scholarly journals Genetics of multiplex familial vitiligo as cases and controls: a preliminary report

2018 ◽  
Vol 4 (3) ◽  
pp. 403 ◽  
Author(s):  
Kirti S. Deo ◽  
Samyak A. Ganjre
Keyword(s):  
Demographic Data ◽  
Clinical History ◽  
Mendelian Inheritance ◽  
Pedigree Analysis ◽  
Gene Defect ◽  
Genetic Studies ◽  
Familial Data ◽  
Whole Exome ◽  
Multiplex Families ◽  
Genetically Determined

<p class="abstract"><strong>Background:</strong> Studies on etiology of generalized vitiligo have established that it is a genetically determined, autoimmune, auto inflammatory diathesis. Polymorphism in myriad genes is associated with vitiligo and newer ones are being identified with advancement in research methods. This study enabled inheritance pattern recognition in multiplex familial cases of vitiligo and subject members to whole exome sequencing (WES) to find out the etiological gene defect in a particular family.</p><p class="abstract"><strong>Methods:</strong> 7 multiplex families with at least two cases and two healthy counterparts, spread across generations were enrolled. Demographic data, clinical history and familial data were collected for pedigree analysis and blood samples were collected for extraction of genomic DNA.<strong></strong></p><p class="abstract"><strong>Results:</strong> Multiple possible modes of Mendelian inheritance could be contemplated to cause disease expression in probands. Autosomal recessive pattern was observed to be the most likely amongst various possible modes, followed closely by autosomal dominant, with X-linked recessive, and X- linked dominant occurring less frequently. WES for one of the multiplex families is desirable and planned at an apex institute of genetic studies which will reveal the etiologic gene defect on conclusion of analysis.</p><p><strong>Conclusions:</strong> In this study we have used to our advantage the familial occurrence of the disease to seek for genes which occurred with a greater frequency in affected members of a family than their healthy counterparts, assuming that the same mutated gene should be universally present in all affected members across generations in the same family, enabling a better understanding of genetic predisposition in familial vitiligo. </p>

scholarly journals Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 430
Author(s):  
Steven R. Bentley ◽  
Ilaria Guella ◽  
Holly E. Sherman ◽  
Hannah M. Neuendorf ◽  
Alex M. Sykes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Rare Variants ◽  
Strong Family History ◽  
Disease Mutations ◽  
Whole Exome ◽  
History Of ◽  
Functional Consequences ◽  
Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

scholarly journals Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

2018 ◽  
Vol 29 (9) ◽  
pp. 2348-2361 ◽  
Author(s):  
Amelie T. van der Ven ◽  
Dervla M. Connaughton ◽  
Hadas Ityel ◽  
Nina Mann ◽  
Makiko Nakayama ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Causative Mutation ◽  
Deleterious Mutations ◽  
Whole Exome ◽  
Multiplex Families ◽  
High Fraction ◽  
Etiologic Diagnosis

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.MethodsWe applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.ResultsIn 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient’s CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).ConclusionsWe identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Diseases of the teeth and supporting structures

2018 ◽  
Author(s):  
Max Robinson ◽  
Keith Hunter ◽  
Michael Pemberton ◽  
Philip Sloan
Keyword(s):  
Dental Health ◽  
Genetic Disorders ◽  
Adult Life ◽  
Mendelian Inheritance ◽  
Structural Basis ◽  
Pathological Examination ◽  
Dental Arch ◽  
Supernumerary Teeth ◽  
Tooth Germs ◽  
Genetically Determined

A wide variety of processes can affect the formation of teeth during development. The number, size, shape, and quality of dental hard tis­sue may be abnormal and teeth may erupt early or be prematurely shed or resorbed. When a child presents with a tooth abnormality, the clin­ical and radiographic features are often distinctive and management depends on diagnosis (Box 5.1). Broadly, developmental abnormal­ities of the teeth can be either genetically determined or acquired as a result of injurious processes affecting the developing teeth. It can be problematic to make a diagnosis, particularly when teeth initially erupt. Sometimes pathological examination of a shed or extracted tooth by ground sectioning (for enamel) or conventional sectioning of a decalci­fied tooth can provide a diagnosis. Research has provided insights into the genetic and structural basis of dental anomalies, and has resulted in a complex and extensive classification of subtypes. Minor abnormal­ities, such as failure of development of a few teeth or enamel erosion in adult life, may be dealt with in general dental practice, but it is advisable to refer younger patients with more complex or extensive dental abnor­malities to a specialist in child dental health, with links to expert diag­nostic facilities and input from orthodontic and restorative colleagues. The publically available Online Mendelian Inheritance in Man (OMIM) database provides an invaluable resource for genetic disorders, including dental abnormalities. Supernumerary teeth are common and may be rudimentary in form or of normal morphology, when they are referred to as supplemental teeth. The most common supernumerary tooth occurs in the mid- line of the maxillary alveolus and is referred to as a mesiodens, which usually has a conical shape. Eruption of adjacent normal successor teeth may be impeded by a mesiodens, which is an indication for its removal. Most supernumerary teeth occur as a sporadic event in devel­opment, but multiple extra teeth can be found in certain developmen­tal disorders. Failure of development of tooth germs results in teeth missing from the dental arch and is referred to as hypodontia. Most often the missing teeth are third molars, second premolars, and upper lateral incisors. Hypodontia is more common in the permanent dentition than in the primary teeth.

