A novel compound heterozygous COL4A4 mutation in a Chinese family with Alport syndrome

Abstract Background Alport syndrome (AS), which is a rare hereditary disease caused by mutations of genes including COL4A3, COL4A4 and COL4A5, has a wide spectrum of phenotypes. Most disease-causing variants of AS are located in the exons or the conservative splicing sites of these genes, while little is known about the intronic disease-causing variants. Methods A Chinese AS family was recruited in this study. All the clinical data of AS patient were collected from medical records. After pedigree analysis, the pathogenic variants were studied by the whole exome sequencing (WES). Minigene assay and in vivo RT-PCR analysis were performed to validate the functions of the variants. Results Renal biopsy showed a typical histopathology changes of AS. WES revealed compound heterozygous substitution, NM_033380 c.991–14(IVS17) A > G, in the intron 17 of the COL4A5 gene, which were confirmed by Sanger sequencing. Moreover, the variant was co-segregated with the phenotype in this family. Minigene assay in cultured cell lines showed that a splicing error was induced by this intronic variant, which further confirmed by in vivo RT-PCR analysis. Conclusion A novel intronic disease-causing variant in COL4A5 gene was identified by WES, which was the molecular pathogenic basis of AS.

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The COL4A3 and COL4A4 Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family

Cytogenetic and Genome Research ◽

10.1159/000488163 ◽

2018 ◽

Vol 154 (3) ◽

pp. 132-136 ◽

Cited By ~ 2

Author(s):

Ang Li ◽

Ying-Xia Cui ◽

Xing Lv ◽

Jian-Hong Liu ◽

Er-Zhi Gao ◽

...

Keyword(s):

Alport Syndrome ◽

Autosomal Dominant ◽

Chinese Family ◽

Compound Heterozygous ◽

Bioinformatics Analyses ◽

Digenic Inheritance ◽

Pedigree Verification ◽

In Cis ◽

Benign Familial Hematuria ◽

Familial Hematuria

Mutations in the COL4A5 gene result in X-linked Alport syndrome, homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are responsible for autosomal recessive Alport syndrome, and heterozygous mutations in COL4A3 or COL4A4 cause autosomal dominant Alport syndrome or benign familial hematuria. Recently, the existence of a digenic inheritance in Alport syndrome has been demonstrated. We here report heterozygous COL4A3 and COL4A4 digenic mutations in cis responsible for benign familial hematuria. Using bioinformatics analyses and pedigree verification, we showed that COL4A4 c.1471C>T and COL4A3 c.3418 + 1G>T variants in cis are pathogenic and co-segregate with the benign familial hematuria. This result suggests that COL4A3 and COL4A4 digenic mutations in cis mimicking an autosomal dominant inheritance should be considered as a novel inheritance pattern of benign familial hematuria, although the disease-causing mechanism remains unknown.

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Atrichia with Papular Lesions in a Chinese Family Caused by Novel Compound Heterozygous Mutations and Literature Review

Dermatology ◽

10.1159/000346753 ◽

2013 ◽

Vol 226 (1) ◽

pp. 68-74 ◽

Cited By ~ 2

Author(s):

Shuang Wang ◽

Chen Tu ◽

Yiguo Feng ◽

Xiaopeng Wang ◽

Dingwei Zhang ◽

...

Keyword(s):

Literature Review ◽

Chinese Family ◽

Compound Heterozygous ◽

Compound Heterozygous Mutations

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Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family

PLoS ONE ◽

10.1371/journal.pone.0124757 ◽

2015 ◽

Vol 10 (4) ◽

pp. e0124757 ◽

Cited By ~ 3

Author(s):

Xue Gao ◽

Yu Su ◽

Yu-Lan Chen ◽

Ming-Yu Han ◽

Yong-Yi Yuan ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Chinese Family ◽

Compound Heterozygous

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Novel compound heterozygous mutations in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct

BioScience Trends ◽

10.5582/bst.2018.01260 ◽

2018 ◽

Vol 12 (5) ◽

pp. 502-506 ◽

Cited By ~ 1

Author(s):

Xuelei Zhao ◽

Xiaohua Cheng ◽

Lihui Huang ◽

Xianlei Wang ◽

Cheng Wen ◽

...

Keyword(s):

Chinese Family ◽

Compound Heterozygous ◽

Enlarged Vestibular Aqueduct ◽

Vestibular Aqueduct ◽

Compound Heterozygous Mutations ◽

I Gene

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Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family

Neural Plasticity ◽

10.1155/2020/3569359 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yue Qiu ◽

Sen Chen ◽

Xia Wu ◽

Wen-Juan Zhang ◽

Wen Xie ◽

...

Keyword(s):

Deaf Child ◽

Gene Mutations ◽

Deaf Children ◽

Chinese Family ◽

Compound Heterozygous ◽

Qtc Interval ◽

Cardiac Events ◽

Life Threatening ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).

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Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

Bioscience Reports ◽

10.1042/bsr20193443 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

Author(s):

Chunli Wei ◽

Ting Xiao ◽

Jingliang Cheng ◽

Jiewen Fu ◽

Qi Zhou ◽

...

Keyword(s):

Novel Mutation ◽

Gene Mutations ◽

Chinese Family ◽

Compound Heterozygous ◽

Missense Mutations ◽

The Novel ◽

Pathogenic Variants ◽

Pathogenic Genes ◽

Compound Heterozygous Variants ◽

Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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Identification of two novel compound heterozygous mutations of ADGRV1 in a Chinese family with Usher syndrome type IIC

Ophthalmic Genetics ◽

10.1080/13816810.2018.1479430 ◽

2018 ◽

Vol 39 (4) ◽

pp. 517-521 ◽

Cited By ~ 1

Author(s):

Nian Zhang ◽

Juan Wang ◽

Shuting Liu ◽

Mugen Liu ◽

Fagang Jiang

Keyword(s):

Usher Syndrome ◽

Chinese Family ◽

Compound Heterozygous ◽

Syndrome Type ◽

Compound Heterozygous Mutations ◽

Usher Syndrome Type

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Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms

BMC Medical Genetics ◽

10.1186/s12881-019-0920-x ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Sha Zhao ◽

Zhenqing Luo ◽

Zhenghui Xiao ◽

Liping Li ◽

Rui Zhao ◽

...

Keyword(s):

Developmental Delay ◽

Chinese Population ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Chinese Family ◽

Compound Heterozygous ◽

Case Presentation ◽

Cohen Syndrome ◽

The Family ◽

Sporadic Cases

Abstract Background Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. Case presentation A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. Conclusions This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

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