scholarly journals Pseudodominant Nanophthalmos in a Roma Family Caused by a Novel PRSS56 Variant

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Lubica Dudakova ◽  
Pavlina Skalicka ◽  
Olga Ulmanová ◽  
Martin Hlozanek ◽  
Viktor Stranecky ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Genetic ◽  
Visual Fields ◽  
Retinal Dystrophy ◽  
Facial Dysmorphism ◽  
Ocular Involvement ◽  
Nucleotide Polymorphisms ◽  
Roma Population ◽  
Pathogenic Variants ◽  
Bilateral Congenital Cataract

Background. The aim of the study was to identify the molecular genetic cause of two different Mendelian traits with ocular involvement present in the members of a single consanguineous Czech Roma family. Methods. We have performed ocular examination and review of medical records in two individuals diagnosed with nanophthalmos (proband and her father) and one individual followed for bilateral congenital cataract and microcornea (uncle of the proband). DNA of subjects with nanophthalmos was analysed by exome sequencing. Sanger sequencing was applied for targeted screening of potentially pathogenic variants and to follow segregation of identified variants within the family. Results. A homozygous variant c.1509G>C; p.(Met503Ile), in PRSS56 was found in the two individuals affected with nanophthalmos. The change was absent from the gnomAD dataset, but two out of 118 control Roma individuals were also shown to be heterozygous carriers. Analysis of single nucleotide polymorphisms in linkage disequilibrium with the c.1509G>C in PRSS56 suggested a shared chromosomal segment. The nanophthalmos phenotype, characterized in detail in the younger individual, encompassed bilateral corneal steepening, retinal folds, buried optic head drusen, and restricted visual fields, but no signs of retinal dystrophy. A known pathogenic founder CTDP1 variant c.863+389C>T in a homozygous state was identified in the other family member confirming the suspected diagnosis of congenital cataracts, facial dysmorphism, and demyelinating neuropathy syndrome. Conclusions. Herein, we report the first occurrence of nanophthalmos in the Roma population. We have identified pseudodominant inheritance for this phenotype caused by a novel variant in PRSS56, representing a possible founder effect. Despite advances in genetic technologies such as exome sequencing, careful phenotype evaluation in patients from an isolated population, along with an awareness of population-specific founder effects, is necessary to ensure that accurate molecular diagnoses are made.

scholarly journals Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1329
Author(s):  
Julia Doll ◽  
Barbara Vona ◽  
Linda Schnapp ◽  
Franz Rüschendorf ◽  
Imran Khan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Splice Site ◽  
Genetic Heterogeneity ◽  
Bioinformatics Analysis ◽  
Molecular Genetic ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss ◽  
Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

scholarly journals A study of new molecular genetic markers of sudden cardiac death identified in the analysis of the results of whole-exome sequencing

2020 ◽  
pp. 33-35
Author(s):  
А.А. Иванова ◽  
Е.С. Мельникова ◽  
А.А. Гуражева ◽  
С.К. Малютина ◽  
В.П. Новоселов ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Markers ◽  
Cardiac Death ◽  
Molecular Genetic ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Molecular Genetic Markers ◽  
Whole Exome

Целью исследования является подтверждение ассоциации с внезапной сердечной смертью однонуклеотидных полиморфизмов rs77270326, rs34643859, выявленных в ходе собственного полноэкзомного секвенирования как возможных молекулярно-генетических маркеров внезапной сердечной смерти. В группе внезапной сердечной смерти (n=400, средний возраст умерших 53,2±8,7 года, доля мужчин - 70,9%, женщин - 29,1%) и контрольной группе (n=400, средний возраст 53,1±8,3 года, мужчины - 68,3 %, женщины - 31,7%) проведено генотипирование по выбранным полиморфизмам методом ПЦР-ПДРФ по авторским протоколам. По частотам генотипов и аллелей полиморфизма rs77270326 не найдено статистически значимых различий между группами (p>0,05). В группе женщин в возрасте до 50 лет выявлено статистически значимое уменьшение доли носительниц генотипа ТТ в группе внезапной сердечной смерти (32,3%) по сравнению с контрольной группой (60,0%) (ОШ=0,32, 95%ДИ 0,11-0,91, р=0,04). Таким образом, однонуклеотидный полиморфизм rs77270326 не ассоциирован с внезапной сердечной смертью. Для женщин младше 50 лет генотип ТТ полиморфизма rs34643859 ассоциирован с протективным эффектом в отношении внезапной сердечной смерти. The aim of the study is to confirm the association with sudden cardiac death of single-nucleotide polymorphisms rs77270326, rs34643859, identified during own whole-exome sequencing as possible molecular genetic markers of sudden cardiac death. In the group of sudden cardiac death (n = 400, the average age of the dead - 53.2 ± 8.7 years, the proportion of men - 70.9%, women - 29.1%) and the control group (n = 400, average age - 53 , 1 ± 8.3 years, men - 68.3%, women - 31.7%) genotyping of the selected polymorphisms was conducted by PCR-RFLP method according to the authors’ protocols. According to the frequencies of genotypes and alleles of rs77270326 polymorphism, no statistically significant differences were found between the groups (p>0.05). A group of women under the age of 50 revealed a statistically significant decrease in the proportion of carriers of the TT genotype in the group of sudden cardiac death (32.3%) compared with the control group (60.0%) (OR = 0.32, 95% CI 0, 11-0.91, p = 0.04). Thus, the rs77270326 is not associated with sudden cardiac death. For women under the age of 50, the TT genotype of rs34643859 polymorphism is associated with a protective effect against sudden cardiac death.

