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Background <p>Pathogenic <i>DNM1</i> variants cause early-onset developmental and epileptic encephalopathy (DEE). The GTPase domain of the DNM1 protein has the most commonly affected sites.</p> Aim <p>This study aimed to delineate additional patients with <i>DNM1</i>-related disorders harboring novel GTPase domain variants.</p> Methods <p>Trio whole-exome sequencing was performed on three Chinese probands with suspected encephalopathy, and Sanger sequencing was used to confirm the variants. Detailed evaluations were used to assess clinical features. Variant plasmids were constructed in vitro and transfected into cells, and the expression of mutant proteins was evaluated using western blotting (WB).</p> Results <p>Three <i>de novo</i> heterozygous <i>DNM1</i> variants were detected in the GTPase domain, namely, NM_004408.4: c.112_120delinsAGCGGCCAC, (p.Gly38_Gln40delinsSerGlyHis), c.457G &gt; A, (p.Glu153Lys), and c.193&#xa0;A &gt; C, (p.Thr65Pro) in Patients 1, 2, and 3, respectively. Patients 2 and 3 exhibited typical DEE phenotypes with early-onset refractory seizures, profound developmental impairment, intellectual disability, and abnormal electroencephalography findings. However, Patient 1 did not have seizures and her clinical symptoms were autism features, mild hearing loss, subtle changes in the brain, and developmental delays. WB indicated that the expression of plasmids carrying the p.Thr65Pro and p.Glu153Lys variants was not significantly different from that in the wild-type control group and that the expression of the p.Gly38_Gln40delinsSerGlyHis plasmid was elevated.</p> Conclusions <p>This study expands the genetic and phenotypic spectrum of <i>DNM1</i>-associated disorders and reveals that <i>de novo</i> pathogenic variants in the GTPase domain can lead to divergent neurological outcomes ranging from infantile epileptic encephalopathy syndromes to predominant developmental delays without seizures.</p>

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Expanding the phenotypic spectrum of DNM1-related disorders: novel GTPase domain variants and their diverse neurological outcomes

  • 期刊论文

  • 发表日期：

    2025年2月15日

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  • Juan Liu,
  • Jihong Hu,
  • Yaqin Duan,
  • Yaqiong Tan,
  • Quwen Gao,
  • Gefei Wu

摘要

Background

Pathogenic DNM1 variants cause early-onset developmental and epileptic encephalopathy (DEE). The GTPase domain of the DNM1 protein has the most commonly affected sites.

Aim

This study aimed to delineate additional patients with DNM1-related disorders harboring novel GTPase domain variants.

Methods

Trio whole-exome sequencing was performed on three Chinese probands with suspected encephalopathy, and Sanger sequencing was used to confirm the variants. Detailed evaluations were used to assess clinical features. Variant plasmids were constructed in vitro and transfected into cells, and the expression of mutant proteins was evaluated using western blotting (WB).

Results

Three de novo heterozygous DNM1 variants were detected in the GTPase domain, namely, NM_004408.4: c.112_120delinsAGCGGCCAC, (p.Gly38_Gln40delinsSerGlyHis), c.457G > A, (p.Glu153Lys), and c.193 A > C, (p.Thr65Pro) in Patients 1, 2, and 3, respectively. Patients 2 and 3 exhibited typical DEE phenotypes with early-onset refractory seizures, profound developmental impairment, intellectual disability, and abnormal electroencephalography findings. However, Patient 1 did not have seizures and her clinical symptoms were autism features, mild hearing loss, subtle changes in the brain, and developmental delays. WB indicated that the expression of plasmids carrying the p.Thr65Pro and p.Glu153Lys variants was not significantly different from that in the wild-type control group and that the expression of the p.Gly38_Gln40delinsSerGlyHis plasmid was elevated.

Conclusions

This study expands the genetic and phenotypic spectrum of DNM1-associated disorders and reveals that de novo pathogenic variants in the GTPase domain can lead to divergent neurological outcomes ranging from infantile epileptic encephalopathy syndromes to predominant developmental delays without seizures.