scholarly journals Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis

2020 ◽  
Vol 4 (12) ◽  
Author(s):  
Manuela G M Rocha-Braz ◽  
Monica M França ◽  
Adriana M Fernandes ◽  
Antonio M Lerario ◽  
Evelin A Zanardo ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Candidate Genes ◽  
Protein Function ◽  
Massively Parallel Sequencing ◽  
Snp Array ◽  
Tertiary Hospital ◽  
Additional Line ◽  
Personalized Care ◽  
Individual Level ◽  
Pathogenic Variants

Abstract Context The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.

scholarly journals Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Li ◽  
Belle W. X. Lim ◽  
Ella R. Thompson ◽  
Simone McInerny ◽  
Magnus Zethoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Candidate Genes ◽  
Familial Aggregation ◽  
Loss Of Function ◽  
Cancer Data ◽  
Pathogenic Variants ◽  
New Genes ◽  
Predisposing Genes ◽  
Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

scholarly journals QTL Analysis of Five Morpho-Physiological Traits in Bread Wheat Using Two Mapping Populations Derived from Common Parents

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 604
Author(s):  
Paolo Vitale ◽  
Fabio Fania ◽  
Salvatore Esposito ◽  
Ivano Pecorella ◽  
Nicola Pecchioni ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Recombinant Inbred Lines ◽  
Snp Array ◽  
Heading Date ◽  
Tiller Number ◽  
Genetic Maps ◽  
Yield Potential ◽  
Adaptation To Climate Change ◽  
Map Resolution ◽  
Mapping Populations

Traits such as plant height (PH), juvenile growth habit (GH), heading date (HD), and tiller number are important for both increasing yield potential and improving crop adaptation to climate change. In the present study, these traits were investigated by using the same bi-parental population at early (F2 and F2-derived F3 families) and late (F6 and F7, recombinant inbred lines, RILs) generations to detect quantitative trait loci (QTLs) and search for candidate genes. A total of 176 and 178 lines were genotyped by the wheat Illumina 25K Infinium SNP array. The two genetic maps spanned 2486.97 cM and 3732.84 cM in length, for the F2 and RILs, respectively. QTLs explaining the highest phenotypic variation were found on chromosomes 2B, 2D, 5A, and 7D for HD and GH, whereas those for PH were found on chromosomes 4B and 4D. Several QTL detected in the early generations (i.e., PH and tiller number) were not detected in the late generations as they were due to dominance effects. Some of the identified QTLs co-mapped to well-known adaptive genes (i.e., Ppd-1, Vrn-1, and Rht-1). Other putative candidate genes were identified for each trait, of which PINE1 and PIF4 may be considered new for GH and TTN in wheat. The use of a large F2 mapping population combined with NGS-based genotyping techniques could improve map resolution and allow closer QTL tagging.

scholarly journals Candidate genes and SNPs associated with stomatal conductance under drought stress in Vitis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Massimiliano Trenti ◽  
Silvia Lorenzi ◽  
Pier Luigi Bianchedi ◽  
Daniele Grossi ◽  
Osvaldo Failla ◽  
...  
Keyword(s):  
Drought Stress ◽  
Stomatal Conductance ◽  
Candidate Genes ◽  
Water Deficit ◽  
Genetic Basis ◽  
Phenotypic Diversity ◽  
Snp Array ◽  
A Genome ◽  
Raffinose Synthase ◽  
Response To Water

Abstract Background Understanding the complexity of the vine plant’s response to water deficit represents a major challenge for sustainable winegrowing. Regulation of water use requires a coordinated action between scions and rootstocks on which cultivars are generally grafted to cope with phylloxera infestations. In this regard, a genome-wide association study (GWAS) approach was applied on an ‘ad hoc’ association mapping panel including different Vitis species, in order to dissect the genetic basis of transpiration-related traits and to identify genomic regions of grape rootstocks associated with drought tolerance mechanisms. The panel was genotyped with the GrapeReSeq Illumina 20 K SNP array and SSR markers, and infrared thermography was applied to estimate stomatal conductance values during progressive water deficit. Results In the association panel the level of genetic diversity was substantially lower for SNPs loci (0.32) than for SSR (0.87). GWAS detected 24 significant marker-trait associations along the various stages of drought-stress experiment and 13 candidate genes with a feasible role in drought response were identified. Gene expression analysis proved that three of these genes (VIT_13s0019g03040, VIT_17s0000g08960, VIT_18s0001g15390) were actually induced by drought stress. Genetic variation of VIT_17s0000g08960 coding for a raffinose synthase was further investigated by resequencing the gene of 85 individuals since a SNP located in the region (chr17_10,497,222_C_T) was significantly associated with stomatal conductance. Conclusions Our results represent a step forward towards the dissection of genetic basis that modulate the response to water deprivation in grape rootstocks. The knowledge derived from this study may be useful to exploit genotypic and phenotypic diversity in practical applications and to assist further investigations.

