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Background <p><i>HACE1</i> encodes a HECT domain and ankyrin repeat containing protein regulating several small GTPases. This protein is involved in several important functions, such as cell division, protein ubiquitination, and localization. Biallelic variants in <i>HACE1</i> have been implicated in spastic paraplegia and psychomotor retardation with or without seizures (MIM: 616756). Previously, 32 patients of various ethnicities have been reported with different types of variants; loss-of-function (LoF), missense, and indels.</p> Results <p>Here, we studied five unrelated families of diverse ethnicities with eight cases of 4.5 years to 31 years of age. Our cases presented global developmental delay, dysarthria, intellectual disability, limb spasticity, and seizures. Exome sequencing identified biallelic/ compound heterozygous loss-of-function variants in <i>HACE1</i> in all families (Family A: <i>HACE1</i> (NM_020771.4): c.2628-1G &gt; C p.(Ile877Tyrfs*58); Family B and C: c.1396&#xa0;C &gt; T p.(Gln466*); Family D: c.2242&#xa0;C &gt; T p.(Arg748*)/c.152&#xa0;C &gt; G p.(Ser51*); Family E: c.355G &gt; T p.(Glu119*)). All variants co-segregated with the phenotype in respective families and are classified as pathogenic by the ACMG criteria.</p> Conclusion <p>This study adds eight new cases of <i>HACE1</i> related spastic paraplegia from five unrelated families to the literature, bringing the total to 40 cases from 22 families. By integrating clinical data from our cohort with the published reports, we defined the phenotypic spectrum linked to <i>HACE1</i> disruption, noting key overlaps and variability, and highlighted gaps in reporting clinical features. It also provides clinical management recommendations and calls for standardized phenotypic documentation to strengthen genotype–phenotype correlations.</p>

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Expanding the repertoire of loss-of-function variants in HACE1 causing complex spastic paraplegia: literature review and recommendations on clinical management

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Hammad Yousaf,
  • Sajid Ali,
  • Ahad Yousuf Moulvi,
  • Lubaba Bintee Khalid,
  • Iram Javed,
  • Rafia Zafar Ghumman,
  • Cindy Colson,
  • Shahnaz Ibrahim,
  • Salma Zia,
  • Muhammad Musawer Khan,
  • Perrine Brunelle,
  • Juan Pablo Trujillo-Quintero,
  • Anna Ruiz,
  • Salman Kirmani,
  • Henry Houlden,
  • Mathias Toft,
  • Ambrin Fatima,
  • Zafar Iqbal

摘要

Background

HACE1 encodes a HECT domain and ankyrin repeat containing protein regulating several small GTPases. This protein is involved in several important functions, such as cell division, protein ubiquitination, and localization. Biallelic variants in HACE1 have been implicated in spastic paraplegia and psychomotor retardation with or without seizures (MIM: 616756). Previously, 32 patients of various ethnicities have been reported with different types of variants; loss-of-function (LoF), missense, and indels.

Results

Here, we studied five unrelated families of diverse ethnicities with eight cases of 4.5 years to 31 years of age. Our cases presented global developmental delay, dysarthria, intellectual disability, limb spasticity, and seizures. Exome sequencing identified biallelic/ compound heterozygous loss-of-function variants in HACE1 in all families (Family A: HACE1 (NM_020771.4): c.2628-1G > C p.(Ile877Tyrfs*58); Family B and C: c.1396 C > T p.(Gln466*); Family D: c.2242 C > T p.(Arg748*)/c.152 C > G p.(Ser51*); Family E: c.355G > T p.(Glu119*)). All variants co-segregated with the phenotype in respective families and are classified as pathogenic by the ACMG criteria.

Conclusion

This study adds eight new cases of HACE1 related spastic paraplegia from five unrelated families to the literature, bringing the total to 40 cases from 22 families. By integrating clinical data from our cohort with the published reports, we defined the phenotypic spectrum linked to HACE1 disruption, noting key overlaps and variability, and highlighted gaps in reporting clinical features. It also provides clinical management recommendations and calls for standardized phenotypic documentation to strengthen genotype–phenotype correlations.