Novel splicing variant c. 208+2T&gt;C in BBS5 segregates with Bardet–Biedl syndrome in an Iranian family by targeted exome sequencing

AbstractBardet–Biedl syndrome (BBS) is a rare genetically heterogeneous ciliopathy which accompanies retinitis pigmentosa (RP). However, the BBS5 mutation remains unclear in Iranians with BBS. The purpose of study is to evaluate genetic analyses of a BBS Iranian family using targetted exome sequencing (TES). A male 11-year-old proband and three related family members were recruited. Biochemical tests, electrocardiography and visual acuity testing, such as funduscopic, fundus photography (FP), optical coherence tomography (OCT), and standard electroretinography, were conducted. Molecular analysis and high-throughput DNA sequence analysis were performed. The proband was diagnosed with possible BBS based on the presence of three primary features and two secondary features. The TES analysis of the proband with BBS resulted in the identification of a novel, homozygous splicing variant c. 208+2T>C of the BBS5 gene (NM_152384.2) in this Iranian BBS family. This variant was confirmed and was completely co-segregated with the disease in this family by Sanger sequencing. Thus, we report a novel, homozygous splicing site variant c.208+2T>C in the BBS5 gene for the first time in the Iranian family.

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Exome Sequencing of 21 Bardet‐Biedl Syndrome (BBS) Genes to Identify Obesity Variants in 6,851 American Indians

Obesity ◽

10.1002/oby.23115 ◽

2021 ◽

Author(s):

Samantha E. Day ◽

Yunhua L. Muller ◽

Cigdem Koroglu ◽

Sayuko Kobes ◽

Kim Wiedrich ◽

...

Keyword(s):

Exome Sequencing ◽

American Indians ◽

Bardet Biedl Syndrome

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Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2021.03.26-35 ◽

2021 ◽

pp. 26-35

Author(s):

М.Д. Орлова ◽

П. Гундорова ◽

А.В. Поляков

Keyword(s):

Autosomal Recessive ◽

Molecular Genetic ◽

Autosomal Recessive Disorder ◽

Genetic Diagnostics ◽

Bardet Biedl Syndrome ◽

Pathogenic Variants ◽

Development Delay ◽

Molecular Genetic Diagnostics ◽

First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

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Rapid exome sequencing and adjunct rna studies confirm pathogenicity of a novel homozygous asns splicing variant in a critically ill neonate

Pathology ◽

10.1016/j.pathol.2020.01.363 ◽

2020 ◽

Vol 52 ◽

pp. S106

Author(s):

Lauren S. Akesson ◽

Adam Bournazos ◽

Andrew Fennell ◽

Emma I. Krzesinski ◽

Kenneth Tan ◽

...

Keyword(s):

Exome Sequencing ◽

Critically Ill ◽

Splicing Variant

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Implementation of medical retina virtual clinics in a tertiary eye care referral centre

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-311494 ◽

2018 ◽

Vol 102 (10) ◽

pp. 1391-1395 ◽

Cited By ~ 23

Author(s):

Karsten Kortuem ◽

Katrin Fasler ◽

Amanda Charnley ◽

Hussain Khambati ◽

Sandro Fasolo ◽

...

Keyword(s):

Fundus Photography ◽

Retinal Diseases ◽

First Line ◽

Face To Face ◽

Visual Acuity Testing ◽

Timely Fashion ◽

Promising Solution ◽

Increasing Demand ◽

Rapid Access Clinic ◽

Medical Retina

BackgroundThe increasing incidence of medical retinal diseases has created capacity issues across UK. In this study, we describe the implementation and outcomes of virtual medical retina clinics (VMRCs) at Moorfields Eye Hospital, South Division, London. It represents a promising solution to ensure that patients are seen and treated in a timely fashionMethodsFirst attendances in the VMRC (September 2016–May 2017) were included. It was open to non-urgent external referrals and to existing patients in a face-to-face clinic (F2FC). All patients received visual acuity testing, dilated fundus photography and optical coherence tomography scans. Grading was performed by consultants, fellows and allied healthcare professionals. Outcomes of these virtual consultations and reasons for F2FC referrals were assessed.ResultsA total number of 1729 patients were included (1543 were internal and 186 external referrals). The majority were diagnosed with diabetic retinopathy (75.1% of internal and 46.8% of external referrals). Of the internal referrals, 14.6% were discharged, 54.5% continued in VMRC and 30.9% were brought to a F2FC. Of the external referrals, 45.5% were discharged, 37.1% continued in VMRC and 17.4% were brought to a F2FC. The main reason for F2FC referrals was image quality (34.7%), followed by detection of potentially treatable disease (20.2%).ConclusionVMRC can be implemented successfully using existing resources within a hospital eye service. It may also serve as a first-line rapid-access clinic for low-risk referrals. This would enable medical retinal services to cope with increasing demand and efficiently allocate resources to those who require treatment.

