Genetic testing in motor neurone disease

A minority (10%–15%) of cases of amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), are currently attributable to pathological variants in a single identifiable gene. With the emergence of new therapies targeting specific genetic subtypes of ALS, there is an increasing role for routine genetic testing for all those with a definite diagnosis. However, potential harm to both affected individuals and particularly to asymptomatic relatives can arise from the indiscriminate use of genetic screening, not least because of uncertainties around incomplete penetrance and variants of unknown significance. The most common hereditary cause of ALS, an intronic hexanucleotide repeat expansion in C9ORF72, may be associated with frontotemporal dementia independently within the same pedigree. The boundary of what constitutes a possible family history of MND has therefore extended to include dementia and associated psychiatric presentations. Notwithstanding the important role of clinical genetics specialists, all neurologists need a basic understanding of the current place of genetic testing in MND, which holds lessons for other neurological disorders.

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The incidence of BRCA1 and BRCA2 variants of unknown significance varies in different ethnic populations

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10002 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10002-10002 ◽

Cited By ~ 1

Author(s):

D. M. Opatt ◽

M. Morrow ◽

M. Daly

Keyword(s):

Breast Cancer ◽

African American ◽

Genetic Testing ◽

African American Women ◽

White Women ◽

Personal History ◽

Brca1 And Brca2 ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

History Of

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

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PTEN Promoter Variants Are Not Associated With Common Cancers: Implications for Multigene Panel Testing

JCO Precision Oncology ◽

10.1200/po.17.00108 ◽

2017 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Mary Helen Black ◽

Shuwei Li ◽

Tina Pesaran ◽

Holly LaDuca ◽

Rachid Karam ◽

...

Keyword(s):

Personal History ◽

Variants Of Unknown Significance ◽

Panel Testing ◽

Multiple Primary ◽

Unknown Significance ◽

Uterine Endometrial Cancer ◽

History Of ◽

Race Ethnicity ◽

Multigene Panel Testing ◽

Multigene Panel

Purpose PTEN mutations are associated with breast, colon, endometrial, kidney, and thyroid cancers. Most PTEN promoter alterations, however, are characterized as variants of unknown significance, and their contribution to cancer risk is unclear. Materials and Methods Personal and family histories of 88,333 patients undergoing PTEN analysis as part of multigene panel testing (MGPT) were retrospectively reviewed. Cases (n = 59,784) were individuals with personal history of PTEN-related cancer. Controls (n = 28,549) had no personal history of cancer. Individuals were categorized as positive for one or more mutations (PATHO), without mutations but carrying one or more promoter variant (PROM), or negative for alterations (WT). Multivariable logistic regression was used to assess PTEN associations with phenotypes, adjusted for race/ethnicity, age, sex, and MGPT. Results Overall, 79 (0.09%) patients were PATHO and 791 (0.9%) were PROM carriers. Compared with WT, PATHOs were 2.30 (95% CI, 1.19 to 4.72) times as likely to have breast, 7.23 (95% CI, 2.74 to 19.14) times as likely to have bilateral/multiple primary breast, and 7.56 (95% CI, 1.97 to 23.98) times as likely to have uterine/endometrial cancer. PROMs were not significantly more likely than WT to have cancer (all 0.84 < odds ratio < 1.15; P > .05). Conclusion PTEN promoter variants were not associated with cancer. These results do not support the inclusion of PTEN promoter sequencing in MGPT.

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Variants in HNRNPDL and SETX Not Necessarily Indicate Familial Amyotrophic Lateral Sclerosis or Limb Girdle Muscular Dystrophy 1G in Acute Muscular Respiratory Failure

Journal of Neurosciences in Rural Practice ◽

10.1055/s-0040-1709375 ◽

2020 ◽

Vol 11 (02) ◽

pp. 353-354

Author(s):

Josef Finsterer ◽

Claudia Stöllberger ◽

Hans Keller ◽

Franco Laccone

Keyword(s):

