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<p>Transcriptome analysis can improve the diagnostic yield for neurodevelopmental disorders. We applied RNA-seq using urine-derived cells (UDCs) to a family with two affected brothers with a muscular dystrophy–dystroglycanopathy and dilated cardiomyopathy. Exome sequencing identified a maternally inherited heterozygous <i>B3GALNT2</i> splice-site variant (NM_152490.5:c.261-2A&gt;G) but no second pathogenic allele. UDCs RNA-seq with OUTRIDER detected markedly decreased expression of <i>B3GALNT2</i> in the proband and a milder decrease in the father, suggesting a paternally inherited non-coding variant. Genome sequencing revealed a 357-bp heterozygous deletion encompassing the <i>B3GALNT2</i> promoter and transcription start site, which segregated with the phenotype. RNA-seq supported aberrant splicing from the splice-site allele and reduction of transcripts from the deletion allele. These findings provide proof of concept that UDCs RNA-seq–guided outlier-expression analysis can identify non-coding second hits and support genetic diagnosis, and they suggest that cardiac surveillance may be warranted in <i>B3GALNT2</i>-related disorder as they age.</p>

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Genetic diagnosis of sibling cases initiated by identification of outlier gene expression using transcriptome analysis of urine-derived cells

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Toru Takagi,
  • Sachiko Miyamoto,
  • Kenji Shimizu,
  • Yasuhiko Tanaka,
  • Tomoko Matsubayashi,
  • Yohei Masunaga,
  • Hirotomo Saitsu

摘要

Transcriptome analysis can improve the diagnostic yield for neurodevelopmental disorders. We applied RNA-seq using urine-derived cells (UDCs) to a family with two affected brothers with a muscular dystrophy–dystroglycanopathy and dilated cardiomyopathy. Exome sequencing identified a maternally inherited heterozygous B3GALNT2 splice-site variant (NM_152490.5:c.261-2A>G) but no second pathogenic allele. UDCs RNA-seq with OUTRIDER detected markedly decreased expression of B3GALNT2 in the proband and a milder decrease in the father, suggesting a paternally inherited non-coding variant. Genome sequencing revealed a 357-bp heterozygous deletion encompassing the B3GALNT2 promoter and transcription start site, which segregated with the phenotype. RNA-seq supported aberrant splicing from the splice-site allele and reduction of transcripts from the deletion allele. These findings provide proof of concept that UDCs RNA-seq–guided outlier-expression analysis can identify non-coding second hits and support genetic diagnosis, and they suggest that cardiac surveillance may be warranted in B3GALNT2-related disorder as they age.