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<p>Smith–Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay and a typical behavioral phenotype. Interstitial 17p11.2 deletions, which include the <i>RAI1</i> gene are detected in &gt;90% of patients, while single nucleotide variants (SNVs) are detected in the rest. The <i>RAI1</i> gene is encoded from exons 3 onwards, while exons 1–2 are noncoding. It is unclear whether genetic variants preceding exon 3 cause SMS. We evaluated a 15-month-old infant for developmental delay and infantile spasms who was found to carry a deletion encompassing exons 1–2 of <i>RAI</i>. To determine whether the deletion of the noncoding exons 1–2 of the <i>RAI1</i> gene is associated with SMS and to elucidate the underlying mechanism of this association. A singleton exome-based gene panel was performed, followed by chromosomal-microarray (CMA) to confirm the results. Real time quantitative PCR (RT-qPCR) analysis was conducted to evaluate <i>RAI1</i> mRNA expression. CMA confirmed a <i>de novo</i> 737.8 kbp deletion on 17p11.2, which includes exons 1–2 of <i>RAI1</i> but spares exons 3 onwards. RT-qPCR analysis on RNA extracted from the patient, father and three unrelated controls revealed that the patient has <i>RAI1</i> haploinsufficiency. We show that deletion of the <i>RAI1</i> noncoding exons 1–2, which spares the gene's coding region, causes <i>RAI1</i> haploinsufficiency by eliminating regulatory elements, including the gene promoter, thus causing SMS and expanding the mutational spectrum of SMS.</p>

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Deletion of RAI1 noncoding exons 1–2 causes Smith–Magenis syndrome

  • 期刊论文

  • 发表日期：

    2025年4月16日

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  • Uri Hamiel,
  • Alina Kurolap,
  • Chofit Chai Gadot,
  • Adi Mory,
  • Anat Bar Shira,
  • Hagit Baris Feldman,
  • Daphna Marom

摘要

Smith–Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay and a typical behavioral phenotype. Interstitial 17p11.2 deletions, which include the RAI1 gene are detected in >90% of patients, while single nucleotide variants (SNVs) are detected in the rest. The RAI1 gene is encoded from exons 3 onwards, while exons 1–2 are noncoding. It is unclear whether genetic variants preceding exon 3 cause SMS. We evaluated a 15-month-old infant for developmental delay and infantile spasms who was found to carry a deletion encompassing exons 1–2 of RAI. To determine whether the deletion of the noncoding exons 1–2 of the RAI1 gene is associated with SMS and to elucidate the underlying mechanism of this association. A singleton exome-based gene panel was performed, followed by chromosomal-microarray (CMA) to confirm the results. Real time quantitative PCR (RT-qPCR) analysis was conducted to evaluate RAI1 mRNA expression. CMA confirmed a de novo 737.8 kbp deletion on 17p11.2, which includes exons 1–2 of RAI1 but spares exons 3 onwards. RT-qPCR analysis on RNA extracted from the patient, father and three unrelated controls revealed that the patient has RAI1 haploinsufficiency. We show that deletion of the RAI1 noncoding exons 1–2, which spares the gene's coding region, causes RAI1 haploinsufficiency by eliminating regulatory elements, including the gene promoter, thus causing SMS and expanding the mutational spectrum of SMS.