scholarly journals Familial Intracranial Aneurysm in Newfoundland: Clinical and Genetic Analysis

2019 ◽  
Vol 46 (5) ◽  
pp. 518-526
Author(s):  
Amy E. Powell ◽  
Bridget A. Fernandez ◽  
Falah Maroun ◽  
Barbara Noble ◽  
Michael O. Woods
Keyword(s):  
Intracranial Aneurysm ◽  
Sanger Sequencing ◽  
Variant Prioritization ◽  
Future Studies ◽  
Whole Exome ◽  
High Prevalence ◽  
History Of ◽  
Multiplex Families ◽  
Genetic And Environmental Factors ◽  
Population Controls

ABSTRACT:Objective:Intracranial aneurysm (IA) is an expansion of the weakened arterial wall that is often asymptomatic until rupture, resulting in subarachnoid hemorrhage. Here we describe the high prevalence of familial IA in a cohort of Newfoundland ancestry. We began to investigate the genetic etiology of IA in affected family members, as the inheritance of this disease is poorly understood.Methods:Whole exome sequencing was completed for a cohort of 12 affected individuals from two multiplex families with a strong family history of IA. A filtering strategy was implemented to identify rare, shared variants. Filtered variants were prioritized based on validation by Sanger sequencing and segregation within the families.Results:In family R1352, six variants passed filtering; while in family R1256, 68 variants remained, so further filtering was pursued. Following validation by Sanger sequencing, top candidates were investigated in a set of population controls, namely,C4orf6c.A1G (p.M1V) andSPDYE4c.C103T (p.P35S). Neither was detected in 100 Newfoundland control samples.Conclusion:Rare and potentially deleterious variants were identified in both families, though incomplete segregation was identified for all filtered variants. Alternate methods of variant prioritization and broader considerations regarding the interplay of genetic and environmental factors are necessary in future studies of this disease.

scholarly journals Új módszertani lehetőségek és ezek alkalmazása a hormonális rendszer daganatainak genetikai kivizsgálásában

2015 ◽  
Vol 156 (51) ◽  
pp. 2063-2069
Author(s):  
Attila Patócs ◽  
István Likó ◽  
Henriett Butz ◽  
Kornélia Baghy ◽  
Károly Rácz
Keyword(s):  
Genetic Testing ◽  
Ethical Issues ◽  
Genetic Alterations ◽  
Clinical Genetic ◽  
Patients With Cancer ◽  
Clinical Genetic Testing ◽  
Technical Developments ◽  
Whole Exome ◽  
Genetically Determined ◽  
Genome Scale

The technical developments leading to revolution in clinical genetic testing offer new approaches for patients with cancer. From one mutation or one gene approach the scale of genetic testing moved to whole exome or whole genome scale. It is well known that many tumours are genetically determined ans they are part of familial tumour syndromes. In addition, some mutations indicate specific molecular targeted therapies. Although sampling and sample preparation are different for testing germline and somatic mutations, the technical background of the analysis is the same. The aim of clinical genetic testing is to identify patients who are carriers of disease-causing mutations or to test tumour tissue for the presence of genetic alterations which may be targets for therapeutic approaches. In this review the authors summarize novel possibilities offered by next-generation sequencing in clinical genetic testing of patients with endocrine tumours. In addition, the authors review recent guidelines on technical and ethical issues related to these novel methods. Orv. Hetil., 2015, 156(51), 2063–2069.

