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Background <p>Coffin-Siris Syndrome 8 (CSS8; MIM# 618362) is a rare neurodevelopmental disorder caused by heterozygous variants in the <i>SMARCC2</i> gene. Patients with CSS8 present with variable phenotypic presentations, with speech abnormalities, behavioral issues, hypotonia, and dysmorphic features being the most common. Here, we report a novel de novo inversion involving <i>SMARCC2,</i> identified through long-read whole-genome sequencing, which highlights its added diagnostic value in uncovering complex structural variants.</p> Case presentation <p>The patient is a 12-year-old male of Arab descent, born to healthy, non-consanguineous parents. He presented with speech difficulties and behavioral issues, including autism spectrum disorder (ASD), obsessive–compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). Long-read sequencing identified a 233&#xa0;kb inversion on chromosome 12, with breakpoint 1 disrupting&#xa0;<i>SMARCC2</i>&#xa0;between exons 16 and 17. This inversion was confirmed by Sanger sequencing. Disruption of <i>SMARCC2</i> is predicted to cause loss of function, resulting in haploinsufficiency.</p> Conclusions <p>This is the first report of a structural variant in a patient with CSS8. This finding expands our genetic understanding of CSS8 and demonstrates the diagnostic utility of long-read sequencing in uncovering clinically relevant structural variants that may be missed by conventional methods.</p>

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Long-read sequencing identifies a novel de novo inversion in SMARCC2 in a pediatric patient with Coffin-siris syndrome 8: a case report

  • 期刊论文

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  • 发表日期：

    2025年11月25日

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  • Amal Abdulsalam Ibrahim,
  • Waleed Aamer,
  • Elbay Aliyev,
  • Aljazi Al-Maraghi,
  • Saba F. Elhag,
  • Mona Abdi,
  • Najeeb Syed,
  • Sasirekha Palaniswamy,
  • Ammira S. A. Akil,
  • Madeeha Kamal,
  • Khalid A. Fakhro

摘要

Background

Coffin-Siris Syndrome 8 (CSS8; MIM# 618362) is a rare neurodevelopmental disorder caused by heterozygous variants in the SMARCC2 gene. Patients with CSS8 present with variable phenotypic presentations, with speech abnormalities, behavioral issues, hypotonia, and dysmorphic features being the most common. Here, we report a novel de novo inversion involving SMARCC2, identified through long-read whole-genome sequencing, which highlights its added diagnostic value in uncovering complex structural variants.

Case presentation

The patient is a 12-year-old male of Arab descent, born to healthy, non-consanguineous parents. He presented with speech difficulties and behavioral issues, including autism spectrum disorder (ASD), obsessive–compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). Long-read sequencing identified a 233 kb inversion on chromosome 12, with breakpoint 1 disrupting SMARCC2 between exons 16 and 17. This inversion was confirmed by Sanger sequencing. Disruption of SMARCC2 is predicted to cause loss of function, resulting in haploinsufficiency.

Conclusions

This is the first report of a structural variant in a patient with CSS8. This finding expands our genetic understanding of CSS8 and demonstrates the diagnostic utility of long-read sequencing in uncovering clinically relevant structural variants that may be missed by conventional methods.