scholarly journals Mutations in BBS2 Cause Apparent Nonsyndromic Retinitis Pigmentosa

2020 ◽  
Author(s):  
Meghan DeBenedictis ◽  
Joseph Fogerty ◽  
Gayle Pauer ◽  
John Chiang ◽  
Stephanie A. Hagstrom ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Protein Localization ◽  
Visual Fields ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Bardet Biedl Syndrome ◽  
Targeted Next Generation Sequencing ◽  
Male Sibling ◽  
Generation Sequencing ◽  
Ciliary Localization

AbstractPurposeTo identify and functionally test the causative mutations in the BBS2 gene in a family presenting with retinitis pigmentosa and infertility and to generate a bbs2−/− mutant zebrafish.MethodsA female proband and her male sibling were clinically evaluated and genetic testing with targeted next-generation sequencing was performed. Mutations were verified by Sanger sequencing. Protein localization was examined by transient expression and immunocytochemistry in cultured HEK-293T cells. Mutations in the zebrafish bbs2 gene were generated by CRISPR/Cas9 and retinal phenotypes were examined by immunohistochemistry.ResultsThe proband and her brother exhibited reduced visual fields, retinal degeneration, and bone spicule deposits, consistent with retinitis pigmentosa. The brother also reported symptoms consistent with infertility. Compound heterozygous mutations in the BBS2 gene; namely NM_031885.4 (BBS2):c.823C>T (p.R275X) and NM_031885.4 (BBS2):c.401C>G (p.P134R), were identified in the proband and her brother. Both mutations interfered with ciliary localization of Bbs2 in cell culture. Mutation of the zebrafish bbs2 gene resulted in progressive cone degeneration and rhodopsin mislocalization.ConclusionMissense mutations of BBS2 leads to non-syndromic retinitis pigmentosa, but not Bardet-Biedl Syndrome, even though Bbs2 fails to localize to cilia. In zebrafish, the complete loss of bbs2 results in cone degeneration and ciliopathy phenotypes, indicating a requirement for Bbs2 in photoreceptor survival.

scholarly journals Dehydrated hereditary stomatocytosis with new missense mutations in PIEZO1 through the use of next-generation sequencing panel

2021 ◽  
Author(s):  
Sultan Aydin Koker ◽  
Tuba Karapınar ◽  
Paola BIANCHI ◽  
Yeşim Oymak ◽  
Elisa Fermo ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Missense Mutation ◽  
Hemolytic Anemia ◽  
Male Patient ◽  
Autoimmune Hemolytic Anemia ◽  
Missense Mutations ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

In this case study, we report an 11-year-old male patient who had jaundice, hepatosplenomegaly, and chronic mild congenital non-autoimmune hemolytic anemia. In our patient, a novel homozygous missense mutation in the PIEZO1 gene was detected using a gene-targeted Next-Generation Sequencing panel: c.3364G>A (p.Glu1122Lys), confirming the diagnosis of DHS.

scholarly journals Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Ling-hui Qu ◽  
Xin Jin ◽  
Yan-ling Long ◽  
Jia-yun Ren ◽  
Chuang-huang Weng ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Molecular Mechanisms ◽  
Usher Syndrome ◽  
Next Generation ◽  
Chinese Families ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Mutations ◽  
Basement Membrane Protein ◽  
Generation Sequencing

Abstract Background: The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. Methods: In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families. Results: We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. Conclusions: These findings provide a basis for investigating genotype–phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.

scholarly journals Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Pengcheng Xu ◽  
Jun Xu ◽  
Hu Peng ◽  
Tao Yang
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Recessive Mutations ◽  
Compound Heterozygous Mutations ◽  
Generation Sequencing

