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Background <p>Alport syndrome is a progressive and hereditary nephropathy characterized by hematuria and proteinuria as well as extra renal manifestations as hearing loss and eye abnormalities. The disease can be expressed as autosomal recessive or autosomal dominant at COL4A3 and COL4A4 <i>loci</i>, respectively, or X-linked at the COL4A5 locus. This study investigated two unrelated families with nephropathy from Brazil with the aim to identify the mutations involved with the disease.</p> Methods <p>Whole Exome Sequencing was performed for 4 people from each pedigree (case, parents and a sibling). DNA sequences were mapped against the human genome (GRCh38/hg38 build) to identify associated mutations.</p> Results <p>Two novel deleterious variants in COL4A3 and COL4A4 loci on chromosome 2 were identified. The variants were detected in the probands with mutant alleles in the homozygous state, a premature stop codon at position 481 of COL4A3 protein and a frameshift mutation leading to a stop codon at position 786 of COL4A4 protein. For both Alport cases the putative variants were surrounded by broad Runs of Homozygosity as well as genes associated with other hereditary nephropathies. Genotyping for COL4A3 validated the exome findings.</p> Conclusions <p>Two novel variants were identified in two unrelated families from northeast of Brazil. The two deleterious variants identified are located on ROH´s locus with all variants in a homozygous state.</p>

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Whole exome sequencing shows novel COL4A3 and COL4A4 variants as causes of Alport syndrome in Rio Grande do Norte, Brazil

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月2日

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  • Washington Candeia de Araújo,
  • Raul Maia Falcão,
  • Raquel Araujo Costa Uchoa,
  • Carlos Alexandre Garcia,
  • Arthur Quintiliano Bezerra da Silva,
  • Kesia Larissa Medeiros Quirino,
  • Francisco Paulo Freire-Neto,
  • Genilson Pereira Gurgel,
  • Paulo Ricardo Porfirio Nascimento,
  • Leonardo Capistrano Ferreira,
  • Priya Duggal,
  • Jorge Estefano S. de Souza,
  • Selma M. B. Jeronimo

摘要

Background

Alport syndrome is a progressive and hereditary nephropathy characterized by hematuria and proteinuria as well as extra renal manifestations as hearing loss and eye abnormalities. The disease can be expressed as autosomal recessive or autosomal dominant at COL4A3 and COL4A4 loci, respectively, or X-linked at the COL4A5 locus. This study investigated two unrelated families with nephropathy from Brazil with the aim to identify the mutations involved with the disease.

Methods

Whole Exome Sequencing was performed for 4 people from each pedigree (case, parents and a sibling). DNA sequences were mapped against the human genome (GRCh38/hg38 build) to identify associated mutations.

Results

Two novel deleterious variants in COL4A3 and COL4A4 loci on chromosome 2 were identified. The variants were detected in the probands with mutant alleles in the homozygous state, a premature stop codon at position 481 of COL4A3 protein and a frameshift mutation leading to a stop codon at position 786 of COL4A4 protein. For both Alport cases the putative variants were surrounded by broad Runs of Homozygosity as well as genes associated with other hereditary nephropathies. Genotyping for COL4A3 validated the exome findings.

Conclusions

Two novel variants were identified in two unrelated families from northeast of Brazil. The two deleterious variants identified are located on ROH´s locus with all variants in a homozygous state.