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<p>Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in <i>CCDC32</i>. So far, CFNDS has only been described in four living individuals and one terminated fetus from four families, and the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies. We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause. Skipping of two exons in <i>CCDC32</i> transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of <i>CCDC32</i>. This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq. Furthermore, we review the clinical phenotype of this rare disorder and its potential disease mechanisms.</p><p></p>

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Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature

  • 期刊论文

  • 发表日期：

    2026年2月4日

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  • Fatimah Albuainain,
  • Myrrhe Venema,
  • Rachel Schot,
  • Gideon Huigen,
  • Grazia M. S. Mancini,
  • Tjakko J. van Ham,
  • Tahsin Stefan Barakat

摘要

Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32. So far, CFNDS has only been described in four living individuals and one terminated fetus from four families, and the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies. We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause. Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of CCDC32. This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq. Furthermore, we review the clinical phenotype of this rare disorder and its potential disease mechanisms.