scholarly journals Weighted Single-Step GWAS Identified Candidate Genes Associated with Growth Traits in a Duroc Pig Population

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 117
Author(s):  
Donglin Ruan ◽  
Zhanwei Zhuang ◽  
Rongrong Ding ◽  
Yibin Qiu ◽  
Shenping Zhou ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Bone Growth ◽  
Genome Wide Association Study ◽  
Growth Traits ◽  
Average Daily Gain ◽  
Snp Array ◽  
Single Step ◽  
Economic Traits ◽  
Association Analyses ◽  
Genealogical Information

Growth traits are important economic traits of pigs that are controlled by several major genes and multiple minor genes. To better understand the genetic architecture of growth traits, we performed a weighted single-step genome-wide association study (wssGWAS) to identify genomic regions and candidate genes that are associated with days to 100 kg (AGE), average daily gain (ADG), backfat thickness (BF) and lean meat percentage (LMP) in a Duroc pig population. In this study, 3945 individuals with phenotypic and genealogical information, of which 2084 pigs were genotyped with a 50 K single-nucleotide polymorphism (SNP) array, were used for association analyses. We found that the most significant regions explained 2.56–3.07% of genetic variance for four traits, and the detected significant regions (>1%) explained 17.07%, 18.59%, 23.87% and 21.94% for four traits. Finally, 21 genes that have been reported to be associated with metabolism, bone growth, and fat deposition were treated as candidate genes for growth traits in pigs. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses implied that the identified genes took part in bone formation, the immune system, and digestion. In conclusion, such full use of phenotypic, genotypic, and genealogical information will accelerate the genetic improvement of growth traits in pigs.

MO039IDENTIFICATION OF A RECURRENT SYNONYMOUS GENETIC VARIANT IN NPHP3 LEADING TO NEPHRONOPHTHISIS AND CONGENITAL HEPATIC FIBROSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eric Olinger ◽  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Eissa Ali Faqeih ◽  
Mohamed Al Hamed ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rna Splicing ◽  
Donor Site ◽  
Saudi Arabian ◽  
Bioinformatic Analysis ◽  
Initial Assessment ◽  
Splice Donor Site ◽  
Uk Biobank ◽  
Pathogenic Variants ◽  
Exon 20

Abstract Background and Aims Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice and has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. Filtering of variants and scoring variants in terms of pathogenicity still represents a major challenge and may explain why ∼50% of patients remain without diagnosis after initial assessment. Method In this study, we performed WES to determine the genetic cause of a hepato-renal ciliopathy syndrome in a genetically unsolved consanguineous family from Oman with 2 affected children. For variants filtering and annotation Qiagen Clinical Insight tool was used. Database searches for identical alleles in patients with similar phenotypes were performed using Genomics England, UK Biobank and a Saudi Arabian cohort. RNA studies were used to confirm a splicing defect. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project and from UK Biobank, a major biomedical database. Results Initial bioinformatic analysis of WES data from 2 affected sibs excluded obvious pathogenic variants in known genes associated with primary ciliopathy syndromes with liver and kidney phenotypes. However, by manual curation of variants in candidate genes, a rare homozygous synonymous allele in NPHP3 was identified (c.2805C>T; p.(Gly935Gly)), mid-exon 20 and within a region of shared homozygosity on chromosome 3. Correct segregation was confirmed via Sanger sequencing in the parents and the 2 affected sibs. The variant was rare in gnomAD (2/251374 alleles) and was found heterozygously in just one individual within the UK Biobank cohort of 200,000 exomes. Using various in silico tools, the allele was shown to activate a cryptic splice donor site in the middle of exon 20. RT-PCR with sequencing of parental whole blood RNA confirmed alternative splicing leading to frameshift p.Gly935GlyfsTer47. The identical homozygous allele was identified in 2 additional unsolved families within the Genomics England 100,000 Genomes Project and in 1 Saudi Arabian family with similar hepato-renal phenotypes. Conclusion This study shows that automated filtering of WES data may exclude synonymous variants which are pathogenic, especially if they are mid-exon. Here we identified a recurrent synonymous NPHP3 variant leading to a splice defect as the cause of a hepato-renal ciliopathy phenotype in four families. In unsolved cases, rare synonymous alleles in candidate genes need to be reassessed for impact on RNA splicing and possible pathogenicity.

