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Background <p>Syndactyly demonstrates high genetic heterogeneity, with many cases lacking molecular diagnosis despite known <i>HOXD13</i> involvement, suggesting conventional methods may miss a sub-class of variants.</p> Results <p>Integrated whole-exome sequencing (WES) and whole-genome sequencing (WGS) analyses identified three novel <i>HOXD13</i> variants: one 2-bp heterozygous deletion c.314_315del, p.(Lys105ArgfsTer131), and two heterozygous polyalanine expansions (PAE): c.186_212dup, p.(Ala63_Ala71dup) and c.203_204insAGCAGCGGCGGCTGCGGCGGCGGC, p.(Ala64_Ala71dup). WGS successfully identified cryptic variants undetectable by WES technology.</p> Conclusions <p>Our findings demonstrate the utility of WGS in identifying <i>HOXD13</i> variants and support the genotype-phenotype correlation of polyalanine expansions in limb malformations, providing new insights for molecular diagnosis.</p>

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Whole-genome sequencing identifies HOXD13 variants in syndactyly pedigrees

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Yi-feng Xu,
  • Jing Zhang,
  • Tian-ying Wei,
  • Man-li Zhang,
  • Jia-en Liu,
  • Kai Yang,
  • Ya-ping Tian,
  • Hua-ying Hu

摘要

Background

Syndactyly demonstrates high genetic heterogeneity, with many cases lacking molecular diagnosis despite known HOXD13 involvement, suggesting conventional methods may miss a sub-class of variants.

Results

Integrated whole-exome sequencing (WES) and whole-genome sequencing (WGS) analyses identified three novel HOXD13 variants: one 2-bp heterozygous deletion c.314_315del, p.(Lys105ArgfsTer131), and two heterozygous polyalanine expansions (PAE): c.186_212dup, p.(Ala63_Ala71dup) and c.203_204insAGCAGCGGCGGCTGCGGCGGCGGC, p.(Ala64_Ala71dup). WGS successfully identified cryptic variants undetectable by WES technology.

Conclusions

Our findings demonstrate the utility of WGS in identifying HOXD13 variants and support the genotype-phenotype correlation of polyalanine expansions in limb malformations, providing new insights for molecular diagnosis.