scholarly journals Classification and Interpretation for 11 FBN1 Variants Responsible for Marfan Syndrome and Pre-implantation Genetic Testing (PGT) for Two Families Successfully Blocked Transmission of the Pathogenic Mutations

2021 ◽  
Vol 8 ◽  
Author(s):  
Songchang Chen ◽  
Hongjun Fei ◽  
Junyun Zhang ◽  
Yiyao Chen ◽  
Hefeng Huang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Marfan Syndrome ◽  
De Novo ◽  
Elective Surgery ◽  
Mutation Screening ◽  
Molecular Genetic ◽  
Preventive Treatment ◽  
Pedigree Analysis ◽  
Nucleotide Polymorphisms ◽  
Multiple Sequence

Background: The lifespan of Marfan Syndrome (MFS) patients is shortened, especially in patients without early diagnostics, preventive treatment, and elective surgery. Clinically, MFS diagnosis is mainly dependent on phenotypes, but for children, sporadic cases, or suspicious MFS patients, molecular genetic testing, and mainly FBN1 mutation screening, plays a significant role in the diagnosis of MFS. PGT-M gives couples that had a family history of monogenic disorders the opportunity to avoid the occurrence of MFS.Methods: In this study, 11 families with MFS were recruited and complete clinical features were collected. Variants were classified and interpreted through pedigree analysis according to guidelines. Two families chose to undergo PGT-M; 16 blastocysts were biopsied and amplified. Haplotype analysis was performed to deduce the embryo’s genotype by using single nucleotide polymorphisms (SNPs) identified in each sample.Results: We identified 11 potential disease-causing FBN1 variants, six of which are novel. All variants were assessed with prediction tools to assess mutation pathogenicity, population databases to evaluate population allele frequency, literature databases to identify whether the variant had been reported in MFS patients, and multiple sequence alignment to carry out conservative analysis. Finally, nine variants were classified as likely pathogenic/pathogenic variants. Among 11 variants, eight variants were missense, and seven of them were located in the Ca-binding EGF-like motifs, moreover, half of them substituted conserved Cysteine residues. We also identified a splice site variant, a frameshift variant, and a synonymous variant. There are two variants that are de novo variants. PGT-M helped two MFS families give birth to a healthy baby not carrying the FBN1 mutation.Conclusions: In the present study, the FBN1 mutation spectrum was enriched, and may help further elucidate the pathogenesis, benefiting clinical diagnosis and management of MFS. We make use of a reliable PGT-M method for the successful birth of healthy babies to two MFS families.

scholarly journals Haplotyping by linked-read sequencing (HLRS) of the genetic disease carriers for preimplantation genetic testing without a proband or relatives

2020 ◽  
Author(s):  
Qing Li ◽  
Yan Mao ◽  
Shaoying Li ◽  
Hongzi Du ◽  
Wenzhi He ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Disease ◽  
De Novo ◽  
Monogenic Disease ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Preimplantation Genetic Testing ◽  
Linkage Analyses ◽  
Alpha Thalassemia ◽  
Polar Bodies

Abstract Background: In order to mitigate the risk of allele dropout (ADO) and ensure the accuracy of preimplantation genetic testing for monogenic disease (PGT-M), it is necessary to construct parental haplotypes.. Typically, haplotype resolution is obtained by genotyping multiple polymorphic markers in both parents and a proband or a relative. Sometimes, single sperm typing, or tests on the polar bodies may also be useful. Nevertheless, this process is time-consuming. At present, there was no simple linkage analysis strategy for patients without affected relatives.Method: To solve this problem, we established a haplotyping by linked-read sequencing (HLRS) method without the requirement for additional relatives. First, the haplotype of the genetic disease carriers in the family was constructed by linked-read sequencing, and then the informative single nucleotide polymorphisms (SNPs) in upstream and downstream mutation region were selected to construct the embryo haplotype and to determine whether the embryo was carrying the mutation. Two families were selected to validate this method; one with alpha thalassemia and the other with NDP gene disorder.Results: The haplotyping by linked-read sequencing (HLRS) method was successfully applied to construct parental haplotypes without recruiting additional family members; the method was also validated for PGT-M. The mutation carriers in these families were sequenced by linked-read sequencing, and their haplotypes were successfully phased. Adjacent SNPs of the mutation gene were identified. The informative SNPs were chosen for linkage analyses to identify the carrier embryos. For the alpha thalassemia family, a normal blastocyst was transferred to the uterus and the accuracy of PGT-M was confirmed by amniocentesis at 16 weeks of gestation. Conclusions: Our results suggest that HLRS can be applied for PGT-M of monogenic disorders or de novo mutations where the mutations haplotype cannot be determined due to absence of affected relatives. Keywords: Preimplantation Genetic Testing for monogenic disease, Linked-read sequencing, Linkage analyses, Haplotype

scholarly journals NovelGUCA1AMutations Suggesting Possible Mechanisms of Pathogenesis in Cone, Cone-Rod, and Macular Dystrophy Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Kunka Kamenarova ◽  
Marta Corton ◽  
Blanca García-Sandoval ◽  
Patricia Fernández-San Jose ◽  
Valentin Panchev ◽  
...  
Keyword(s):  
De Novo ◽  
Novel Mutation ◽  
Mutation Screening ◽  
Disease Model ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Macular Dystrophy ◽  
Nucleotide Polymorphisms ◽  
Positional Candidate ◽  
Functional Studies

