scholarly journals Genetic diagnosis of Mendelian disorders via RNA sequencing

2016 ◽  
Author(s):  
Laura S Kremer ◽  
Daniel M Bader ◽  
Christian Mertes ◽  
Robert Kopajtich ◽  
Garwin Pichler ◽  
...  
Keyword(s):  
Rare Variants ◽  
Genetic Diagnosis ◽  
Underlying Disease ◽  
Diagnostic Tools ◽  
Loss Of Function ◽  
Mendelian Disorders ◽  
Whole Exome ◽  
Established Disease ◽  
Assembly Factor ◽  
Strong Candidate

AbstractAcross a large variety of Mendelian disorders, ~50-75% of patients do not receive a genetic diagnosis by whole exome sequencing indicative of underlying disease-causing variants in non-coding regions. In contrast, whole genome sequencing facilitates the discovery of all genetic variants, but their sizeable number, coupled with a poor understanding of the non-coding genome, makes their prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to provide a confirmed genetic diagnosis for 10% (5 of 48) of undiagnosed mitochondrial disease patients and identify strong candidate genes for patients remaining without diagnosis. We found a median of 1 aberrantly expressed gene, 5 aberrant splicing events, and 6 mono-allelically expressed rare variants in patient-derived fibroblasts and established disease-causing roles for each kind. Private exons often arose from sites that are weakly spliced in other individuals, providing an important clue for future variant prioritization. One such intronic exon-creating variant was found in three unrelated families in the complex I assembly factor TIMMDC1, which we consequently established as a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants of Mendelian disorders and provides examples of intronic loss-of-function variants with pathological relevance.

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 Identification of sixteen novel candidate genes for late onset Parkinson’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Alessandro Gialluisi ◽  
Mafalda Giovanna Reccia ◽  
Nicola Modugno ◽  
Teresa Nutile ◽  
Alessia Lombardi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Candidate Genes ◽  
Rare Variants ◽  
Late Onset ◽  
High Specificity ◽  
Diagnostic Tools ◽  
Multi Stage ◽  
Whole Exome ◽  
Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

scholarly journals A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke

2020 ◽  
Author(s):  
Elli Katharine Greisenegger ◽  
Sara Llufriu ◽  
Angel Chamorro ◽  
Alvaro Cervera ◽  
Adriano Jimenez-Escrig ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Underlying Disease ◽  
Allelic Loss ◽  
Pediatric Stroke ◽  
Loss Of Function ◽  
Whole Exome ◽  
Epidermal Growth ◽  
Epidermal Growth Factor Repeat ◽  
Homozygous Nonsense Mutation ◽  
Sneddon Syndrome

Abstract Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

scholarly journals Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

2020 ◽  
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 ◽  
Paediatric Patients ◽  
Whole Exome ◽  
Prediction Of Prognosis

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 targeted 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. Conclusion: 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 using targeted therapies. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals A Bi-allelic Frameshift Mutation in NPNT Causes Bilateral Renal Agenesis in Humans

2021 ◽  
pp. ASN.2020121762
Author(s):  
Lei Dai ◽  
Jingzhi Li ◽  
Liangqun Xie ◽  
Weinan Wang ◽  
Yang Lu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Kidney Development ◽  
Renal Agenesis ◽  
Genetic Diagnosis ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Fetal Ultrasonography ◽  
Whole Exome ◽  
Recessive Form

Background: Bilateral renal agenesis (BRA) is a lethal congenital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios upon fetal ultrasonography reveals BRA. Although exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics cannot pick up many clinical cases. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. Methods: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy due to suspicion of BRA. Whole-exome sequencing-(WES)-:based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. Results: WES and evaluation of homozygous regions in II-3 and II-4 revealed a pathological homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. Conclusions: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.

scholarly journals Gene-level analysis of rare variants in 363,977 whole exome sequences reveals an association of GIGYF1 loss of function with diabetes

