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<p>Robinow syndrome is a rare genetic disorder characterized by distinct craniofacial dysmorphism, mesomelic limb shortening and genital hypoplasia. The disorder has been reported to be inherited in an autosomal dominant as well as recessive patterns with a prevalence of 1:500000. In this study, we aimed to identify the genetic basis and structural consequences of disease in a clinically diagnosed case. A 3-months old male child from the Southwest Punjab region of India, born out of a consanguineous marriage, was presented with features including hypertelorism, midface hypoplasia, short stature, brachydactyly and genital anomalies. Whole-exome sequencing revealed a novel heterozygous pathogenic frameshift mutation, c.1644del (p.F549Sfs*125) in exon 14 of the <i>DVL1</i> gene. This variant was absent in significant population databases and was therefore classified as pathogenic based on ACMG criteria. Familial segregation analysis by Sanger sequencing indicated it to be a de novo mutation since it was not observed in the parents as well as the elder male sibling. Further, comparative molecular dynamics analyses reveal that the mutation profoundly destabilizes <i>DVL1</i>, as the wild-type protein maintains stable Root Mean Square Deviation (RMSD), moderate flexibility, compact folding, and controlled essential motions, consistent with a properly folded, functional state. In contrast, the mutant displays persistent structural instability, excessive flexibility, loss of compactness, disrupted hydrogen-bond networks, and exaggerated collective motions, collectively indicating loss of stable dynamic features required for normal <i>DVL1</i> function and likely non-functionality. In conclusion, this study reports a novel pathogenic variant in DVL1 associated with Robinow syndrome in this geographical region and highlights the importance of integrating genomic and structural analyses to understand disease mechanisms. These findings expand the mutational spectrum and have important implications for precise diagnosis, genetic counselling, and future studies on targeted molecular mechanisms.</p>

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Identification and functional characterization of a novel pathogenic DVL1 gene variant in Robinow syndrome

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Anil Kumar,
  • Seema Rai,
  • Ajay Kumar,
  • Chandraniv Dey,
  • Sudip Chakraborty,
  • Anjana Munshi

摘要

Robinow syndrome is a rare genetic disorder characterized by distinct craniofacial dysmorphism, mesomelic limb shortening and genital hypoplasia. The disorder has been reported to be inherited in an autosomal dominant as well as recessive patterns with a prevalence of 1:500000. In this study, we aimed to identify the genetic basis and structural consequences of disease in a clinically diagnosed case. A 3-months old male child from the Southwest Punjab region of India, born out of a consanguineous marriage, was presented with features including hypertelorism, midface hypoplasia, short stature, brachydactyly and genital anomalies. Whole-exome sequencing revealed a novel heterozygous pathogenic frameshift mutation, c.1644del (p.F549Sfs*125) in exon 14 of the DVL1 gene. This variant was absent in significant population databases and was therefore classified as pathogenic based on ACMG criteria. Familial segregation analysis by Sanger sequencing indicated it to be a de novo mutation since it was not observed in the parents as well as the elder male sibling. Further, comparative molecular dynamics analyses reveal that the mutation profoundly destabilizes DVL1, as the wild-type protein maintains stable Root Mean Square Deviation (RMSD), moderate flexibility, compact folding, and controlled essential motions, consistent with a properly folded, functional state. In contrast, the mutant displays persistent structural instability, excessive flexibility, loss of compactness, disrupted hydrogen-bond networks, and exaggerated collective motions, collectively indicating loss of stable dynamic features required for normal DVL1 function and likely non-functionality. In conclusion, this study reports a novel pathogenic variant in DVL1 associated with Robinow syndrome in this geographical region and highlights the importance of integrating genomic and structural analyses to understand disease mechanisms. These findings expand the mutational spectrum and have important implications for precise diagnosis, genetic counselling, and future studies on targeted molecular mechanisms.