scholarly journals Clinical and Genetic Analysis of a European Cohort with Pericentral Retinitis Pigmentosa

2019 ◽  
Vol 21 (1) ◽  
pp. 86 ◽  
Author(s):  
Marianthi Karali ◽  
Francesco Testa ◽  
Raffaella Brunetti-Pierri ◽  
Valentina Di Iorio ◽  
Mariateresa Pizzo ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Retinitis Pigmentosa ◽  
Ophthalmological Examination ◽  
Mild Phenotype ◽  
Atypical Form ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Independent Families ◽  
Gene Panel Sequencing ◽  
Panel Sequencing

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.

scholarly journals Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR

2019 ◽  
Vol 8 (5) ◽  
pp. 590-595 ◽  
Author(s):  
Marilena Nakaguma ◽  
Fernanda A Correa ◽  
Lucas S Santana ◽  
Anna F F Benedetti ◽  
Ricardo V Perez ◽  
...  
Keyword(s):  
Target Gene ◽  
Gh Deficiency ◽  
Massively Parallel Sequencing ◽  
Genetic Diagnosis ◽  
Pituitary Hormones ◽  
Gene Panel ◽  
Massively Parallel ◽  
Parallel Sequencing ◽  
Pathogenic Variants ◽  
Congenital Hypopituitarism

Aim Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. Methods Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. Results We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A]. Conclusions Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

scholarly journals GENETIC ANALYSIS OF FAMILIES HAVING AUTOSOMAL RECESSIVE INTELLECTUAL DISABILITY

2019 ◽  
Vol 17 (2) ◽  
Author(s):  
Jamshed Khan ◽  
Muhammad Junaid ◽  
Shahab Uddin ◽  
Khalida Moeed ◽  
Usman Ullah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Genetic Analysis ◽  
Single Gene ◽  
Cross Sectional Study ◽  
Molecular Diagnostic ◽  
Developmental Defect ◽  
Chromosomal Disorders ◽  
Cross Sectional ◽  
Pathogenic Variants ◽  
Development Delay

Background: Intellectual disability (ID) is a neuro-developmental defect that is manifested by development delay and learning disability. Such defects may be caused due to chromosomal disorders (trisomy 18 or Down syndrome) or single gene mutation. Its worldwide prevalence is estimated to be 1-3%. The genetic etiology of non-syndromic ID is poorly understood. To date, more than 100 loci have been reported to be associated with non-syndromic ID. The objective of this study was to identify the causative genes for three Materials & Methods: This cross-sectional study was conducted in the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan from March 2014 to August 2015. The inclusion criteria set for the families was consanguineous relation and more than two patients per family (including cousins). All the patients were tested individually in friendly atmosphere using IQ test to scale the ID on the basis of performance. Thereafter, blood samples were taken by aseptic method and DNA was extracted for the purpose of doing genetic analysis. In genetic analysis, exome sequencing was performed to find the pathogenic variants. Subsequently. Sanger sequencing was also done to see the segregation of pathogenic variants. Results: Genetic analysis found mutation in AP4B1 in Family 1, in WDR62 in Family 2, while Family 3 was unremarkable. Conclusion: The study involved genetic analysis of three consanguineous families and found mutation in AP4B1 in Family 1, in WDR62 in Family 2, while Family 3 was unremarkable. The present research will help in devising molecular diagnostic technics for pre-marital and pre-conception testing.

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