Novel Variants in Phosphodiesterase 6A and Phosphodiesterase 6B Genes and Its Phenotypes in Patients With Retinitis Pigmentosa in Chinese Families

Mapping Intimacies ◽

10.21203/rs.3.rs-507306/v1 ◽

2021 ◽

Author(s):

Yuyu Li ◽

Ruyi Li ◽

Hehua Dai ◽

Genlin Li

Keyword(s):

Retinitis Pigmentosa ◽

Sanger Sequencing ◽

Autosomal Recessive ◽

Eye Disease ◽

Specific Enzyme ◽

Novel Mutations ◽

Chinese Families ◽

Novel Variants

Abstract Background: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with 65 causative genes identified to date. However, only approximately 60% of RP cases genetically solved to date, predicating that many novel disease-causing variants are yet to be identified. The purpose of this study is to identify novel variants in phosphodiesterase 6A and phosphodiesterase 6B genes and present its phenotypes in patients with retinitis pigmentosa in Chinese families.Methods: Five retinitis pigmentosa patients with PDE6A variants and three with PDE6B variants were identified through a hereditary eye disease enrichment panel (HEDEP), all patients’ medical and ophthalmic histories were collected, and ophthalmological examinations were performed, then we analysed the possible causative variants. Sanger sequencing was used to verify the variants.Results: We identified 20 mutations sites in eight patients, two heterozygous variants were identified per patient of either PDE6A or PDE6B variants, others are from CA4, OPTN, RHO, ADGRA3 variants. We identified two novel variants in PDE6A: c.1246G > A;p.(Asp416Asn) and c.1747T > A;p.(Tyr583Asn). Three novel mutations in PDE6B: c.401T > C;p.(Leu134Pro), c.2293G > C;p.(Ala765Pro) and c.1610-1612del;p.(537-538del).CA4: c.243G > A;p.(Trp81*) and RHO: c.688G>A;p.(Val230Ile) are novel variants and maybe affecting the phenotype. Among them, c.401T > C;p.(Leu134Pro) variant in PDE6B is non- pathogenic; RHO: c.688G>A;p.(Val230Ile) is conflicting interpretations of pathogenicity;Other novel variants are all pathogenic.Conclusions: This study reveals novel and known variants in Chinese families with PDE6A and PDE6B mutations in autosomal recessive RP, expanding the clinical and genetic findings of photoreceptor-specific enzyme deficiencies.

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Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families

BMC Ophthalmology ◽

10.1186/s12886-021-02242-5 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Yuyu Li ◽

Ruyi Li ◽

Hehua Dai ◽

Genlin Li

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Recessive ◽

Compound Heterozygous ◽

The Novel ◽

Specific Enzyme ◽

Genetic Changes ◽

Chinese Families ◽

Novel Variants ◽

Novel Variant ◽

Compound Heterozygous State

Abstract Background Retinitis pigmentosa (RP) is a genetically heterogeneous disease with 89 causative genes identified to date. However, only approximately 60% of RP cases genetically solved to date, predicating that many novel disease-causing variants are yet to be identified. The purpose of this study is to identify novel variants in PDE6A and PDE6B genes and present its phenotypes in patients with retinitis pigmentosa in Chinese families. Methods Five retinitis pigmentosa patients with PDE6A variants and three with PDE6B variants were identified through a hereditary eye disease enrichment panel (HEDEP), all patients’ medical and ophthalmic histories were collected, and ophthalmological examinations were performed, followed by an analysis of the possible causative variants. Sanger sequencing was used to verify the variants. Results We identified 20 variants in eight patients: 16 of them were identified in either PDE6A or PDE6B in a compound heterozygous state. Additional four heterozygous variants were identified in the genes ADGRA3, CA4, OPTN, RHO. Two novel genetic changes in PDE6A were identified (c.1246G > A and c.1747 T > A), three novel genetic changes in PDE6B were identified (c.401 T > C, c.2293G > C and c.1610-1612del), out of the novel identified variants one was most probably non-pathogenic (c.2293G > C), all other novel variants are pathogenic. Additional variant was identified in CA4 and RHO, which can cause ADRP (c.243G > A, c.688G > A). In addition, a novel variant in ADGRA3 was identified (c.921-1G > A). Conclusions This study reveals novel and known variants in PDE6A and PDE6B genes in Chinese families with autosomal recessive RP, and expands the clinical and genetic findings of photoreceptor-specific enzyme deficiencies.

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Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population

Genes ◽

10.3390/genes12040537 ◽

2021 ◽

Vol 12 (4) ◽

pp. 537

Author(s):

Lujia Zhang ◽

Ya Li ◽

Litao Qin ◽

Yu Wu ◽

Bo Lei

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Recessive ◽

Cultured Cells ◽

Missense Variant ◽

Chinese Families ◽

Targeted Next Generation Sequencing ◽

Novel Variants ◽

Next Generation Sequencing Ngs ◽

Computational Predictions

Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with in vitro cellular experiments were applied to evaluate the pathogenicity of the newly found variants. Three novel variants in REEP6, including one missense variant, c.268G>C, one frameshift variant, c.468delC, and one splicing variant, c.598+1G>C, were found, while c.268G>C was detected in all probands. The three variants were classified as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG). REEP6 variant proteins c.268G>C and c.468delC in cultured cells destabilized the REEP6 protein and induced intracellular inclusions. Our data suggested that REEP6 c.268G>C may be a recurrent causative variant in Chinese autosomal recessive retinitis pigmentosa patients.

