Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

BackgroundAutosomal recessive Alport syndrome (ARAS) is an inherited renal disorder caused by homozygous and compound heterozygous mutations in COL4A3 or COL4A4, but the prognostic predictors for this disorder are not yet fully understood. Recently, the magnitude of the clinical spectrum of the COL4A3 and COL4A4 heterozygous state has attracted attention. This spectrum includes asymptomatic carriers of ARAS, benign familial hematuria, thin basement membrane disease, and autosomal dominant Alport syndrome.MethodsWe retrospectively analyzed 49 patients with ARAS from 41 families with a median age of 19 years to examine the clinical features and prognostic factors of ARAS, including the associated genotypes.ResultsThe median age of patients with ARAS at ESKD onset was 27 years. There was no significant association between the presence or absence of hearing loss or truncating mutations and renal prognosis. However, there was a statistically significant correlation between renal prognosis and heterozygous variants that cause urinary abnormalities. Where the urinary abnormality–causing variant was absent or present in only one allele, the median age of ESKD onset was 45 years, whereas the same variant present on both alleles was associated with an age of onset of 15 years (P<0.001).ConclusionsThis study was the first to demonstrate the clinical importance in ARAS of focusing on variants in COL4A3 or COL4A4 that cause urinary abnormalities in both the homozygous or heterozygous state. Although heterozygous mutation carriers of COL4A3 and COL4A4 comprise a broad clinical spectrum, clinical information regarding each variant is important for predicting ARAS prognosis.

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A disease-causing variant of COL4A5 in a Chinese family with Alport syndrome: a case series

BMC Nephrology ◽

10.1186/s12882-021-02585-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jing Wu ◽

Jun Zhang ◽

Li Liu ◽

Bo Zhang ◽

Tomohiko Yamamura ◽

...

Keyword(s):

Alport Syndrome ◽

Wide Spectrum ◽

Case Series ◽

Pcr Analysis ◽

Chinese Family ◽

Compound Heterozygous ◽

Rt Pcr ◽

Col4a5 Gene ◽

Minigene Assay

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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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

European Journal of Human Genetics ◽

10.1038/s41431-021-00858-1 ◽

2021 ◽

Author(s):

Judy Savige ◽

Helen Storey ◽

Elizabeth Watson ◽

Jens Michael Hertz ◽

Constantinos Deltas ◽

...

Keyword(s):

Renal Failure ◽

Alport Syndrome ◽

Pathogenic Variants ◽

Persistent Proteinuria ◽

Mutational Hotspots ◽

Splicing Variants ◽

History Of ◽

Standards And Guidelines ◽

Reference Databases ◽

End Stage

AbstractThe recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

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

Medicine ◽

10.1097/md.0000000000027890 ◽

2021 ◽

Vol 100 (47) ◽

pp. e27890

Author(s):

Ji-Yu Chen ◽

Jing-Jing Cui ◽

Xi-Ran Yang ◽

Yan-Fang Li ◽

Yan-Hua Zhang ◽

...

Keyword(s):

Alport Syndrome ◽

Chinese Family ◽

Compound Heterozygous

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Identification of a Novel COL4A4 Variant in Compound-Heterozygous State in a Patient With Alport Syndrome and Histological Findings Similar to Focal Segmental Glomerulosclerosis (FSGS)

Frontiers in Genetics ◽

10.3389/fgene.2018.00748 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Feng Zhu ◽

Wencheng Li ◽

Zhenqiong Li ◽

Hongyan Zhu ◽

Jing Xiong

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

Alport Syndrome ◽

Compound Heterozygous ◽

Heterozygous State ◽

Histological Findings ◽

Segmental Glomerulosclerosis ◽

Compound Heterozygous State

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A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations

Pediatric Nephrology ◽

10.1007/s00467-013-2682-6 ◽

2013 ◽

Vol 29 (3) ◽

pp. 481-485 ◽

Cited By ~ 6

Author(s):

Mardhiah Mohammad ◽

Ranjit Nanra ◽

Deb Colville ◽

Paul Trevillian ◽

Yanyan Wang ◽

...

