scholarly journals Contributions of Rare Gene Variants to Familial and Sporadic FSGS

2019 ◽  
Vol 30 (9) ◽  
pp. 1625-1640 ◽  
Author(s):  
Minxian Wang ◽  
Justin Chun ◽  
Giulio Genovese ◽  
Andrea U. Knob ◽  
Ava Benjamin ◽  
...  
Keyword(s):  
Rare Variants ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Unrelated Family ◽  
The Past ◽  
New Genes ◽  
Rare Gene ◽  
Gene Defects ◽  
Disease Associated Genes ◽  
Burden Tests

BackgroundOver the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases.MethodsTo investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes.ResultsWe validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as “causal” if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1, SETD2, and LY9. Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes.ConclusionsAlthough our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported “disease-causing” variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.

scholarly journals ESHRE PGT Consortium good practice recommendations for the organisation of PGT†

2020 ◽  
Vol 2020 (3) ◽  
Author(s):  
Filipa Carvalho ◽  
Edith Coonen ◽  
Veerle Goossens ◽  
Georgia Kokkali ◽  
Carmen Rubio ◽  
...  
Keyword(s):  
Best Practice ◽  
Single Gene ◽  
Good Practice ◽  
Diagnostic Testing ◽  
Genetic Diagnosis ◽  
Information Provision ◽  
Embryo Biopsy ◽  
Preimplantation Genetic Testing ◽  
Gene Defects

Abstract The field of preimplantation genetic testing (PGT) is evolving fast, and best practice advice is essential for regulation and standardisation of diagnostic testing. The previous ESHRE guidelines on best practice for preimplantation genetic diagnosis, published in 2005 and 2011, are considered outdated and the development of new papers outlining recommendations for good practice in PGT was necessary. The current updated version of the recommendations for good practice is, similar to the 2011 version, split into four documents, one of which covers the organisation of a PGT centre. The other documents focus on the different technical aspects of embryo biopsy, PGT for monogenic/single-gene defects (PGT-M) and PGT for chromosomal structural rearrangements/aneuploidies (PGT-SR/PGT-A). The current document outlines the steps prior to starting a PGT cycle, with details on patient inclusion and exclusion, and counselling and information provision. Also, recommendations are provided on the follow-up of PGT pregnancies and babies. Finally, some further recommendations are made on the practical organisation of an IVF/PGT centre, including basic requirements, transport PGT and quality management. This document, together with the documents on embryo biopsy, PGT-M and PGT-SR/PGT-A, should assist everyone interested in PGT in developing the best laboratory and clinical practice possible.

scholarly journals Egészséges gyermek születése karyomapping eljárással történő preimplantációs genetikai diagnózist követően

2016 ◽  
Vol 157 (51) ◽  
pp. 2048-2050
Author(s):  
László Nánássy ◽  
Gyöngyvér Téglás ◽  
Marianna Csenki ◽  
Attila Vereczkey
Keyword(s):  
Preimplantation Genetic Diagnosis ◽  
Assisted Reproductive Technologies ◽  
Single Nucleotide Polymorphism Array ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Reproductive Technologies ◽  
Congenital Glaucoma ◽  
Primary Congenital Glaucoma ◽  
A Genome ◽  
Gene Defects

Abstract: Preimplantation genetic diagnosis for single gene defects is a well established method in assisted reproductive technologies. Karyomapping is a genome wide parental haplotyping using a high density single nucleotide polymorphism array that allows the diagnosis of any single gene defects. A couple with an affected child with primary congenital glaucoma attended at our clinic. Six oocyte-cumulus-complex was retrieved and all three mature oocytes were inseminated. One zygote showed the signs of normal fertilization and was cultured for five days. Trophectoderm biopsy and karyomapping analysis were carried out. Result showed a heterozygous carrier for primary congenital glaucoma. Embryo was thawed and transferred and a healthy girl was delivered at term. Here we report the first live birth following in vitro fertilization combined with preimplantation genetic diagnosis using karyomapping in Hungary. Karyomapping is able to accurately detect single gene disorders from a limited amount of samples without a significant preclinical workup. Orv. Hetil., 2016, 157(51), 2048–2050.

scholarly journals Exome-Based Rare-Variant Analyses in CKD

2019 ◽  
Vol 30 (6) ◽  
pp. 1109-1122 ◽  
Author(s):  
Sophia Cameron-Christie ◽  
Charles J. Wolock ◽  
Emily Groopman ◽  
Slavé Petrovski ◽  
Sitharthan Kamalakaran ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rare Variant ◽  
Rare Variants ◽  
Genetic Modifier ◽  
Genetic Associations ◽  
New Genes ◽  
Causal Genes ◽  
Disease Associated Genes ◽  
Biallelic Mutations ◽  
Carnitine Palmitoyltransferase Ii

