Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN

Background: Little is known about genotype–phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. Results: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. Conclusions: Our results suggest a genotype–phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.

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Unique Variant Spectrum in a Jordanian Cohort with Inherited Retinal Dystrophies

Genes ◽

10.3390/genes12040593 ◽

2021 ◽

Vol 12 (4) ◽

pp. 593

Author(s):

Bilal Azab ◽

Zain Dardas ◽

Dunia Aburizeg ◽

Muawyah Al-Bdour ◽

Mohammed Abu-Ameerh ◽

...

Keyword(s):

Sanger Sequencing ◽

Segregation Analysis ◽

Clinical Findings ◽

Genetic Defects ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Large Patient ◽

Whole Exome ◽

Sequence Variations ◽

Powerful Approach

Whole Exome Sequencing (WES) is a powerful approach for detecting sequence variations in the human genome. The aim of this study was to investigate the genetic defects in Jordanian patients with inherited retinal dystrophies (IRDs) using WES. WES was performed on proband patients’ DNA samples from 55 Jordanian families. Sanger sequencing was used for validation and segregation analysis of the detected, potential disease-causing variants (DCVs). Thirty-five putatively causative variants (6 novel and 29 known) in 21 IRD-associated genes were identified in 71% of probands (39 of the 55 families). Three families showed phenotypes different from the typically reported clinical findings associated with the causative genes. To our knowledge, this is the largest genetic analysis of IRDs in the Jordanian population to date. Our study also confirms that WES is a powerful tool for the molecular diagnosis of IRDs in large patient cohorts.

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Prevalence and Clinical Characteristics of Psoriatic Arthritis in Japan

The Journal of Rheumatology ◽

10.3899/jrheum.141598 ◽

2015 ◽

Vol 42 (8) ◽

pp. 1439-1442 ◽

Cited By ~ 32

Author(s):

Yuri Ohara ◽

Mitsumasa Kishimoto ◽

Naoho Takizawa ◽

Kazuki Yoshida ◽

Masato Okada ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Clinical Characteristics ◽

Tertiary Care ◽

Age At Onset ◽

Japanese Patients ◽

Cross Sectional Study ◽

Clinical Findings ◽

Cross Sectional ◽

Western Countries ◽

Tertiary Care Centers

Objective.To investigate the prevalence of psoriatic arthritis (PsA) in Japanese patients with psoriasis.Methods.A multicenter, noninterventional, retrospective cross-sectional study was conducted at 3 tertiary care centers in Japan. PsA was diagnosed by rheumatologists based on clinical findings. Prevalence of PsA, clinical characteristics, comorbidities, and treatment patterns were examined.Results.PsA was identified in 431 of 3021 patients with psoriasis, with a mean prevalence of 14.3% (range, 8.8–20.4%). No large differences between these results and previous reports from Western countries were observed in arthritis distribution, skin disease type, or treatment selection.Conclusion.The prevalence of PsA in patients with psoriasis in Japan approaches 20% in some areas, similar to that observed in Western countries, and is higher than previously reported in Asia. Clinical features including age, sex, age at onset, and manifestation patterns were also similar to those reported in the West.

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Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies

Scientific Reports ◽

10.1038/s41598-019-52660-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Kei Mizobuchi ◽

Takaaki Hayashi ◽

Satoshi Katagiri ◽

Kazutoshi Yoshitake ◽

Kaoru Fujinami ◽

...

Keyword(s):

Japanese Patients ◽

Cone Dystrophy ◽

Progressive Retinal Atrophy ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Japanese Cohort ◽

Whole Exome ◽

Ef Hand ◽

Genetic Features ◽

Low Prevalence

AbstractGUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as “pathogenic”, whereas the other five variants, which did not co-segregate with IRDs, were considered “non-pathogenic”. Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

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Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01673-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Noémi Széll ◽

Tamás Fehér ◽

Zoltán Maróti ◽

Tibor Kalmár ◽

Dóra Latinovics ◽

...

Keyword(s):

Middle Ages ◽

Early Onset ◽

Colour Vision ◽

High Myopia ◽

Field Testing ◽

Cone Dystrophy ◽

Ophthalmological Examination ◽

Whole Exome ◽

Caucasian Family ◽

Cone System

Abstract Background Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis. Results We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

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Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00709-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Dongdong Tang ◽

Yanwei Sha ◽

Yang Gao ◽

Jingjing Zhang ◽

Huiru Cheng ◽

...