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Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2619 ◽

2014 ◽

Vol 99 (1) ◽

pp. E169-E176 ◽

Cited By ~ 30

Author(s):

Peter Kühnen ◽

Serap Turan ◽

Sebastian Fröhler ◽

Tülay Güran ◽

Saygin Abali ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Congenital Hypothyroidism ◽

Thyroid Tissue ◽

Primary Defect ◽

Thyroid Dysgenesis ◽

Homozygous Missense Mutation ◽

Slc26a4 Gene ◽

Thyroid Hormone Biosynthesis ◽

First Time

Context: Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Objectives: Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. Patients and Methods: In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. Results: By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. Conclusion: We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

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Exome Sequencing of a Family with Bardet-Biedl Syndrome Identifies the Common Russian Mutation c.1967_1968delTAinsC in BBS7

Molecular Syndromology ◽

10.1159/000371408 ◽

2015 ◽

Vol 6 (2) ◽

pp. 96-98 ◽

Cited By ~ 6

Author(s):

Evgeny N. Suspitsin ◽

Anna P. Sokolenko ◽

Lydia V. Lyazina ◽

Elena V. Preobrazhenskaya ◽

Alla Y. Lepenchuk ◽

...

Keyword(s):

Exome Sequencing ◽

Bardet Biedl Syndrome ◽

The Common

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Characterization and epidemiological relationships of SpanishBrachyspira hyodysenteriaefield isolates

Epidemiology and Infection ◽

10.1017/s0950268809002817 ◽

2009 ◽

Vol 138 (1) ◽

pp. 76-85 ◽

Cited By ~ 17

Author(s):

Á. HIDALGO ◽

A. CARVAJAL ◽

M. PRINGLE ◽

P. RUBIO ◽

C. FELLSTRÖM

Keyword(s):

Phenotypic Diversity ◽

Random Amplified Polymorphic Dna ◽

Pulsed Field Gel Electrophoresis ◽

Pcr Analysis ◽

Biochemical Tests ◽

Diagnostic Pcr ◽

Brachyspira Hyodysenteriae ◽

Antimicrobial Susceptibility Tests ◽

Susceptibility Tests ◽

First Time

SUMMARYThis research aimed to describe the genetic and phenotypic diversity of 74 SpanishBrachyspira hyodysenteriaefield isolates, to establish epidemiological relationships between the isolates and to confirm the presence of tiamulin-resistant isolates in Spain. For these purposes, we performed biochemical tests in combination with diagnostic PCR analysis for the identification ofBrachyspiraspp. and for detection of thesmpA/smpBgene. We also used antimicrobial susceptibility tests, random amplified polymorphic DNA (RAPD) and a new pulsed-field gel electrophoresis (PFGE) protocol. The combination of RAPD and PFGE allowed the study of epidemiological relationships. Both indole-negative and tiamulin-resistant isolates ofB. hyodysenteriaeare reported in Spain for the first time. The genetic analyses indicated a relationship between these Spanish isolates and indole-negative isolates previously obtained from Germany and Belgium.

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A Novel BBS9 Mutation Identified via Whole-Exome Sequencing in a Chinese Family with Bardet-Biedl Syndrome

BioMed Research International ◽

10.1155/2021/4514967 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Yue Zhang ◽

Manhong Xu ◽

Minglian Zhang ◽

Guoxing Yang ◽

Xiaorong Li

Keyword(s):

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Cone Dystrophy ◽

Bardet Biedl Syndrome ◽

Homozygous Variant ◽

Whole Exome

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by polydactyly, obesity, rod-cone dystrophy, and mental retardation. Twenty-one genes have been identified as causing BBS. This study collected a BBS pedigree from two patients and performed whole-exome sequencing on one patient. We identified a novel homozygous variant c.1114C>T (p.Q372X) in the BBS9 of the two siblings. This variant was confirmed and completely cosegregated with the disease of this family by Sanger sequencing. We report a novel homozygous variant c.1114C>T in the BBS9 gene in a Chinese family.

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Diagnosing Mitochondrial Disorders Remains Challenging in the Omics Era

Neurology Genetics ◽

10.1212/nxg.0000000000000597 ◽

2021 ◽

Vol 7 (3) ◽

pp. e597

Author(s):

Patrick Forny ◽

Emma Footitt ◽

James E. Davison ◽

Amanda Lam ◽

Cathy E. Woodward ◽

...

Keyword(s):

Exome Sequencing ◽

Muscle Biopsy ◽

Mitochondrial Disease ◽

Biochemical Markers ◽

Genetic Diagnosis ◽

Mitochondrial Disorders ◽

Biochemical Tests ◽

Respiratory Chain Enzyme ◽

Clinical Exome Sequencing ◽

Respiratory Chain Enzyme Activity

ObjectiveWe hypothesized that novel investigative pathways are needed to decrease diagnostic odysseys in pediatric mitochondrial disease and sought to determine the utility of clinical exome sequencing in a large cohort with suspected mitochondrial disease and to explore whether any of the traditional indicators of mitochondrial disease predict a confirmed genetic diagnosis.MethodsWe investigated a cohort of 85 pediatric patients using clinical exome sequencing and compared the results with the outcome of traditional diagnostic tests, including biochemical testing of routine parameters (lactate, alanine, and proline), neuroimaging, and muscle biopsy with histology and respiratory chain enzyme activity studies.ResultsWe established a genetic diagnosis in 36.5% of the cohort and report 20 novel disease-causing variants (1 mitochondrial DNA). Counterintuitively, routine biochemical markers were more predictive of mitochondrial disease than more invasive and elaborate muscle studies.ConclusionsWe propose using biochemical markers to support the clinical suspicion of mitochondrial disease and then apply first-line clinical exome sequencing to identify a definite diagnosis. Muscle biopsy studies should only be used in clinically urgent situations or to confirm an inconclusive genetic result.Classification of EvidenceThis is a Class II diagnostic accuracy study showing that the combination of CSF and plasma biochemical tests plus neuroimaging could predict the presence or absence of exome sequencing confirmed mitochondrial disorders.

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