Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome

Krol, Rafal P.; Nozu, Kandai; Nakanishi, Koichi; Iijima, Kazumoto; Takeshima, Yasuhiro; Fu, Xue Jun; Nozu, Yoshimi; Kono, Hiroshi; Kanda, Kyoko; Matsuo, Masafumi; Yoshikawa, Norishige

doi:10.1093/ndt/gfn005

Cited by 27 publications

(23 citation statements)

References 16 publications

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“…7 Although at the time of this study (2008), we thought that our methods were highly efficient, it now appears that they were not reliable because the two techniques used in the current study (TruSight One and targeted resequencing) achieved almost identical frequencies, which differed from our previous data.…”

Section: Discussioncontrasting

confidence: 59%

“…His kidney biopsy expressed α5(IV) mosaicism in the glomerulus, which was associated with the somatic mosaic variant. 7 To date, however, only six patients in four reports have been described with somatic mosaic variants in COL4A5, including our previous report (Table 4). 7,[19][20][21] Although all six cases showed a milder phenotype and some of the female cases were asymptomatic, no asymptomatic male cases have previously been reported.…”

Section: Discussionmentioning

confidence: 79%

“…7 To date, however, only six patients in four reports have been described with somatic mosaic variants in COL4A5, including our previous report (Table 4). 7,[19][20][21] Although all six cases showed a milder phenotype and some of the female cases were asymptomatic, no asymptomatic male cases have previously been reported. A recent publication by Beicht et al 19 described an asymptomatic female XLAS patient with a somatic mosaic variant who had variant allele frequencies of 14, 7, 4, and 7% in leukocytes, urine sediments, hair roots, and oral mucosa, respectively, as shown by NGS.…”

Section: Discussionmentioning

confidence: 79%

“…The precise clinical course of this patient has been reported previously. 7 At 16 years of age, the patient had microhematuria and moderate proteinuria with 0.74 g/g creatinine (Cr). Genetic analysis revealed the presence of an intron 43 splicing acceptor site variant (c.3998-2A4T, IVS44-2A4T).…”

Section: Patient Id14mentioning

confidence: 99%

“…One of these patients has been described in a previous case report. 7 This implies that men with XLAS and somatic mosaic variants show milder phenotypes; however, no case series has reported the correlation between variant frequency and disease severity in patients with somatic mosaic variants. The present study, therefore, examined the correlation between variant frequency and phenotype in a case series of male XLAS patients with somatic mosaic variants using next-generation sequencing (NGS).…”

Section: Introductionmentioning

confidence: 99%

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Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

Nozu

Kono

et al. 2015

Eur J Hum Genet

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X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥ 50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of o50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

Section: Patient Id14mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

Nozu

Kono

et al. 2015

Eur J Hum Genet

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A characterization of postzygotic mutations identified in monozygotic twins

Ouwens

Jansen

Tolhuis³

et al. 2018

Human Mutation

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Postzygotic mutations are DNA changes acquired from the zygote stage onwards throughout the lifespan. These changes lead to differences in DNA sequence among cells of an individual, potentially contributing to the etiology of complex disorders. Here we compared whole genome DNA sequence data of two monozygotic twin pairs, 40 and 100 years old, to detect somatic mosaicism. DNA samples were sequenced twice on two Illumina platforms (13X and 40X read depth) for increased specificity. Using differences in allelic ratios resulted in sets of 1,720 and 1,739 putative postzygotic mutations in the 40‐year‐old twin pair and 100‐year‐old twin pair, respectively, for subsequent enrichment analysis. This set of putative mutations was strongly (p < 4.37e–91) enriched in both twin pairs for regulatory elements. The corresponding genes were significantly enriched for genes that are alternatively spliced, and for genes involved in GTPase activity. This research shows that somatic mosaicism can be detected in monozygotic twin pairs by using allelic ratios calculated from DNA sequence data and that the mutations which are found by this approach are not randomly distributed throughout the genome.

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Low frequency of parental mosaicism in de novo COL4A5 mutations in X‐linked Alport syndrome

Helle

Pedersen

Ousager

et al. 2020

Molec Gen & Gen Med

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Alport syndrome (AS) is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease (ESRD). It is often accompanied by high tone hearing loss and ocular abnormalities (Kruegel, Rubel, & Gross, 2013). The frequency of AS in the general population is unknown but the most commonly cited estimate of the prevalence is 1:5000, from a North American study (Hasstedt & Atkin, 1983). Two studies from the Nordic countries found an incidence of 1:17,000 in live births in southern Sweden

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Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome

Cited by 27 publications

References 16 publications

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

A characterization of postzygotic mutations identified in monozygotic twins

Low frequency of parental mosaicism in de novo COL4A5 mutations in X‐linked Alport syndrome

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