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Long-term follow-up of an Alport syndrome patient with a novel mutation of COL4A5.

ABSTRACT: BACKGROUND:Alport syndrome (AS) is a genetic disease characterized by progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD), sensorineural hearing loss and ocular abnormalities. So far, a lot of mutations were reported in COL4A3, COL4A4 and COL4A5 genes, which are related to AS. METHODS:Whole-exome sequencing in combination with AS-related genes filtering strategy was applied to investigate a Chinese AS family. We also employed Sanger sequencing to confirm the family co-segregation. In addition, we also summed up a long-term follow-up data from 2003 to 2016. RESULTS:In this study, we have detected a novel insertion mutation (c.348_349insTCCGG/p.G117Sfs×40) of COL4A5, which may lead to a truncated protein in the proband. Sanger sequencing confirmed that this novel mutation was co-segregated with all the family members. The long-term follow-up data showed that the progress of chronic kidney disease become more and more serious in the proband. CONCLUSIONS:A novel mutation (c.348_349insTCCGG/p.G117Sfs×40) of COL4A5 was identified in this study. In addition, approximately 15 years long-term follow-up data was provided in this paper. Our study not only expands the spectrum of COL4A5 mutations, but also analysis the progress of AS and fills the knowledge about course and potential further complications and health risks of AS.

SUBMITTER: Xiang R

PROVIDER: S-EPMC6965389 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Long-term follow-up of an Alport syndrome patient with a novel mutation of <i>COL4A5</i>.

Xiang Rong R Li Jing-Jing JJ Liu Ji-Shi JS Fan Liang-Liang LL Li Lin L Xia Kun K Zhang Hao H

International journal of clinical and experimental pathology 20170801 8

<h4>Background</h4>Alport syndrome (AS) is a genetic disease characterized by progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD), sensorineural hearing loss and ocular abnormalities. So far, a lot of mutations were reported in <i>COL4A3</i>, <i>COL4A4</i> and <i>COL4A5</i> genes, which are related to AS.<h4>Methods</h4>Whole-exome sequencing in combination with AS-related genes filtering strategy was applied to investigate a Chinese AS family. We also em ...[more]

PMID: 31966729

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Project description:Background and objectivesX-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.Design, setting, participants, & measurementsIn total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.ResultsSix splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.ConclusionsThis report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

Project description:BackgroundThe past years have witnessed dramatic changes in the population admitted to the intensive care unit (ICU). Older and sicker patients are now commonly treated in this setting due to the newly available sophisticated life support. However, the short- and long-term benefit of this strategy is scarcely studied.MethodsThe Critically Ill patients' mortality by age: Long-Term follow-up (CIMbA-LT) was a multicentric, nationwide, retrospective, observational study addressing short- and long-term prognosis of patients admitted to Portuguese multipurpose ICUs, during 4 years, according to their age and disease severity. Patients were followed for two years after ICU admission. The standardized hospital mortality ratio (SMR) was calculated according to the Simplified Acute Physiology Score (SAPS) II and the follow-up risk, for patients discharged alive from the hospital, according to official demographic national data for age and gender. Survival curves were plotted according to age group.ResultsWe included 37.118 patients, including 15.8% over 80 years old. The mean SAPS II score was 42.8 ± 19.4. The ICU all-cause mortality was 16.1% and 76% of all patients survive until hospital discharge. The SAPS II score overestimated hospital mortality [SMR at hospital discharge 0.7; 95% confidence interval (CI) 0.63-0.76] but accurately predicted one-year all-cause mortality [1-year SMR 1.01; (95% CI 0.98-1.08)]. Survival curves showed a peak in mortality, during the first 30 days, followed by a much slower survival decline thereafter. Older patients had higher short- and long-term mortality and their hospital SMR was also slightly higher (0.76 vs. 0.69). Patients discharged alive from the hospital had a 1-year relative mortality risk of 6.3; [95% CI 5.8-6.7]. This increased risk was higher for younger patients [21.1; (95% CI 15.1-39.6) vs. 2.4; (95% CI 2.2-2.7) for older patients].ConclusionsCritically ill patients' mortality peaked in the first 30 days after ICU admission. Older critically ill patients had higher all-cause mortality, including a higher hospital SMR. A long-term increased relative mortality risk was noted in patients discharged alive from the hospital, but this was more noticeable in younger patients.

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Long-term follow-up of an Alport syndrome patient with a novel mutation of COL4A5.

Publications

Long-term follow-up of an Alport syndrome patient with a novel mutation of <i>COL4A5</i>.

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