scholarly journals 99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Zanxin Wang ◽  
Xianmian Zhuang ◽  
Bailang Chen ◽  
Junmin Wen ◽  
Fang Peng ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Pathogenic Variants ◽  
Whole Exome

Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

scholarly journals Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes

2021 ◽  
Author(s):  
Mohamed Al-Hamed ◽  
Wesam Kurdi ◽  
Rubina Khan ◽  
Maha Tulbah ◽  
Maha AlNemer ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Microarray Analysis ◽  
Molecular Genetic ◽  
Genetic Diagnostics ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Fetal Anomalies ◽  
Fetal Abnormalities ◽  
Pathogenic Variants ◽  
Structural Anomalies

Abstract Background Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. Methods In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. Results The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic / likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in 4 fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Conclusion Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

scholarly journals Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

2021 ◽  
pp. jnnp-2020-325437
Author(s):  
Christopher Grunseich ◽  
Nathan Sarkar ◽  
Joyce Lu ◽  
Mallory Owen ◽  
Alice Schindler ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Exome Sequencing ◽  
Late Onset ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Facial Dysmorphism ◽  
Single Nucleotide Variants ◽  
Biological Assays ◽  
Pathogenic Variants

BackgroundWe used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.MethodsWES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.ResultsMolecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients.ConclusionsIntegrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.

New Nucleotide Polymorphisms in the BTC1 gene of Sugar Beet

2020 ◽  
Vol 36 (6) ◽  
pp. 49-54
Author(s):  
A.A. Nalbandyan ◽  
T.P. Fedulova ◽  
I.V. Cherepukhina ◽  
T.I. Kryukova ◽  
N.R. Mikheeva ◽  
...  
Keyword(s):  
Sugar Beet ◽  
Flowering Time ◽  
Molecular Genetic ◽  
Bioinformatic Analysis ◽  
Early Flowering ◽  
Nucleotide Polymorphisms ◽  
Nucleotide Substitutions ◽  
Time Control ◽  
Flowering Time Control ◽  
Exon 10

The flowering time control gene of various sugar beet plants has been studied. The BTC1 gene is a regulator for the suppressor (flowering time 1) and inducer (flowering time 2) genes of this physiological process. The F9/R9 primer pair was used for polymerase chain reaction; these primers are specific to the BTC1 gene region containing exon 9, as well as intron and exon 10. For the first time, nucleotide substitutions in exon 10 of BTC1 gene were identified in bolting sensitive samples (HF1 and BF1), which led to a change in the amino acid composition of the coded polypeptide chain. Based on the results of bioinformatic analysis, it can be assumed that certain nucleotide polymorphisms in the BTC1 gene may determine with a high probability the predisposition of sugar beet genotypes to early flowering. The use of the Geneious Prime tool for the analysis of the BTC1 gene sequences may allow the culling of genotypes prone to early flowering at early stages of selection. sugar beet, flowering gene, BTC1, genetic polymorphism, PCR, molecular genetic markers, selection

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

2021 ◽  
pp. jmedgenet-2020-107369
Author(s):  
Quentin Thomas ◽  
Antonio Vitobello ◽  
Frederic Tran Mau-Them ◽  
Yannis Duffourd ◽  
Agnès Fromont ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
High Efficiency ◽  
Neuromuscular Disorders ◽  
Daily Practice ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Cerebellar Ataxias ◽  
Mitochondrial Origin ◽  
Second Tier

ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

scholarly journals Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 968
Author(s):  
Julien Van Gils ◽  
Frederique Magdinier ◽  
Patricia Fergelot ◽  
Didier Lacombe
Keyword(s):  
Chromatin Remodeling ◽  
Developmental Disorder ◽  
Facial Dysmorphism ◽  
Diagnostic Efficiency ◽  
Mendelian Disorders ◽  
Pathogenic Variants ◽  
Epigenetic Machinery ◽  
Lysine Acetyltransferase ◽  
Definition Of ◽  
Crebbp Gene

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.

Sign in / Sign up

Export Citation Format

Share Document