Genetic and Clinical Analyses of 13 Chinese Families With Cystine Urolithiasis and Identification of 15 Novel Pathogenic Variants in SLC3A1 and SLC7A9

BMP4 variants have been reported to be associated with syndromic microphthalmia (MCOPS6, OMIM 607932). This study aims to describe BMP4 truncation mutations contributing to a novel phenotype in eight patients from four Chinese families. In this study, BMP4 variants were collected from a large dataset from in-house exome sequencing. Candidate variants were filtered by multiple in silico tools as well as comparison with data from multiple databases. Potential pathogenic variants were further confirmed by Sanger sequencing and cosegregation analysis. Four novel truncation variants in BMP4 were detected in four out of 7,314 unrelated probands with different eye conditions. These four mutations in the four families solely cosegregated in all eight patients with a specific form of pathologic myopia, characterized by significantly extended axial length, posterior staphyloma, macula patchy, chorioretinal atrophy, myopic optic neuropathy or glaucoma, vitreous opacity, and unique peripheral snow-grain retinopathy. The extreme rarity of the truncations in BMP4 (classified as intolerant in the gnomAD database, pLI = 0.96), the exclusive presence of these variants in the four families with pathologic myopia, variants fully co-segregated with the same specific phenotypes in eight patients from the four families, and the association of the pathogenicity of truncations with syndromic microphthalmia in previous studies, all support a novel association of BMP4 truncations with a specific form of pathologic myopia. The data presented in this study demonstrated that heterozygous BMP4 truncations contributed to a novel phenotype: pathologic myopia rather than microphthalmia. Mutations in the same gene resulting in both high myopia and microphthalmia have been observed for a few other genes like FZD5 and PAX6, suggesting bidirectional roles of these genes in early ocular development. Further studies are expected to elucidate the molecular mechanism of the bidirectional regulation.

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Novel variants of ABCA4 in Han Chinese families with Stargardt disease

BMC Medical Genetics ◽

10.1186/s12881-020-01152-5 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Fang-Yuan Hu ◽

Feng-Juan Gao ◽

Jian-kang Li ◽

Ping Xu ◽

Dan-Dan Wang ◽

...

Keyword(s):

In Silico ◽

Early Adulthood ◽

Han Chinese ◽

Macular Dystrophy ◽

Stargardt Disease ◽

Causative Gene ◽

Chinese Families ◽

Pathogenic Variants ◽

Potential Pathogenicity ◽

Coding Variants

Abstract Background Stargardt disease (STGD1) is a common recessive hereditary macular dystrophy in early adulthood or childhood, with an estimated prevalence of 1:8000 to 1:10,000. ABCA4 is the causative gene for STGD1. The current study aims at identifying the novel disease-related ABCA4 variants in Han Chinese families with STGD1 using next-generation sequencing (NGS). Methods In the present study, 12 unrelated Han Chinese families (19 males and 17 females) with STGD1 were tested by panel-based NGS. In order to capture the coding exons and the untranslated regions (UTRs) plus 30 bp of intronic flanking sequences of 792 genes, which were closely associated with usual ophthalmic genetic disease, we designed a customized panel, namely, Target_Eye_792_V2 chip. STGD1 patients were clinically diagnosed by experienced ophthalmologists. All the detected variants were filtered and analyzed through the public databases and in silico programs to assess potential pathogenicity. Results Twenty-one ABCA4 mutant variants were detected in 12 unrelated Han Chinese families with STGD1, containing 14 missense, three splicing, two frameshift, one small deletion, and one nonsense variants. Base on the American College of Medical Genetics (ACMG) guidelines, 8 likely pathogenic and 13 pathogenic variants were determined. The functional consequences of these mutant variants were predicted through in silico programs. Of the 21 mutant variants in ABCA4, two novel coding variants c.3017G > A and c.5167 T > C and one novel null variant c.3051-1G > A were detected in three unrelated probands. Conclusions By panel-based NGS, 21 ABCA4 variants were confirmed in 12 unrelated Han Chinese families. Among them, 3 novel mutant variants were found, which further expanded the ABCA4 mutation spectrum in STGD1 patients.

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Genotype–Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review

Frontiers in Genetics ◽

10.3389/fgene.2021.600210 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junxing Yang ◽

Lin Zhou ◽

Jiamin Ouyang ◽

Xueshan Xiao ◽

Wenmin Sun ◽

...

