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. 2022 Jan 31;10(3):e1874. doi: 10.1002/mgg3.1874

De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations

Tangfeng Su 1, Yu Yan 2, Qingqing Hu 1, Yan Liu 1, Sanqing Xu 1,✉
PMCID: PMC8922968  PMID: 35099838

Abstract

Background

The human dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene encodes a large subunit of the cytoplasmic dynein complex. DYNC1H1 mutations are associated with various neurological diseases involving both the peripheral and central nervous systems.

Methods

The clinical characteristics and genetic data of an infant carrying the de novo DYNC1H1 variant identified by trio exome sequencing were analyzed. Patients with epilepsy with DYNC1H1 mutations were summarized by reviewing the literature.

Results

We first identified an infant presenting with epileptic spasms harboring a de novo missense mutation in DYNC1H1 (c.874C>T; p. Arg292Trp), once reported in an adult case, and further summarized another 54 patients with seizures or epilepsy caused by DYNC1H1 pathogenic variants in the literature. Refractory epilepsy, intellectual disability, and cortical developmental malformations are crucial characteristics of patients with developmental and epileptic encephalopathy (DEE) caused by DYNC1H1 variants. Notably, epileptic spasms in this case were resistant to multiple anti‐seizure medications, corticosteroids, ketogenic diet, and vagus nerve stimulation treatment. The child also showed cortical gyrus malformation and global developmental delay.

Conclusion

DYNC1H1 variants can cause infantile developmental and epileptic encephalopathy, in which Arg292Trp is a mutation hotspot of the DYNC1H1 gene. Epileptic seizures in this type of DYNC1H1‐related DEE are mostly resistant to multiple antiepileptic strategies and need to explore optimized treatments.

Keywords: developmental and epileptic encephalopathy, dynein cytoplasmic 1 heavy chain 1, epileptic spasms, ketogenic diet, vagus nerve stimulation

DYNC1H1 variants can cause infantile developmental and epileptic encephalopathy, in which Arg292Trp is one of the hot spot mutations of DYNC1H1 gene. Epileptic seizures in this kind of DYNC1H1‐related DEE are mostly resistant to multiple antiepileptic strategies and need to explore optimized treatments.

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1. INTRODUCTION

Dynein cytoplasmic 1 heavy chain 1 (DYNC1H1, MIM #600112) encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that transports organelles, vesicles, and macromolecules to the minus ends of microtubules. Mutations in DYNC1H1 are associated with various clinical manifestations, including spinal muscular atrophy, lower extremity‐predominant 1 (SMALED1; MIM #158600) (Harms et al., 2010), Charcot–Marie–Tooth (CMT) disease, axonal type 20 (CMT2O; MIM #614228) (Strickland et al., 2015; Weedon et al., 2011), mental retardation, autosomal dominant 13 (MRD13; MIM #614563) (Willemsen et al., 2012), and other phenotypes reported in the literature, including hereditary spastic paraplegia (Strickland et al., 2015), malformations of cortical development (MCD) (Poirier et al., 2013), and epileptic encephalopathies (EE) (Lin et al., 2017).

To the best of our knowledge, up to October 2021, at least 24 articles had reported 54 cases with seizures or epilepsy due to DYNC1H1 variants, including seven infants with epileptic spasms (Table 1) (Amabile et al., 2020; Becker et al., 2020; Benson et al., 2020; Das et al., 2018; Di Donato et al., 2018; Gelineau‐Morel et al., 2016; Gou et al., 2019; Helbig et al., 2016; Hertecant et al., 2016; Hu et al., 2018; Jamuar et al., 2014; Li et al., 2019; Lin et al., 2017; Matsumoto et al., 2021; Otten et al., 2017; Palmer et al., 2018; Poirier et al., 2013; Punetha et al., 2015; Rochtus et al., 2020; Scoto et al., 2013; Singh et al., 2015; Strickland et al., 2015; Tumienė et al., 2018; Willemsen et al., 2012). Most of these patients have brain developmental malformations and severe intellectual disability (ID). Developmental and epileptic encephalopathies (DEEs) are genetically heterogeneous conditions often characterized by early onset drug‐refractory epilepsy, frequent epileptiform activity, and neurodevelopmental impairments (Scheffer et al., 2016). Here, we report the first case of a de novo p. Arg292Trp change caused by the DYNC1H1 gene that exhibited epileptic spasms, intellectual disability, and brain malformation in a Chinese family, further summarizing the clinical characteristics of this kind of DEE related to DYNC1H1 variants and its treatment and prognosis. Our observation of epileptic spasms in this patient further broadens the clinical spectrum of the known mutation p. Arg292Trp. However, this case was unable to become seizure‐free through multiple treatment methods, including anti‐seizure medications (ASMs), corticosteroids, ketogenic diet (KD), and vagus nerve stimulation (VNS).

