderson, Michael J.; Powers, Maureen A.; Garcia, John; Herrera, Blanca; Ho, Yu‐Ling; Kobayashi, Yuya; Patil, Nila; Thusberg, Janita; Westbrook, M Jody; Aguilar, Sienna; Aradhya, Swaroop; Beltrán, Daniel; Bunker, Brandon D.; Daly, Amy; Deucher, Anne; Ekstein, Tali; Entezam, Ali; Erhard, Karl F.; Fulbright, Jennifer; Fuller, Amy; Gibson, Kristen McDonald; Hambuch, Tina; Harte, Rachel A.; Hartshorne, Christy; Haverfield, Eden; Heidari, Nastaran; Hogue, Michelle; Iacoboni, Daniela; Johnson, Britt; Kang, Hio Chung; Lewis, Roger D.; Martin, Shiloh; McCalmon, Sarah A.; Michalski, Scott T.; Morgan, C I; Murillo, Laura; Nicolosi, Piper; Ouyang, Karen; Pardo, Carolina E.; Quintana, Rita M.; Rabideau, Marina; Riethmaier, Darlene; Stafford, Amanda; Tahiliani, Jackie; Tan, C. Y.; Taylor, Samantha-Su; Wang, Shu‐Huei; White, Hannah; Wilson, I. J.; Winder, Tom; Zeman, Michelle K.

doi:10.1038/s41436-019-0624-9

Cited by 9 publications

(4 citation statements)

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“…A detailed description of testing services has been previously described (22,23). Variant interpretation was conducted in adherence with an expansion of the American College of Medical Genetics guidelines (24). Results were presented by the following variant classifications: pathogenic or likely pathogenic (P/LP) variants identified, uncertain (variants of uncertain significance -VUS-identified), and negative (no reportable variants identified).…”

Section: The Global Programmentioning

confidence: 99%

Global Expansion of Jeffrey’s Insights: Jeffrey Modell Foundation’s Genetic Sequencing Program for Primary Immunodeficiency

et al. 2022

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Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey. The resulting diagnostic delay prohibits proper disease management and treatment, causing unnecessary distress and diminished QOL. Next-generation sequencing (NGS) offers relief from the distress of the diagnostic odyssey, but because of cost and barriers to access, it is regularly unobtainable. The Jeffrey Modell Foundation (JMF) introduced “Jeffrey’s Insights”, a no-charge genetic sequencing pilot program, in January 2019 for patients within the Jeffrey Modell Centers Network (JMCN) with an underlying PI, but no genetic diagnosis. Building on the success of the pilot program, JMF expanded it globally to more than 400 Centers in the JMCN in early 2020. The most current version of Invitae’s PI Panel available was used for this program. All participating clinicians were invited to complete a brief questionnaire assessing prior impediments to access and post-sequencing alterations in disease management and treatment. A total of 1,398 patients were tested, with 20.3% receiving a molecular diagnosis and many more receiving helpful diagnostic leads. Results obtained from genetic sequencing led to an alteration of clinical diagnosis, disease management, treatment, and genetic counseling in 39%, 38%, 35%, and 53% of patients, respectively. The global expansion of this program further underscores the crucial need for NGS for PI, along with its efficiency and potential cost savings. The results of this program to date further define rationale for the availability of comprehensive diagnostic NGS for patients with PI when requisitioned by an expert immunologist.

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Section: The Global Programmentioning

confidence: 99%

Global Expansion of Jeffrey’s Insights: Jeffrey Modell Foundation’s Genetic Sequencing Program for Primary Immunodeficiency

et al. 2022

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“…The pathogenicity of candidate variants was evaluated on the base of mutated frequency, conservation of amino acid change and structural or function domain of the protein as well as inheritance pattern. The pathogenicity of identified variants was assessed in accordance with the American College of Medical Genetics (ACMG) guidelines and Sherloc (16,17).…”

Section: Whole Exome Sequencing and Data Analysismentioning

confidence: 99%

Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families

Luo

Chen

Wei

et al. 2021

Front. Cardiovasc. Med.

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Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive.Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed.Results: All the three couples had no family history, and mid-gestation ultrasound revealed LHH and other variable cardiovascular defects in the fetuses. Trio-WES revealed de novo pathogenic variations in KMT2D (p.Gly3465Aspfs*37) (NM_003482) and WDFY3 (p.Ser117Xfs*) (NM_014991), and CNV-seq identified a deletion of 150 kb encompassing NOTCH1. KMT2D and NOTCH1 previously have been reported to be associated with CHDs, however, WDFY3 is reported for the first time to be possibly related to CHD in human.Conclusion: Our study suggested that genetic component is an important risk factor for the development of LHH, and next generation sequencing is a powerful tool for genetic diagnosis in fetuses with CHDs and genetic counseling, however, more studies and data are need to establish the correlation of fetal phenotypes and genotypes.

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“…NGS testing was performed by Invitae as previously described [20], and variant interpretation was carried out based on an expansion of the American College of Medical Genetics guidelines [21]. Patient results were reviewed and categorized by variant classifications, i.e., negative (no reportable variants were identified), positive (pathogenic or likely pathogenic (P/LP) variants identified), and uncertain (variants of uncertain significance (VUS) identified).…”

Section: Description Of Testing Servicesmentioning

confidence: 99%

Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment

et al. 2020

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Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic and often life-threatening infections and/or life-threatening autoimmunity if not diagnosed and treated. Patients with a suspected PI, but without a genetic diagnosis, commonly undergo a diagnostic odyssey that is costly, time-consuming, and arduous. This delay in diagnosis prevents appropriate disease management and treatment, contributing to prolonged suffering and decreased quality of life. Although next generation sequencing (NGS) can provide these patients with relief from such a diagnostic odyssey, it is often unavailable, mainly due to cost and inaccessibility. In January 2019, the Jeffrey Modell Foundation (JMF) launched a free genetic sequencing pilot program for Jeffrey Modell Centers Network (JMCN) patients clinically diagnosed with an underlying PI. A total of 21 sites within the JMCN were invited to participate. JMF collaborated with Invitae, and testing was comprised of Invitae's Primary Immunodeficiency Panel, which currently includes 207 genes. A questionnaire was disseminated to each participating physician to evaluate barriers to access to genetic sequencing and changes in disease management and treatment after testing. One hundred fifty-eight patients and 29 family members were tested in this pilot study. Twenty-one percent of patients with a suspected monogenic disorder received a molecular diagnosis, and others received potentially useful diagnostic leads. Based on the results of genetic sequencing, clinical diagnosis was altered in 45% of patients, disease management was altered in 40%, treatment was altered in 36%, and genetic counseling was altered in 62%. The results of this pilot program demonstrate the utility, costefficiency, and critical importance of NGS for PI and make the case for broad scale sequence-based diagnostics for PI patients when requested by expert immunologists.

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Correction: Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Cited by 9 publications

References 0 publications

Global Expansion of Jeffrey’s Insights: Jeffrey Modell Foundation’s Genetic Sequencing Program for Primary Immunodeficiency

Global Expansion of Jeffrey’s Insights: Jeffrey Modell Foundation’s Genetic Sequencing Program for Primary Immunodeficiency

Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families

Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment

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