Genetic hearing loss is a common sensory disorder, and its cause is highly heterogeneous. In this study, by targeted next-generation sequencing of 414 known deafness genes, we identified compound heterozygous mutations p.R34X/p.M413T in TMC1 and p.S3417del/p.R1407T in MYO15A in two recessive Chinese Han deaf families. Intrafamilial cosegregation of the mutations with the hearing phenotype was confirmed in both families by the Sanger sequencing. Auditory features of the affected individuals are consistent with that previously reported for recessive mutations in TMC1 and MYO15A. The two novel mutations identified in this study, p.M413T in TMC1 and p.R1407T in MYO15A, are classified as likely pathogenic according to the guidelines of ACMG. Our study expanded the mutation spectrums of TMC1 and MYO15A and illustrated that genotype-phenotype correlation in combination with next-generation sequencing may improve the accuracy for genetic diagnosis of deafness.

scholarly journals Targeted Next-Generation Sequencing Identified Compound Heterozygous Mutations in MYO15A as the Probable Cause of Nonsyndromic Deafness in a Chinese Han Family

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Longhao Wang ◽  
Lin Zhao ◽  
Hu Peng ◽  
Jun Xu ◽  
Yun Lin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Cochlear Implantation ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Before And After ◽  
Compound Heterozygous Mutations ◽  
Generation Sequencing

Hearing loss is a highly heterogeneous disorder, with more than 60% of congenital cases caused by genetic factors. This study is aimed at identifying the genetic cause of congenital hearing loss in a Chinese Han family. Auditory evaluation before and after cochlear implantation and targeted next-generation sequencing of 140 deafness-related genes were performed for the deaf proband. Compound heterozygous mutations c.3658_3662del (p. E1221Wfs∗23) and c.6177+1G>T were identified in MYO15A as the only candidate pathogenic mutations cosegregated with the hearing loss in this family. These two variants were absent in 200 normal-hearing Chinese Hans and were classified as likely pathogenic and pathogenic, respectively, based on the ACMG guideline. Our study further expanded the mutation spectrum of MYO15A as the c.3658_3662del mutation is novel and confirmed that deaf patients with recessive MYO15A mutations have a good outcome for cochlear implantation.

scholarly journals X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers

2019 ◽  
Vol 20 (6) ◽  
pp. 1518 ◽  
Author(s):  
Kentaro Kurata ◽  
Katsuhiro Hosono ◽  
Takaaki Hayashi ◽  
Kei Mizobuchi ◽  
Satoshi Katagiri ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Visual Fields ◽  
Retinal Dystrophy ◽  
Clinical Findings ◽  
Clinical Severity ◽  
Targeted Next Generation Sequencing ◽  
Japanese Cohort ◽  
Pathogenic Mutations ◽  
Male Patients ◽  
Female Carriers

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan.

Identification of a Disease-Causing Mutation in a Chinese Patient with Retinitis Pigmentosa by Targeted Next-Generation Sequencing

2017 ◽  
Vol 27 (6) ◽  
pp. 791-796 ◽  
Author(s):  
Jianping Xiao ◽  
Xueqin Guo ◽  
Yong Wang ◽  
Mingkun Shao ◽  
Xiaoming Wei ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Sanger Sequencing ◽  
Bioinformatics Analysis ◽  
Family Members ◽  
Chinese Patient ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

Purpose To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate disease-causing mutations. Sanger sequencing was performed on all subjects to confirm the candidate mutations and assess cosegregation within the family. Results Clinical examinations of the proband showed typical characteristics of RP. Three candidate heterozygous mutations in 3 genes associated with RP were detected in the proband by targeted NGS. The 3 mutations were confirmed by Sanger sequencing and the deletion (c.357_358delAA) in PRPF31 was shown to cosegregate with RP phenotype in 7 affected family members, but not in 3 unaffected family members. Conclusions The deletion (c.357_358delAA) in PRPF31 was the disease-causing mutation for the proband and his affected family members with RP. To our knowledge, this is the second report of the deletion and the first report of the other 2 mutations in the Chinese population. Targeted NGS combined with bioinformatics analysis proved to be an effective molecular diagnostic tool for RP.

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