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Whole Exome Sequencing of Six Chinese Families With Hereditary Non-Syndromic Hearing Loss: A Genetic Etiology Study

10.21203/rs.3.rs-132767/v1 ◽

2020 ◽

Author(s):

Pengfei Liang ◽

Fengping Chen ◽

Shujuan Wang ◽

Qiong Li ◽

Wei Li ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Large Scale ◽

Autosomal Recessive ◽

Autosomal Recessive Inheritance ◽

Chinese Families ◽

Whole Exome ◽

Syndromic Hearing Loss

Abstract Background: Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identified as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families.Methods: After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were verified by Sanger sequencing in all patients and their parents.Results: Biallelic mutations were identified in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identified. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family.Conclusions: Next-generation sequencing (NGS) approach becomes more cost-effective and efficient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current findings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive significance for genetic counseling.

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Novel mutations of RPGR in Chinese families with X-linked retinitis pigmentosa

BMC Ophthalmology ◽

10.1186/s12886-019-1250-7 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Zhimeng Zhang ◽

Hehua Dai ◽

Lei Wang ◽

Tianchang Tao ◽

Jing Xu ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Mutation Screening ◽

Phenotype Correlation ◽

Novel Mutations ◽

Pathological Myopia ◽

Nonsense Mutations ◽

Chinese Families ◽

Coding Regions ◽

Genotype Phenotype Correlation ◽

Male Patients

Abstract Background RP (retinitis pigmentosa) is a group of hereditary retinal degenerative diseases. XLRP is a relatively severe subtype of RP. Thus, it is necessary to identify genes and mutations in patients who present with X-linked retinitis pigmentosa. Methods Genomic DNA was extracted from peripheral blood. The coding regions and intron-exon boundaries of the retinitis pigmentosa GTPase regulator (RPGR) and RP2 genes were amplified by PCR and then sequenced directly. Ophthalmic examinations were performed to identify affected individuals from two families and to characterize the phenotype of the disease. Results Mutation screening demonstrated two novel nonsense mutations (c.1541C > G; p.S514X and c.2833G > T; p.E945X) in the RPGR gene. The clinical manifestation of family 1 with mutations in exon 13 was mild. Genotype-phenotype correlation analysis suggested that patients with mutations close to the downstream region of ORF15 in family 2 manifested an early loss of cone function. Family 2 carried a nonsense mutation in ORF15 that appeared to have a semi-dominant pattern of inheritance. All male patients and two female carriers in family 2 manifested pathological myopia (PM), indicating that there may be a distinctive X-linked genotype-phenotype correlation between RP and PM. Conclusions We identified two novel mutations of the RPGR gene, which broadens the spectrum of RPGR mutations and the phenotypic spectrum of the disease in Chinese families.

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Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families

Postgraduate Medicine ◽

10.1080/00325481.2017.1386529 ◽

2017 ◽

Vol 129 (8) ◽

pp. 934-942 ◽

Cited By ~ 1

Author(s):

Xiaoya Zhang ◽

Zhanying Wei ◽

Jinwei He ◽

Chun Wang ◽

Zhenlin Zhang

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

Type Ii ◽

Novel Mutations ◽

Chinese Families ◽

Autosomal Dominant Osteopetrosis ◽

Autosomal Recessive Osteopetrosis

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Genetic Analysis of 28 Chinese Families With Tyrosinase-Positive Oculocutaneous Albinism

Frontiers in Genetics ◽

10.3389/fgene.2021.715437 ◽

2021 ◽

Vol 12 ◽

Author(s):

Linya Ma ◽

Jianjian Zhu ◽

Jing Wang ◽

Yazhou Huang ◽

Jibo Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Oculocutaneous Albinism ◽

Type Ii ◽

Related Disorder ◽

Chinese Families ◽

Missense Variants ◽

Clinical Presentations ◽

Splicing Variants ◽

Novel Variants ◽

Generation Sequencing

BackgroundTyrosinase-positive oculocutaneous albinism (OCA, type II, OCA2) is an autosomal recessive genetic disease in which the biosynthesis of melanin decreases in the skin, hair, and eyes. OCA2 disease is caused by mutations in OCA2 gene. The gene product plays a role in regulating the pH of melanosomes. Up to now, hundreds of OCA2 mutations have been reported and novel variants are still being discovered.MethodsIn this study, we reviewed the records of OCA2 patients who had conducted albinism genetic testing, and then analyzed the clinical and genetic information of 28 OCA2 patients who had been genetically diagnosed by using Sanger sequencing and next-generation sequencing.ResultsIn this study, we reported 31 variants screened from 28 Chinese OCA2 families, and characterized the detailed molecular and clinical presentations. There were 12 novel variants among all detected variants, including 3 missense variants (p.G393V, p.T482A, and p.R720P), 4 frameshift variants (p.R53Gfs∗49, p.N279Kfs∗17, p.I469Lfs∗4, p.I655Nfs∗12), 2 splicing variants (c.1637-2A > G, c.1951 + 1G > C), 2 stopgain variants (p.L278X, p.W652X) and 1 insertion variants (p.P315LinsT). One potential cluster of missense variants was implicated indicating the important roles of the underlying domains in OCA2 pathogenesis.ConclusionOur results were beneficial for diagnosis and precision clinical management for OCA2-related disorder, and this study expanded the mutation spectrum of oculocutaneous albinism.

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Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2021/9957712 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Xiao-Hui Wang ◽

Le Xie ◽

Sen Chen ◽

Kai Xu ◽

Xue Bai ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Bioinformatics Analysis ◽

Compound Heterozygous ◽

Congenital Deafness ◽

Chinese Families ◽

Novel Variants ◽

Common Causes ◽

Compound Heterozygous Variants ◽

Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

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