Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling

BackgroundX-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS.MethodsWe examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level.ResultsWe detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001).ConclusionsWe report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

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Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.741 ◽

2019 ◽

Vol 7 (7) ◽

Cited By ~ 2

Author(s):

Shunlai Shang ◽

Fei Peng ◽

Tao Wang ◽

Xiaoyuan Wu ◽

Ping Li ◽

...

Keyword(s):

Alport Syndrome ◽

Chinese Patients ◽

Prognostic Impact ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation

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A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis

Journal of Personalized Medicine ◽

10.3390/jpm11010046 ◽

2021 ◽

Vol 11 (1) ◽

pp. 46

Author(s):

Saeed Anwar ◽

Merry He ◽

Kenji Rowel Q. Lim ◽

Rika Maruyama ◽

Toshifumi Yokota

Keyword(s):

Muscular Dystrophy ◽

Rational Design ◽

Meta Analysis ◽

Exon Skipping ◽

Correlation Study ◽

Phenotype Correlation ◽

Patient Registries ◽

Genotype Phenotype Correlation ◽

Exon Skip ◽

Dmd Gene

Dystrophinopathies are caused by mutations in the DMD gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for DMD exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the DMD gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.

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