2021 ◽  
Author(s):  
Aimee M. Deaton ◽  
Margaret M. Parker ◽  
Lucas D. Ward ◽  
Alexander O. Flynn-Carroll ◽  
Lucas BonDurant ◽  
...  
Keyword(s):  
Rare Variants ◽  
Loss Of Function ◽  
Cholesterol Levels ◽  
Whole Exome ◽  
Increased Risk ◽  
Gene Level ◽  
Rare Genetic Variants ◽  
The Uk ◽  
Novel Associations

AbstractSequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and T2D diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified known associations with diabetes including variants in GCK, HNF1A and PDX1, genes involved in Mendelian forms of diabetes. Novel associations were identified for GIGYF1 predicted loss of function (pLOF), TNRC6B pLOF and PFAS predicted damaging missense variants. Multiple rare variants contributed to these associations, including singleton variants. The most significant novel associations were seen for GIGYF1 pLOF which associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10−12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10−14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x10−11). GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. An independent common variant association for glucose and T2D was identified at GIGYF1 which replicated in additional datasets. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.

scholarly journals Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

2019 ◽  
Author(s):  
Youngha Lee ◽  
Soojin Park ◽  
Jin Sook Lee ◽  
Soo Yeon Kim ◽  
Jaeso Cho ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Pathogenic Variant ◽  
Mendelian Disease ◽  
Loss Of Function ◽  
Variant Discovery ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Neurodevelopmental Problems

AbstractBackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.MethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.ResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.ConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

scholarly journals Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

2018 ◽  
Author(s):  
Neha S. Raghavan ◽  
Adam M. Brickman ◽  
Howard Andrews ◽  
Jennifer J. Manly ◽  
Nicole Schupf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Age At Onset ◽  
Genomic Medicine ◽  
Loss Of Function ◽  
Whole Exome ◽  
A Genome

AbstractObjectiveThe genetic bases of Alzheimer’s disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer’s disease using whole exome sequencing in 20,197 individuals.MethodsWe used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer’s Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.ResultsWe identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (p = 2.17 × 10-8; OR 36.2 [95%CI 5.8 – 1493.0]). Age-at-onset was seven years earlier for patients with SORL1 qualifying variant compared with non-carriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP, WDR76 and GRN, were among candidates for follow-up studies.InterpretationThis study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer’s disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer’s disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer’s disease in a large whole-exome study of unrelated cases and controls.

scholarly journals Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5927 ◽  
Author(s):  
Zhening Pu ◽  
Haoliang Sun ◽  
Junjie Du ◽  
Yue Cheng ◽  
Keshuai He ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Connective Tissue Disorder ◽  
Pedigree Analysis ◽  
Vital Role ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Background Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

scholarly journals Loss of function mutation in ELF4 causes autoinflammatory and immunodeficiency disease in human

2021 ◽  
Author(s):  
Gan Sun ◽  
Luyao Qiu ◽  
Yunfei An ◽  
Yuan Ding ◽  
Lina Zhou ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Exome Sequencing ◽  
Pediatric Patient ◽  
Experimental Approach ◽  
Genetic Diagnosis ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Familial Cases ◽  
Whole Exome ◽  
Immunodeficiency Disease

Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various specific genetic causes. Genetic diagnosis of mAIDs can assist in the patient's management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Here, we described a pediatric patient suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer and constipation, who was clinically diagnosed of inborn errors of immunity (IEI). In an effort to establish genetic diagnosis, no known causative genes were identified by whole-exome sequencing. However, manually going through bioinformatically predicted candidate genes, we suspected and prioritized ELF4 (chrX:129205133 A>G, c.691T>C, p.W231R) as the genetic cause for our patient. We then evaluated the pathogenicity of this mutation by both various bioinformatic methods and preliminary but definitive experimental approach. Our data suggested that W231R mutant ELF4 is a "loss of function" mutation causing decreased protein stability and decreased trans-activation activity. Thus, we identified a novel mAID, which we termed "X-linked autoinflammatory and immunodeficiency disease associated with ELF4, X-AIDE".

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