TABLE 1.

Comparison of clinical phenotypes in DYNC1H1 mutation patients with seizure or epilepsy

Author year (N) No. Case, gender Age cDNA Protein Inherit‐ance ID/DD Cerebral MRI/CT Seizure onset Seizure types
Willemsen (2012) (1) 1 Patient 2/F 51 y c.4552 G>A p.Glu1518Lys De novo Severe ID MCD 3 y GS
Poirier (2013) (11) 2 P144 NA 15 y c.del1976‐1987 p.del659‐662 De novo Bedridden Pachygyria (P>A) Early onset NA
3 P582 NA 10 y c.386A>T p.Lys129Ile De novo Severe ID Pachygyria (P>A) Late onset NA
4 P122 NA 12 y c.10008G>T p.Lys3336Asn De novo Bedridden Pachygyria (P>A) Early onset NA
5 P217 NA 10 y c.10151G>A p.Arg3384Gln De novo Bedridden Pachygyria (P>A) Early onset NA
6 P398 NA 7 y c.4700G>A p.Arg1567Gln De novo Severe ID PMG (A>P) NA Absent
7 P535 NA 5 y c.10031G>A p.Arg3344Gln De novo Severe ID, autistic Agyria (P>A) NA LGS
8 360 J NA 19 y c.5884C>T p.Arg1962Cys De novo Severe ID Pachygyria (P>A) 2 m Focal
9 346D1/M 11 y c.9722A>C p.Lys3241Thr Familial Normal Pachygyria (P>A) 2 y5 m Focal
10 346D2/M 8 y c.9722A>C p.Lys3241Thr Familial Mild ID Pachygyria (P>A) 1 y2 m Focal
11 346Dmother 39 y c.9722A>C p.Lys3241Thr Familial Normal Pachygyria (P>A) 10 y Focal
12 574C NA 3 y c.10031G>A p.Arg3344Gln De novo Moderate ID Pachygyria (P>A) 5 m Focal
Jamaur (2014) (1) 13 BFP‐601/M NA NA p.Glu561Gly De novo Mental and motor retardation Pachygyria (P>A) 5 y NA
Strickland (2015) (1) 14 IHG26107/F 36 y c.3185 A>G p.Asp1062Gly De novo Cognitive deficits PMG (perisylvian) 17 y Focal, sGS
Punetha (2015) (1) 15 F 3.6 y c.1792C>T p.Arg598Cys De novo Normal Normal NA Febrile seizures
Singh (2015) (1) 16 F NA c.4259 T>G p.Leul420Arg De novo EE PMG (perisylvian) 7 m Myoclonic, atonic
Scoto (2015) (2) 17 UK8‐INA 2.5 y NA p.Arg1603Thr De novo Delay NA NA NA
18 US1‐IINA 9 y NA p.Ile584Leu NA Mild ID NA Neonatal NA
Gelineau‐Morel (2016) (1) 19 F 10 y c.6994C>T; p.Arg2332Cys De novo Severe ID PMG (A>P) 2 y NA
Hertecant (2016) (1) 20 M 16 m c.10973G>A p.Gly3658Glu De novo Severe ID Pachygyria/agyria 3 m flexor spasms
Helbig (2016) (1) 21 ID32/ NA NA c.3278 T>C p.Phe1093Ser De novo EE NA Infantile Spasms
Lin (2017) (1) 22 E3P/M NA c.10174A>G p.Met3392Val De novo Autism, ID NA NA Spasms
Otten (2017) (2) 23 Twins/F NA c.11015C>T p.Ser3672Leu De novo Severe ID PMG 4 y NA
24 Twins/F NA c.11015C>T p.Ser3672Leu De novo Severe ID Multiple cortical dysplasia 6 m NA
Di Donato (2018) (13) 25 LR15‐028/F 4 y c.915A>T p.Lys305Asn De novo Mild Pachygyria (P>A) 1 y NA
26 LR15‐025/M 2 y 3 m c.926G>A p.Arg309His De novo Severe ID Pachygyria (P>A) 5 m NA
27 LP98‐088/F 1 y 4 m c.926G>A p.Arg309His NA Severe Pachygyria/agyria (P>A) 3 m NA
28 LR13‐015/M 1 y 11 m c.926G>A p.Arg309His De novo Severe DD Pachygyria (P>A) 3 m NA
29 LP97‐114/M 1 y 8 m c.2003 T>A p.Val668Asp De novo Severe Pachygyria (P>A) 1 y7 m NA
30 LR01‐087/F 9 m c.4868G>A p.Arg1623Gln De novo Mild DD Pachygyria (A>P) 4 m NA
31 LR15‐140/F 4 y c.7813_7815del p.Leu2605del De novo Severe Pachygyria (A>P) 9 m NA
32 LR07‐192/M 2 y 6 m c.9954G>T p.Lys3318Asn NA Severe Pachygyria (P>A) 6 w NA
33 LR00‐012/M 2 y 6 m c.10030C>T p.Arg3344Trp NA DD Dysgyria (P>A) perisylvian 3 m NA