Respiratory Failure ◽

Variants Of Unknown Significance ◽

Non Invasive ◽

Non Invasive Ventilation ◽

Unknown Significance ◽

History Of ◽

History Of Epilepsy ◽

Diagnostic Work ◽

Conclusive Diagnosis ◽

Work Up

AbstractGenetic work-up is useful for the identification of a primary myopathy. However, even sophisticated genetic methods may fail to detect the underlying cause of myopathy as in the following case. The patient is a 52-year-old female with a history of epilepsy, arterial hypertension, atrial flutter requiring cardioversion, ablation, and anticoagulation, coronary heart disease, hyperlipidemia, and hyper-CKemia. At age 52 years, she was referred for heart failure due to ischemic cardiomyopathy requiring appropriate medication and implantation of an ICD. During hospitalization she developed acute muscular respiratory failure requiring mechanical ventilation. Genetic panels for myopathy, neuropathy, and cardiomyopathy revealed variants of unknown significance in the HNRNPDL and SETX genes respectively. Clinical presentation and muscle biopsy, however, suggested metabolic myopathy. Acute muscular respiratory failure may require traditional diagnostic work-up for primary myopathy and long-term invasive and non-invasive ventilation. Panel investigations not necessarily lead to a conclusive diagnosis. The multisystem nature of the condition rather suggests a metabolic defect than LGMD-1G or fALS as genetic findings suggested.

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Facilitations and Hurdles of Genetic Testing in Neuromuscular Disorders

Diagnostics ◽

10.3390/diagnostics11040701 ◽

2021 ◽

Vol 11 (4) ◽

pp. 701

Author(s):

Andrea Barp ◽

Lorena Mosca ◽

Valeria Ada Sansone

Keyword(s):

Genetic Testing ◽

Neuromuscular Disorders ◽

Single Nucleotide Variants ◽

Gene Therapies ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

New Gene ◽

Genetic Techniques ◽

Definition Of ◽

Next Generation Sequencing Ngs

Neuromuscular disorders (NMDs) comprise a heterogeneous group of disorders that affect about one in every thousand individuals worldwide. The vast majority of NMDs has a genetic cause, with about 600 genes already identified. Application of genetic testing in NMDs can be useful for several reasons: correct diagnostic definition of a proband, extensive familial counselling to identify subjects at risk, and prenatal diagnosis to prevent the recurrence of the disease; furthermore, identification of specific genetic mutations still remains mandatory in some cases for clinical trial enrollment where new gene therapies are now approaching. Even though genetic analysis is catching on in the neuromuscular field, pitfalls and hurdles still remain and they should be taken into account by clinicians, as for example the use of next generation sequencing (NGS) where many single nucleotide variants of “unknown significance” can emerge, complicating the correct interpretation of genotype-phenotype relationship. Finally, when all efforts in terms of molecular analysis have been carried on, a portion of patients affected by NMDs still remain “not genetically defined”. In the present review we analyze the evolution of genetic techniques, from Sanger sequencing to NGS, and we discuss “facilitations and hurdles” of genetic testing which must always be balanced by clinicians, in order to ensure a correct diagnostic definition, but taking always into account the benefit that the patient could obtain especially in terms of “therapeutic offer”.

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The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

Genetics in Medicine ◽

10.1038/s41436-021-01127-8 ◽

2021 ◽

Author(s):

Eva Schrezenmeier ◽

Elisa Kremerskothen ◽

Fabian Halleck ◽

Oliver Staeck ◽

Lutz Liefeldt ◽

...

Keyword(s):

Kidney Transplantation ◽

Genetic Testing ◽

Kidney Disease ◽

Diagnostic Value ◽

Considerable Proportion ◽

Major Health ◽

Variants Of Unknown Significance ◽

Health Care Burden ◽

Unknown Significance ◽

Next Generation Sequencing Ngs

Abstract Purpose Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. Methods In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. Results In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. Conclusion Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

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In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

Scientific Reports ◽

10.1038/s41598-021-88586-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kok-Siong Poon

Keyword(s):

Genetic Testing ◽

Molecular Genetic ◽

In Silico Analysis ◽

Molecular Testing ◽

Brca1 And Brca2 ◽

Missense Variants ◽

Variants Of Unknown Significance ◽

Sorting Intolerant From Tolerant ◽

Unknown Significance ◽

High Concordance

AbstractOver the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.

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Identification of novel missense mutation in a patient with an asymptomatic para-aortic paraganglioma

BMJ Case Reports ◽

10.1136/bcr-2021-245427 ◽

2021 ◽

Vol 14 (10) ◽

pp. e245427

Author(s):

Salah Daghlas ◽

Rajani Gundluru ◽

Ayman Nada ◽

Uzma Khan

Keyword(s):

