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Background <p>The unbiased detection of multiple genetic hits can aid in the identification of molecular etiologies of congenital anomalies and neurodevelopmental disorders, providing deeper insights into their complex genetic underpinnings.</p> Purpose <p>To clarify the etiology of a syndromic intellectual disability (ID) case, we performed a reanalysis of exome sequencing data complemented with an optical genome mapping (OGM) assay.</p> Case Presentation <p>The patient is a 23-year-old Brazilian male presenting with mild ID associated with speech impairment; behavioral alterations, including self-injury and polyphagia; class III obesity; impaired glomerular function; macrocephaly; facial and foot anomalies; and cryptorchidism.</p> Genetic Findings <p>Two genomic variants were detected, each of which was inherited from a parent: a 7q11.22 4.4&#xa0;Mb duplication encompassing <i>AUTS2</i>, which was inherited from an apparently normal father, and an <i>ACTB</i> likely pathogenic variant (NM_001101.5:c.328dup:p. Leu110Pro<i>fs</i>*16), inherited from a mildly affected mother. OGM analysis revealed that the duplicated 7q11.21q11.22 segment was in tandem and encompassed the entire <i>AUTS2</i> sequence; therefore, this gene was not disrupted or inserted into another genomic site.</p> Conclusion <p>The presence of these two genomic variants highlights the importance of exploring further genetic factors in patients with more complex phenotypes via molecular testing techniques. In addition, OGM allowed precise localization of the duplication in the patient’s genome and provided insights into its structure, a capability not offered by previous cytogenomic techniques. This is the first publication supporting the simultaneous involvement of both the <i>ACTB</i> loss-of-function (LoF) variant and the <i>AUTS2</i> duplication in a patient with a complex ID phenotype, suggesting that <i>AUTS2</i> duplications may have a functional impact.</p>

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ACTB Loss-of-Function Variant and AUTS2 Duplication in a Patient with Syndromic Intellectual Disability

  • 期刊论文

  • 发表日期：

    2025年5月17日

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  • Ana Claudia Dantas Machado,
  • Laura Machado Lara Carvalho,
  • Felipe Tadeu Galante Rocha de Vasconcelos,
  • Débora Romeo Bertola,
  • Carla Rosenberg,
  • Ana Cristina Victorino Krepischi

摘要

Background

The unbiased detection of multiple genetic hits can aid in the identification of molecular etiologies of congenital anomalies and neurodevelopmental disorders, providing deeper insights into their complex genetic underpinnings.

Purpose

To clarify the etiology of a syndromic intellectual disability (ID) case, we performed a reanalysis of exome sequencing data complemented with an optical genome mapping (OGM) assay.

Case Presentation

The patient is a 23-year-old Brazilian male presenting with mild ID associated with speech impairment; behavioral alterations, including self-injury and polyphagia; class III obesity; impaired glomerular function; macrocephaly; facial and foot anomalies; and cryptorchidism.

Genetic Findings

Two genomic variants were detected, each of which was inherited from a parent: a 7q11.22 4.4 Mb duplication encompassing AUTS2, which was inherited from an apparently normal father, and an ACTB likely pathogenic variant (NM_001101.5:c.328dup:p. Leu110Profs*16), inherited from a mildly affected mother. OGM analysis revealed that the duplicated 7q11.21q11.22 segment was in tandem and encompassed the entire AUTS2 sequence; therefore, this gene was not disrupted or inserted into another genomic site.

Conclusion

The presence of these two genomic variants highlights the importance of exploring further genetic factors in patients with more complex phenotypes via molecular testing techniques. In addition, OGM allowed precise localization of the duplication in the patient’s genome and provided insights into its structure, a capability not offered by previous cytogenomic techniques. This is the first publication supporting the simultaneous involvement of both the ACTB loss-of-function (LoF) variant and the AUTS2 duplication in a patient with a complex ID phenotype, suggesting that AUTS2 duplications may have a functional impact.