Here, we report two novelGUCA1A(the gene for guanylate cyclase activating protein 1) mutations identified in unrelated Spanish families affected by autosomal dominant retinal degeneration (adRD) with cone and rod involvement. All patients from a three-generation adRD pedigree underwent detailed ophthalmic evaluation. Total genome scan using single-nucleotide polymorphisms and then the linkage analysis were undertaken on the pedigree. Haplotype analysis revealed a 55.37 Mb genomic interval cosegregating with the disease phenotype on chromosome 6p21.31-q15. Mutation screening of positional candidate genes found a heterozygous transition c.250C>T in exon 4 ofGUCA1A, corresponding to a novel mutation p.L84F. A second missense mutation, c.320T>C (p.I107T), was detected by screening of the gene in a Spanish patients cohort. Using bioinformatics approach, we predicted that either haploinsufficiency or dominant-negative effect accompanied by creation of a novel function for the mutant protein is a possible mechanism of the disease due to c.250C>T and c.320T>C. Although additional functional studies are required, our data in relation to the c.250C>T mutation open the possibility thattransacting factors binding to de novo created recognition site resulting in formation of aberrant splicing variant is a disease model which may be more widespread than previously recognized as a mechanism causing inherited RD.

Molecular Genetic Testing for Malignant Hyperthermia Susceptibility

2004 ◽  
Vol 100 (5) ◽  
pp. 1076-1080 ◽  
Author(s):  
Thierry Girard ◽  
Susan Treves ◽  
Evgueni Voronkov ◽  
Martin Siegemund ◽  
Albert Urwyler
Keyword(s):  
Genetic Testing ◽  
Malignant Hyperthermia ◽  
Elective Surgery ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Malignant Hyperthermia Susceptibility ◽  
Restriction Enzyme Digestion ◽  
In Vitro Contracture Test ◽  
Genetic Test Results

Background For more than 30 yr, the in vitro contracture test (IVCT) was the only appropriate diagnostic tool for malignant hyperthermia (MH). After the introduction of molecular genetics into MH research, guidelines for molecular genetic diagnosis of MH susceptibility were published. The aim of this study was to establish applicability of the guidelines, sensitivity, and specificity of genetic testing in MH and advantages for studied patients. Methods The IVCT was performed following the guidelines of the European MH Group. Mutation analyses were performed by amplification of genomic DNA by polymerase chain reaction and restriction enzyme digestion. Results Two hundred eight individuals underwent MH testing between January 2001 and April 2003. In 32 of 67 initially genetic-tested patients, the familial mutation was identified, and they were diagnosed as MH susceptible. The IVCT followed negative genetic test results in 20 patients, and all but one had negative IVCT results. Three patients were scheduled to undergo elective surgery, and IVCT and genetic testing were performed simultaneously. All three had positive IVCT results and were carriers of their familial mutation. Conclusions In families with known MH mutations, there is a 50% chance of reliably confirming MH susceptibility by noninvasive testing. The authors found the negative predictive value of genetic testing to be 0.95 (95% confidence interval, 0.75-0.99), but for patient safety, they still recommend following the guidelines for genetic testing in MH and therefore performing an IVCT in case of negative genetic results.

Genetic testing for autistic spectrum disorders

2020 ◽  
pp. 78-79
Author(s):  
Е.А. Померанцева ◽  
А.А. Исаев ◽  
А.П. Есакова ◽  
И.В. Поволоцкая ◽  
Е.В. Денисенкова ◽  
...  
Keyword(s):  
Genetic Testing ◽  
American Academy ◽  
Autistic Spectrum Disorder ◽  
Genetic Factors ◽  
Molecular Genetic ◽  
Autistic Spectrum Disorders ◽  
Autistic Spectrum ◽  
American Academy Of Pediatrics ◽  
Spectrum Disorders ◽  
Testing Algorithm

Согласно рекомендациям Американской академии педиатрии при постановке диагноза аутизм, следует направить семью на консультацию генетика и генетическое обследование. Однако оптимальный подход к алгоритму генетического обследования при выявлении расстройства аутистического спектра еще предстоит разработать. В рамках исследования было проведено сравнение выявляемости генетических факторов аутизма различными молекулярно-генетическими тестами. According to American Academy of Pediatrics recent guidelines, each family with a child diagnosed with autistic spectrum disorder should be reffered to a medical geneticist and offered genetic tests. However, an optimal genetic testing algorithm has yet to be developed. This study was conducted to compare abilities of different molecular-genetic methods to detect genetic factors of autistic spectrum disorders.