Keyword(s):

Refractive Error ◽

Similar Data ◽

Sequencing Data ◽

Systematic Analysis ◽

Chinese Families ◽

Pathogenic Variants ◽

Significant Difference ◽

Phenotype Analysis ◽

Male Patients ◽

Female Carriers

PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR.

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Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

European Journal of Human Genetics ◽

10.1038/s41431-019-0523-1 ◽

2019 ◽

Vol 28 (2) ◽

pp. 244-252 ◽

Cited By ~ 1

Author(s):

Yanqin Zhang ◽

Jie Ding ◽

Suxia Wang ◽

Hongwen Zhang ◽

Xuhui Zhong ◽

...

Keyword(s):

Alport Syndrome ◽

Urine Analysis ◽

Family Members ◽

Clinical Manifestations ◽

Pathogenic Variant ◽

The Other ◽

Normal Result ◽

Chinese Families ◽

Col4a5 Gene ◽

Pathogenic Variants

Abstract X-linked Alport syndrome (XLAS) is an inherited renal disease caused by mutations in COL4A5 gene. The c.2858G>T(p.(G953V)) in COL4A5 gene (rs78972735) has been considered pathogenic previously. However, there are conflicting interpretations of its pathogenicity recently. Here we presented 19 Chinese families, out of which 36 individuals (18 probands and 18 family members) carried the c.2858G>T(p.(G953V)) in COL4A5 gene. The clinical manifestations and genetic findings of them were analyzed. We found there were no clinical features of Alport syndrome not only in six probands with c.2858G>T(p.(G953V)) in COL4A5 plus pathogenic variants in other genes (e.g., WT1, ADCK4, NPHP1, TRPC6, COL4A4, and PAX2) but also in another six probands with only the c.2858G>T(p.(G953V)) variant. The other six probands with a combination of c.2858G>T(p.(G953V)) and another pathogenic variant in COL4A5 had XLAS. Eleven family members (11/18, nine females and two males) who had only the c.2858G>T(p.(G953V)) variant were asymptomatic. These two males (at age of 42 and 35 years) had normal result of urine analysis and no more clinical traits of Alport syndrome. We conclude c.2858G>T(p.(G953V)) in COL4A5 gene is not a pathogenic variant for XLAS. Individuals should not be diagnosed as XLAS only based on the detection of c.2858G>T(p.(G953V)) in COL4A5 gene.

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Five novel NF1 gene pathogenic variants in 10 different Chinese families with neurofibromatosis type 1

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.904 ◽

2019 ◽

Vol 7 (9) ◽

Author(s):

Linlin Chen ◽

Feng Xue ◽

Jia Xu ◽

Jinwei He ◽

Wenzhen Fu ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Chinese Families ◽

Pathogenic Variants ◽

Nf1 Gene

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Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1194-2 ◽

2019 ◽

Vol 14 (1) ◽

Author(s):

Qian Jiang ◽

Yang Wang ◽

Qi Li ◽

Zhen Zhang ◽

Ping Xiao ◽

...

Keyword(s):

De Novo ◽

Hirschsprung Disease ◽

Causative Gene ◽

High Coverage ◽

Chinese Families ◽

Sequence Characterization ◽

Pathogenic Variants ◽

Enteric Ganglia ◽

Digital Polymerase Chain Reaction ◽

Coding Variants

Abstract Background Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. Results To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13–27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. Conclusion Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.

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Phenotypic variability and genetic characteristics of PRRT2-associated paroxysmal movement disorders in 13 Chinese families

10.21203/rs.3.rs-288854/v1 ◽

2021 ◽

Author(s):

Lulu Wu ◽

Xinyu Yang ◽

Xiaocui Wang ◽

Shuang Yu ◽

Bin Yang

Keyword(s):

