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

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Title: Expanding the phenotypic spectrum of DNM1-related disorders: novel GTPase domain variants and their diverse neurological outcomes.
Authors: Liu, Juan (AUTHOR), Hu, Jihong (AUTHOR), Duan, Yaqin (AUTHOR), Tan, Yaqiong (AUTHOR), Gao, Quwen (AUTHOR), Wu, Gefei (AUTHOR)
Source: Neurological Sciences. Jun2025, Vol. 46 Issue 6, p2809-2817. 9p.
Subjects: Medical sciences, Medical genetics, Genetic variation, Mutant proteins, Life sciences
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Neurological Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Expanding the phenotypic spectrum of DNM1-related disorders: novel GTPase domain variants and their diverse neurological outcomes.
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  Data: <searchLink fieldCode="JN" term="%22Neurological+Sciences%22">Neurological Sciences</searchLink>. Jun2025, Vol. 46 Issue 6, p2809-2817. 9p.
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Neurological Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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