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 R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

2021 ◽  
pp. 123-130
Author(s):  
Anker Stubberud ◽  
Emer O’Connor ◽  
Erling Tronvik ◽  
Henry Houlden ◽  
Manjit Matharu
Keyword(s):  
Mental Retardation ◽  
Case Report ◽  
Genetic Testing ◽  
Head Trauma ◽  
Cerebral Oedema ◽  
De Novo ◽  
Minor Head Trauma ◽  
Hemiplegic Migraine ◽  
Wide Range ◽  
History Of

Mutations in the <i>CACNA1A</i> gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the <i>CACNA1A</i> gene (c.4055G&#x3e;A, p.R1352Q). The R1352Q <i>CACNA1A</i> variant shares the phenotype with other described <i>CACNA1A</i> mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

scholarly journals Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 435-446
Author(s):  
Isabelle Marey ◽  
Véronique Fressart ◽  
Caroline Rambaud ◽  
Paul Fornes ◽  
Laurent Martin ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cardiac Death ◽  
De Novo ◽  
Family Care ◽  
Prenatal Testing ◽  
Added Value ◽  
Molecular Testing ◽  
Post Mortem ◽  
Genetic Analyses ◽  
Conventional Autopsy

AbstractPost-mortem genetic analyses may help to elucidate the cause of cardiac death. The added value is however unclear when a cardiac disease is already suspected or affirmed. Our aim was to study the feasibility and medical impact of post-mortem genetic analyses in suspected cardiomyopathy. We studied 35 patients with cardiac death and suspected cardiomyopathy based on autopsy or clinical data. After targeted sequencing, we identified 15 causal variants in 15 patients (yield 43%) in sarcomeric (n = 8), desmosomal (n = 3), lamin A/C (n = 3) and transthyretin (n = 1) genes. The results had various impacts on families, i.e. allowed predictive genetic testing in relatives (15 families), planned early therapeutics based on the specific underlying gene (5 families), rectified the suspected cardiomyopathy subtype (2 families), assessed the genetic origin of cardiomyopathy that usually has an acquired cause (1 family), assessed the diagnosis in a patient with uncertain borderline cardiomyopathy (1 family), reassured the siblings because of a de novo mutation (2 families) and allowed prenatal testing (1 family). Our findings suggest that post-mortem molecular testing should be included in the strategy of family care after cardiac death and suspected cardiomyopathy, since genetic findings provide additional information useful for relatives, which are beyond conventional autopsy.

scholarly journals Prenatal Sonographic Features of CHARGE Syndrome

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 415
Author(s):  
Kuntharee Traisrisilp ◽  
Wisit Chankhunaphas ◽  
Rekwan Sittiwangkul ◽  
Chureerat Phokaew ◽  
Vorasuk Shotelersuk ◽  
...  
Keyword(s):  
De Novo ◽  
Heart Defects ◽  
Molecular Genetic ◽  
Choanal Atresia ◽  
Charge Syndrome ◽  
Acoustic Stimulation ◽  
Genetic Mutation ◽  
Suspected Case ◽  
Autosomal Dominant Disorder ◽  
Canal Stenosis

CHARGE syndrome is a rare autosomal dominant disorder, associated with coloboma (C), heart defects (H), choanal atresia (A), retardation of growth and/or central nervous system (R), genitourinary anomalies (G) and ear abnormalities (E). Prenatal diagnosis of the syndrome is very rare but may be suspected when a combination of such abnormalities is identified. We describe a prenatally suspected case of CHARGE syndrome due to unique findings of cardiac defects (DORV) in combination with minor clues, including a structurally malformed ear with persistent non-response to an acoustic stimulation (which has never been prenatally described elsewhere), renal malrotation and growth restriction. Postnatal diagnosis was made based on confirmation of the prenatal findings and additional specific findings of bilateral coloboma, choanal atresia and ear canal stenosis. Finally, molecular genetic testing by whole exome sequencing of the neonate and her parents revealed a novel de novo heterozygous frameshift c.3506_3509dup variant in the CHD7 gene, confirming the clinical diagnosis of CHARGE syndrome. In conclusion, we describe unique prenatal features of CHARGE syndrome. Educationally, this is one of the rare examples of CHARGE syndrome, comprising all of the six specific anomalies as originally described; it is also supported by the identification of a specific genetic mutation. The identified genetic variant has never been previously reported, thereby expanding the mutational spectrum of CHD7. Finally, this case can inspire prenatal sonographers to increase awareness of subtle or minor abnormalities as genetic sonomarkers.

scholarly journals Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Cao ◽  
Ruixue Zhang ◽  
Liang Yong ◽  
Shirui Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Molecular Genetic ◽  
Family Members ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Chinese Family ◽  
Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

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