Movement Disorders ◽

Novel Mutation ◽

Phenotypic Variability ◽

Infantile Spasm ◽

Family Members ◽

Clinical Findings ◽

Genetic Characteristics ◽

Chinese Families ◽

Pathogenic Variants ◽

Infantile Epilepsy

Abstract PRRT2-associated paroxysmal movement disorders (PRRT2-PxMDs) include paroxysmal kinesigenic dyskinesias (PKD), benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), episodic ataxia (EA), paroxysmal nonkinesiasgenic dyskinesias (PNKD), and, in addition, other childhood-onset movement disorders and different types of seizures may be caused by PRRT2 mutations, suggesting that the understanding of the spectrum of PRRT2-PxMDs is still evolving. We collected and analyzed retrospectively the clinical of children diagnosed with paroxysmal movement disorders by the Department of Neurology of Anhui Provincial Children's Hospital from January 2015 to June 2020. The genetic tests were performed in the probands and their family members. Thirteen children and their family members, 30 in total, were tested. Twenty six patients and 4 (13.34%) carriers from 13 families were identified, 14 (46.67%) were diagnosed with BIE, 7 (23.33%) with PKD, 2 (6.67%) with ICCA, 1 (3.33%) with epilepsy (focal), 1 (3.33%) with infantile spasm (IS), and 1 (3.33%)was diagnosed with PKD and PNKD, Eight different variants were identified in 13 families, and NM_145239.2:c.640-641insC was found in 4 families while recurrent mutation c.649dupC was not found. Three novel mutation, c.884G > C, c.865G > C, and c.-65-1G > C were identified in this study. This study confirmed that there is no clear genotype-phenotype correlation in patients with PRRT2-PxMDs, in addition, the clinical findings show variable phenotype within families, including the families affected due to the newly identified pathogenic variants in this study.

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EXT1 and EXT2 Variants in 22 Chinese Families With Multiple Osteochondromas: Seven New Variants and Potentiation of Preimplantation Genetic Testing and Prenatal Diagnosis

Frontiers in Genetics ◽

10.3389/fgene.2020.607838 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ye Wang ◽

Liangying Zhong ◽

Yan Xu ◽

Lei Ding ◽

Yuanjun Ji ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Genetic Testing ◽

Successful Implementation ◽

Preimplantation Genetic Testing ◽

Chinese Families ◽

Pathogenic Variants ◽

Multiple Osteochondromas ◽

Whole Exome ◽

Splicing Variants ◽

Phenotypic And Genetic Characterization

Multiple osteochondromas (MO), the most common type of benign bone tumor, is an autosomal dominant skeletal disorder characterized by multiple cartilage-capped bony protuberances. In most cases, EXT1 and EXT2, which encode glycosyltransferases involved in the biosynthesis of heparan sulfate, are the genes responsible. Here we describe the clinical, phenotypic and genetic characterization of MO in 22 unrelated Chinese families involving a total of 60 patients. Variant detection was performed by means of a battery of different techniques including Sanger sequencing and whole-exome sequencing (WES). The pathogenicity of the missense and splicing variants was explored by means of in silico prediction algorithms. Sixteen unique pathogenic variants, including 10 in the EXT1 gene and 6 in the EXT2 gene, were identified in 18 (82%) of the 22 families. Fourteen (88%) of the 16 variants were predicted to give rise to truncated proteins whereas the remaining two were missense. Seven variants were newly described here, further expanding the spectrum of MO-causing variants in the EXT1 and EXT2 genes. More importantly, the identification of causative variants allowed us to provide genetic counseling to 8 MO patients in terms either of preimplantation genetic testing (PGT) or prenatal diagnosis, thereby preventing the reoccurrence of MO in the corresponding families. This study is the first to report the successful implementation of PGT in MO families and describes the largest number of subjects undergoing prenatal diagnosis to date.

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AQP5 pathogenic variants induce palmoplantar keratoderma Bothnia type in two Chinese families

The Journal of Dermatology ◽

10.1111/1346-8138.16281 ◽

2022 ◽

Author(s):

Yumeng Wang ◽

Jianbo Wang ◽

Yue Li ◽

Chaolan Pan ◽

Wange Zhou ◽

...

Keyword(s):

Palmoplantar Keratoderma ◽

Chinese Families ◽

Pathogenic Variants

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Genetic Etiology Study of Ten Chinese Families with Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2018/4920980 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Songqun Hu ◽

Feifei Sun ◽

Jie Zhang ◽

Yan Tang ◽

Jinhong Qiu ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Chinese Population ◽

Sanger Sequencing ◽

Nonsyndromic Hearing Loss ◽

Genetic Etiology ◽

Chinese Families ◽

Pathogenic Variants ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. In this report, we aimed to disclose the genetic causes of the subjects from the ten Chinese deaf families who did not have pathogenic common genes/mutation. Next-generation sequencing (NGS) of 142 known deafness genes was performed in the probands of ten families followed by cosegregation analysis of all family members. We identified novel pathogenic variants in six families including p.D1806E/p.R1588W, p.R964W/p.R1588W, and p.G17C/p.G1449D in CDH23; p.T584M/p.D1939N in LOXHD1; p.P1225L in MYO7A; and p.K612X in EYA4. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family. In four families, no pathogenic variants were identified. Our study provided better understanding of the mutation spectrum of hearing loss in the Chinese population.

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