Keyword(s):

Alport Syndrome ◽

Compound Heterozygous

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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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Prevalence Estimates of Predicted Pathogenic COL4A3 - COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2020071065 ◽

2021 ◽

pp. ASN.2020071065

Author(s):

Joel Gibson ◽

Rachel Fieldhouse ◽

Melanie Chan ◽

Omid Sadeghi-Alavijeh ◽

Leslie Burnett ◽

...

Keyword(s):

Alport Syndrome ◽

Compound Heterozygous ◽

Normal Donor ◽

Donor Kidney ◽

Thin Basement Membrane Nephropathy ◽

Pathogenic Variants ◽

Prevalence Estimates ◽

Disease Penetrance ◽

Genetic And Environmental Factors ◽

Compound Heterozygous Variants

Background: The prevalence of Alport syndrome varies from one in 5,000 to one in 53,000. This study estimated the frequencies of predicted pathogenic COL4A3- COL4A5 variants in sequencing databases of populations without known kidney disease. Methods: Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria that considered collagen IV α3-α5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3-COL4A5 variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants. Results:COL4A3-COL4A5 variants resulting in position 1 Gly substitutions were confirmed associated with haematuria (p each <0.0001). Predicted pathogenic COL4A5 variants were found in at least one in 2,320 individuals. p.(Gly624Asp), represented nearly half (16/33, 48%) the variants in Europeans. Most COL4A5 variants (54/59, 92%) had a biochemical feature that potentially mitigated clinical impact. Predicted pathogenic heterozygous COL4A3 and COL4A4 variants affected one in 106 of the population, consistent with the finding of Thin basement membrane nephropathy in normal donor kidney biopsies. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals and digenic variants in at least one in 44,793. Conclusions: The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3-COL4A5 variants but must be adjusted for the disease penetrance of individual variants, as well as the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.

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Compound Heterozygous Splicing Variants In KIAA0586 Cause Fetal Short-Rib Thoracic Dysplasia And Cerebellar Malformation: The Use of Whole Exome Sequencing In Prenatal Diagnosis

10.21203/rs.3.rs-886998/v1 ◽

2021 ◽

Author(s):

Qianying Zhao ◽

Bocheng Xu ◽

Qinqin Xiang ◽

Yu Tan ◽

Hanbin Xie ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Fetal Monitoring ◽

Joubert Syndrome ◽

Compound Heterozygous ◽

Thoracic Cage ◽

Cerebellar Malformation ◽

Dna And Rna ◽

Whole Exome ◽

Splicing Variants

Abstract Background: Short-rib thoracic dysplasia (SRTD) and Joubert syndrome (JS) are rare genetic ciliopathies, both patients can manifest cerebellar malformation and variable developmental delays. However, neither could be easily diagnosed during pregnancy due to limited fetal phenotype. Here, we investigated a fetus with short limbs, polydactyly initially and uncovered a compound heterozygous pathogenesis through whole exome sequencing (WES).Results: Merely short limbs and polydactyly of the fetus were detected during second trimester of gestation. Two variants (c.3940+1G>A and c.3303G>A), affecting splicing of KIAA0586 gene, were identified from amniocytes through WES. The presence and effect of these mutations were further validated on DNA and RNA level through Sanger sequencing. More intensive fetal monitoring was applied; deformed cerebellar malformation and restricted thoracic cage of the fetus were additionally uncovered. Conclusion: Herein, we discovered a genetic pathogenesis of KIAA0586 gene associated with SRTD and/or JS in a fetus with mild ultrasound anomalies initially. With the information of prenatal WES and distinct phenotypes of the fetus uncovered by imaging examination, we could reach more accurate clinical diagnosis and provide valuable prognosis information for parents.

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