Missense Mutation ◽

In Silico Analysis ◽

Caucasian Woman ◽

Donor Kidney ◽

Urinary Catecholamines ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

History Of ◽

Silico Analysis ◽

Kidney Transplant Donor

A 31-year-old Caucasian woman underwent a standard workup as a potential kidney transplant donor. Kidney donor protocol CT showed a left para-aortic hypervascular mass suspicious for a paraganglioma. Biochemical workup revealed elevated urinary catecholamines, supporting this suspicion. The patient underwent surgical resection with histopathological evaluation that confirmed the diagnosis. Endocrine evaluation 2 years later revealed a family history of a cousin with a history of pheochromocytoma as a teenager. A genetic panel identified a missense mutation in succinate dehydrogenase C (c.202T>C; p.Ser68Pro), which was described as a variant of unknown significance. In silico analysis suggested that it may be a deleterious mutation. We concluded that this mutation may be pathogenic, considering these supporting pieces of evidence and her early-onset paraganglioma. This report highlights the importance of genetic screening in patients with paragangliomas/pheochromocytomas, since many cases are familial. Additionally, it underscores the importance of evaluating and documenting cases of variants of unknown significance.

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Genetic risk assessment for hereditary RCC: Report from the consensus panel meeting.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.615 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 615-615

Author(s):

Michael Daneshvar ◽

Neil Mendhiratta ◽

Ramaprasad Srinivasan ◽

Eric Jonasch ◽

Mark Wayne Ball ◽

...

Keyword(s):

Risk Assessment ◽

Genetic Testing ◽

Kidney Cancer ◽

Genetic Risk ◽

Genetic Counselors ◽

Genetic Risk Assessment ◽

Variants Of Unknown Significance ◽

Modified Delphi ◽

Unknown Significance ◽

Patient Advocates

615 Background: While many genes are now known to be associated with hereditary kidney cancer syndromes, there is a paucity of guidelines or uniform consensus on genetic testing for these patients. An expert panel was organized to assess who, what, when and how patients should be evaluated and what testing should be initiated. Methods: A national, multidisciplinary, panel of experts in urology, medical oncology, clinical geneticists, genetic counselors and patient advocates with background and knowledge in hereditary syndromic kidney cancer convened in person in September 2019. A renal cell carcinoma (RCC) genetic risk assessment questionnaire consisting of 52 questions was compiled prior to the meeting using modified Delphi methodology. The questions were then discussed and reviewed with uniform consensus defined as a minimum of 85% agreement in accordance with the National Comprehensive Cancer Network criteria. Results: The panel consisted of twenty-six attendees represented by urologists (43%), medical oncologist (23%), genetic counselors (13%), clinical geneticists (7%), and patient advocates (3%). The questionnaire consisted of fifty-five statements focusing on who, what, when and how genetic testing should be performed in a patient suspected of hereditary RCC syndrome. A >85% agreement was reached on 30/52 statements with 18/25 (72%) achieving consensus addressing “who”, 2/6 (33%) achieving consensus in “what’ category, 2/7 (29%) in ‘when’ and 4/6 (67%) on how. The questions with least consensus were found in the “what/when?” category with only 4/13 questions with minimum 85% agreement. Specific areas of debate included an age cutoff for prompting a genetic risk assessment as well as need for familial testing in patients with variants of unknown significance. Conclusions: Despite experience of the panel in management of hereditary RCC, the consensus was reached only on 66% of genetic testing. While many issues will need to be discussed further, those statements with consensus may be used to guide physicians and patients on who, what, when and how genetic RCC risk assessment should be performed.

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Ethical Considerations in Neurogenetic Testing

Seminars in Neurology ◽

10.1055/s-0038-1667382 ◽

2018 ◽

Vol 38 (05) ◽

pp. 505-514 ◽

Cited By ~ 2

Author(s):

Xiaowei Su ◽

Zachary Simmons

Keyword(s):

Genetic Testing ◽

Ethical Issues ◽

Diagnostic Testing ◽

Ethical Principles ◽

Ethical Framework ◽

Complex Nature ◽

Neurologic Diseases ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

The One

AbstractRecent advances in the genetics of neurologic diseases coupled with improvements in sensitivity and specificity are making genetic testing an increasingly important part of diagnosis and management for neurologists. However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions. This review summarizes ethical issues related to genetic testing for neurologic diseases, with a focus on clinical practice. Informed consent for genetic testing of patients and asymptomatic at-risk family members is discussed. The roles and responsibilities of physicians as genetic counselors are reviewed, including the framing of incidental findings and variants of unknown significance that impact individuals' decisions about whether to pursue genetic testing and what results they wish to know. Disclosure and its consequences for the patient are placed within an ethical framework to permit a better understanding of why genetic testing is different from most other diagnostic testing ordered by physicians. The review ends with clinical vignettes that attempt to place ethical principles into familiar clinical settings involving physicians, patients and their families.

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