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

2018 ◽  
Vol 55 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Wen-Bin He ◽  
Chao-Feng Tu ◽  
Qiang Liu ◽  
Lan-Lan Meng ◽  
Shi-Min Yuan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Male Patient ◽  
Histological Analysis ◽  
Pedigree Analysis ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Causative Gene ◽  
Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

scholarly journals Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies

2018 ◽  
Vol 4 (2) ◽  
pp. e222 ◽  
Author(s):  
Claire G. Salter ◽  
Danique Beijer ◽  
Holly Hardy ◽  
Katy E.S. Barwick ◽  
Matthew Bower ◽  
...  
Keyword(s):  
Clinical History ◽  
Dominant Negative ◽  
Clinical Feature ◽  
Gene Encoding ◽  
Genetic Studies ◽  
Hereditary Motor ◽  
C Terminus ◽  
Type V ◽  
Peripheral Motor ◽  
Distal Limb Muscle

ObjectiveTo identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs).MethodsThe first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation.ResultsdHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family.ConclusionsThis study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.

Teaching Mitochondrial Genetics & Disease: A GENA Project Curriculum Intervention

2012 ◽  
Vol 74 (4) ◽  
pp. 224-230
Author(s):  
Ryan A. Reardon ◽  
J. Daniel Sharer
Keyword(s):  
Mendelian Inheritance ◽  
Pedigree Analysis ◽  
Educational Outreach ◽  
Educational Goals ◽  
Mitochondrial Genetics ◽  
Interactive Approach ◽  
Inquiry Based Learning ◽  
Learning Plan ◽  
Laboratory Techniques ◽  
Curriculum Intervention

This report describes a novel, inquiry-based learning plan developed as part of the GENA educational outreach project. Focusing on mitochondrial genetics and disease, this interactive approach utilizes pedigree analysis and laboratory techniques to address non-Mendelian inheritance. The plan can be modified to fit a variety of educational goals and is now commercially available.

scholarly journals UFM1 founder mutation in the Roma population causes recessive variant of H-ABC

Neurology ◽  
2017 ◽  
Vol 89 (17) ◽  
pp. 1821-1828 ◽  
Author(s):  
Eline M.C. Hamilton ◽  
Enrico Bertini ◽  
Luba Kalaydjieva ◽  
Bharti Morar ◽  
Dana Dojčáková ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism Array ◽  
Homozygosity Mapping ◽  
Homozygous Deletion ◽  
Epileptic Encephalopathy ◽  
Luciferase Reporter ◽  
Taqman Assay ◽  
Gene Defect ◽  
Luciferase Reporter Construct ◽  
Roma Population ◽  
Whole Exome

Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.Methods:We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.Results:Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%–25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.Conclusions:UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.

Microsatellite DNA in peach (Prunus persica L. Batsch) and its use in fingerprinting and testing the genetic origin of cultivars

Genome ◽  
2000 ◽  
Vol 43 (3) ◽  
pp. 512-520 ◽  
Author(s):  
Raffaele Testolin ◽  
Teresa Marrazzo ◽  
Guido Cipriani ◽  
Roberta Quarta ◽  
Ignazio Verde ◽  
...  
Keyword(s):  
Microsatellite Dna ◽  
Simple Sequence Repeat ◽  
Prunus Persica ◽  
Mendelian Inheritance ◽  
Pedigree Analysis ◽  
Paternity Analysis ◽  
Genetic Origin ◽  
Discrimination Power ◽  
Genomic Libraries ◽  
Simple Sequence

We isolated and sequenced 26 microsatellites from two genomic libraries of peach cultivar 'Redhaven', enriched for AC/GT and AG/CT repeats, respectively. For 17 of these microsatellites, it was possible to demonstrate Mendelian inheritance. Microsatellite polymorphism was assayed in 50 peach and nectarine cultivars. Of the 1300 PCRs carried out, all but two produced amplified products of the expected size. All microsatellites were polymorphic, showing 2-8 alleles per locus. Heterozygosity ranged from 0.04-0.74 (mean 0.47); the discrimination power (PD) ranged from 0.04-0.84 (mean 0.60). Cultivar heterozygosity varied greatly, with one cultivar ('Independence') being homozygous at all loci. The set of microsatellites discriminated all cultivars investigated, except several sport mutations, i.e., 'Dixitime' vs. 'Springcrest', 'Compact Redhaven' vs. 'Redhaven', and two pairs of cultivars, 'Venus' vs. 'Orion' and 'Elegant Lady' vs. 'Rome Star', whose pedigrees are controversial. We were able to analyze the paternity of several cultivars. In most cases, the parenthood was confirmed. The comparison of three long-living 'Redhaven' accessions supplied by different repositories did not provide any evidence of somatic instability of microsatellites. Hence, microsatellites, ranked according to their information content, are recommended as markers of choice for peach fingerprinting and suggestions are provided for interpreting band profiles and the correct sizing of alleles.Key words: genetics, molecular markers, paternity analysis, pedigree analysis, simple sequence repeat.

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