Keyword(s):

Sanger Sequencing ◽

Sperm Morphology ◽

Immunofluorescence Staining ◽

Compound Heterozygous ◽

Sperm Tail ◽

Transmission Electron ◽

Whole Exome ◽

Detailed Medical History ◽

Novel Variants ◽

Common Causes

Abstract Background Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported. Methods Whole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied. Results By WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy. Conclusions We identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.

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Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

BMC Medical Genetics ◽

10.1186/s12881-020-01168-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Somayeh Khatami ◽

Masomeh Askari ◽

Fatemeh Bahreini ◽

Morteza Hashemzadeh-Chaleshtori ◽

Saeed Hematian ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Diagnosis ◽

Clinical Genetic ◽

Large Size ◽

Whole Exome ◽

Novel Variants ◽

Syndromic Hearing Loss ◽

Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

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An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0679 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ting Xu ◽

Liang Shi ◽

Weiqian Dai ◽

Xuefan Gu ◽

Yongguo Yu ◽

...

Keyword(s):

De Novo ◽

Clinical Findings ◽

Recurrent Mutation ◽

Mrna Splicing ◽

Additional Patient ◽

Missense Mutations ◽

Splicing Variant ◽

Amino Acid Insertion ◽

Whole Exome ◽

Minigene Assay

Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

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Identification of novel exonic variants responsible for hereditary breast and ovarian cancer in West Indian population

10.21203/rs.3.rs-952462/v1 ◽

2021 ◽

Author(s):

Bhargav N. Waghela ◽

Ramesh J. Pandit ◽

Apurvasinh Puvar ◽

Franky D. Shah ◽

Prabhudas S. Patel ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Diagnosis ◽

West Indian ◽

Disease Association ◽

Dna Integrity ◽

Degree Relative ◽

Mortality And Morbidity ◽

Whole Exome ◽

Novel Variants ◽

Next Generation Sequencing Ngs

Abstract Background Breast and ovarian cancers are the most common cancer types in females in India which pertain to higher mortality and morbidity due to late diagnosis and poor prognosis. Early diagnosis for better prognosis improve the patient’s treatment and survival. The next-generation sequencing (NGS)-based screening has accelerated molecular diagnosis of various cancers. Methods We performed whole exome sequencing (WES) of 30 patients who had a first or second degree relative with breast or ovarian cancer. Further, all these patients are tested negative for BRCA1/2 or other high and moderate risk genes reported for HBOC. WES data from 30 patients were analyzed and variants were called using bcftools. Functional annotation of variants and variant prioritization was performed by Exomiser. The clinical significance of variants was determined by Varsome tool. The functional analysis of genes was determined by STRING analysis and disease association was determined by open target tool. Results We examined the variants based on the prevalence of variants among 30 patients i.e. frequency and disease association determined by the phenotype score of exomiser. From both the approaches, we found novel variants and novel gene candidates associated with HBOC conditions. The variants in HYDIN, AVIL, IWS1, PLA2G6, PRDM4, ST3GAL2, and ZNF717 were predicted highly oncogenic. Moreover, we also found 59 genes having higher phenotype score (phenotype score >0.75) and which are associated with various biological processes such as DNA integrity maintenance, transcriptional regulation, cell cycle and apoptosis. Conclusion The gene variants associated with HBOC condition in West Indian cohort have been revisited. Our findings provide novel as well as highly prevalent variants in the population which could be further studied in detail for their use in early diagnosis and better prognosis of HBOC patients.

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Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy

Clinical Genetics ◽

10.1111/cge.13453 ◽

2018 ◽

Vol 95 (2) ◽

pp. 329-333 ◽

Cited By ~ 7

Author(s):

Cécile Méjécase ◽

Aurélie Hummel ◽

Saddek Mohand-Saïd ◽

Camille Andrieu ◽

Said El Shamieh ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cone Dystrophy ◽

Complex Phenotype ◽

Whole Exome

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Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Journal of Dental Research ◽

10.1177/0022034517724149 ◽

2017 ◽

Vol 97 (1) ◽

pp. 49-59 ◽

Cited By ~ 16

Author(s):

N. Dinckan ◽

R. Du ◽

L.E. Petty ◽

Z. Coban-Akdemir ◽

S.N. Jhangiani ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Permanent Teeth ◽

Tooth Agenesis ◽

Disease Genes ◽

Nonsense Mediated Decay ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants ◽

Complex Inheritance

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

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