BackgroundStudies have identified many common genetic associations that influence renal function and all-cause CKD, but these explain only a small fraction of variance in these traits. The contribution of rare variants has not been systematically examined.MethodsWe performed exome sequencing of 3150 individuals, who collectively encompassed diverse CKD subtypes, and 9563 controls. To detect causal genes and evaluate the contribution of rare variants we used collapsing analysis, in which we compared the proportion of cases and controls carrying rare variants per gene.ResultsThe analyses captured five established monogenic causes of CKD: variants in PKD1, PKD2, and COL4A5 achieved study-wide significance, and we observed suggestive case enrichment for COL4A4 and COL4A3. Beyond known disease-associated genes, collapsing analyses incorporating regional variant intolerance identified suggestive dominant signals in CPT2 and several other candidate genes. Biallelic mutations in CPT2 cause carnitine palmitoyltransferase II deficiency, sometimes associated with rhabdomyolysis and acute renal injury. Genetic modifier analysis among cases with APOL1 risk genotypes identified a suggestive signal in AHDC1, implicated in Xia–Gibbs syndrome, which involves intellectual disability and other features. On the basis of the observed distribution of rare variants, we estimate that a two- to three-fold larger cohort would provide 80% power to implicate new genes for all-cause CKD.ConclusionsThis study demonstrates that rare-variant collapsing analyses can validate known genes and identify candidate genes and modifiers for kidney disease. In so doing, these findings provide a motivation for larger-scale investigation of rare-variant risk contributions across major clinical CKD categories.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Personalized Medicine in Cancer

2015 ◽  
Vol 32 (3) ◽  
pp. 153-163
Author(s):  
Md Mizanur Rahman
Keyword(s):  
Personalized Medicine ◽  
Single Gene ◽  
Biomedical Science ◽  
Practical Application ◽  
Molecular Alteration ◽  
New Era ◽  
Patients With Cancer ◽  
The Past ◽  
Molecular Aspects

Current and emerging biomedical science efforts are driven by determining how to improve clini-cal outcomes for patients. High-throughput tech-nology has revolutionized the area of transla-tional research, confirming the high complexity and heterogeneity of common diseases, partic-ularly cancer. Therefore, moving from ‘classic’ single-gene-based molecular investigation to molecular network research might result in dis-covering clinical implications faster and more efficiently .Molecular characterization of tumour cells enables refinement of classifications for many cancers and can sometimes guide treatment. Malignant diseases are no longer classified only by tumour site and histology but are separated into various homogenous molecular subtypes, distinguished by a presumed key molecular alteration. Therapies for patients with cancer have changed gradually over the past decade, moving away from the administration of broadly acting cytotoxic drugs towards the use of more-specific therapies that are targeted to each tumour. To facilitate this shift, tests need to be developed to identify those individuals who require therapy and those who are most likely to benefit from certain therapies. In particular, tests that predict the clinical outcome for patients on the basis of the genes expressed by their tumours are likely to increasingly affect patient management, heralding a new era of personalized medicine. In this review a brief discussion on definition and molecular aspects of personalized medicine and its practical application for the management of common solid cancers are highlighted.J Bangladesh Coll Phys Surg 2014; 32: 153-163

Optimal sampling for pedigree analysis: tracing a single gene

1982 ◽  
Vol 14 (4) ◽  
pp. 752-762 ◽  
Author(s):  
E. A. Thompson
Keyword(s):  
Probability Distribution ◽  
Single Gene ◽  
Pedigree Analysis ◽  
Genetic Models ◽  
Optimal Sampling ◽  
Large Pedigree ◽  
Sequential Procedures ◽  
Rare Gene ◽  
Enhance Efficiency ◽  
Sampling Rule

In fitting genetic models on the basis of observations on an interrelated structure, sequential procedures can enhance efficiency. In this paper we consider the case of a rare gene segregating in a single large pedigree. The sampling rule is dictated by the effect of observations on the genotypic probability distribution of unobserved relatives; this effect is investigated.

scholarly journals Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

2018 ◽  
Author(s):  
Lucilla Pizzo ◽  
Matthew Jensen ◽  
Andrew Polyak ◽  
Jill A. Rosenfeld ◽  
Katrin Mannik ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Background ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Disease Genes ◽  
Complete Evaluation ◽  
Rare Cnvs ◽  
Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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