34 LR12‐456/M 2 y c.10031G>A p.Arg3344Gln De novo Severe Pachygyria (P>A) 7 m NA
35 LP99‐041/F 3 y 8 m c.10888G>A p.Gly3630Ser NA Severe DD Pachygyria (P>A) 1 y? NA
36 LR15‐095/M 1 y 4 m c.11311G>A p.Glu3771Lys De novo Mild–moderate DD Pachygyria (P>A) 8 m NA
37 LR03‐176/M 6 y 6 m c.11941 + 2 T>A NA NA Moderate Dysgyria (P>A) 3 y myoclonic
Das (2018) (1) 38 II 1/M 60 y c.1809A>T p.Glu603Asp Familial Learning difficulties NA NA NA
Tumienė (2018) (1) 39 No.3/ NA NA c.6994C>T p.Arg2332Cys De novo Autism, ID NA NA Focal
Palmer (2018) (1) 40 Fam10/M 4 y c.5884C>T p.Arg1962Cys De novo Severe DD Focal pachygyria. 3 m/6 m Focal/spasms
Hu (2018) (1) 41 NA NA c.1682A>G p.Glu561Gly De novo EOEE Pachygyria (A‐P) N/A Focal, spasms
Gou (2019) (2) 42 Twins/F 10 m c.10213A>C p.Met3405Leu De novo Severe ID Brain dysplasia 7 m Spasms
43 Twins/F 10 m c.10213A>C p.Met3405Leu De novo Severe ID Brain dysplasia 7 m Spasms
Li (2019) (1) 44 M 3 y c.4075–2 A>T NA De novo MRD13 Normal (1 y3 m), FCD (6 y) 1 y5 m LGS
Rochtus (2020) (1) 45 F 17 y c.11095G>A p.Val3699Ile Familial Severe DD Atrophy 1 day Ohtahara syndrome
Benson (2020) (1) 46 F Adult c.874C>T p. Arg292Trp De novo ID FCD 13–18 m GAS, GTCS
Amabile (2020) (2) 47 Patient 1/F 4 y NA p.Val1116Ala De novo DD PMG (A>P) NA NA
48 Patient 4/M 4 y 5 m NA p.Gly3658Glu De novo ID, DD Enlarged ventricle NA Focal
Becker (2020) (4) 49 P2/ NA c.10432C>T p.Leu3478Phe De novo Severe ID Enlarged ventricle 11–48 m Focal
50 P4/ NA c.6880G>A p.Glu2294Lys De novo Severe ID Pachygyria (A>P) 11–48 m Focal
51 P8/ NA c.9518C>G p.Pro3173Arg De novo DD, ID Pachygyria (A>P) 11–48 m Focal
52 P10/ NA c.1998A>T p.Glu666Asp De novo DD, Severe ID Pachygyria (A>P) 11–48 m Focal
Matsumoto (2021) (2) 53 P1/F 6 y c.4691A>T p.Glu1564Val De novo Severe ID Pachygyria (P>A) 2 m Myoclonic, focal, GTS
54 P2/M 13 y c.12536 T>C p.Leu4179Ser De novo Severe ID, ASD Normal 7 y GTCS, Myoclonic
This case (1) 55 F 3 y 2 m c.874C>T p. Arg292Trp De novo Moderate ID Oligogyri (P>A) 5 m Spasms
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Abbreviations: A, anterior; CC, corpus callosum; DD, developmental delay; EE, epileptic encephalopathy; EOEE, early onset epileptic encephalopathy; FCD, frontal cortical dysplasia; GAS, generalized atonic seizures; GS, generalized seizures; GTCS, generalized tonic–clonic seizures; ID, intellectual disability; IS, infant spasms; LGS, Lennox–Gastaut syndrome; m, months; MRD13, Mental retardation, autosomal dominant 13; NA, not available; No., patient number; P, posterior; PMG, polymicrogyria; sGS, secondary generalized seizures; y, year.

2. MATERIALS AND METHODS

2.1. Ethical compliance

This study was approved by the Medical Ethics Committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China. Written informed consent was obtained from the patient for publication of this case report and the accompanying images.

2.2. Whole exome and Sanger sequencing

Whole exome sequencing (WES) was performed by the WuXi NextCODE Genomics, Shanghai, China (CLIA Lab ID: 99D2064856) using a previously described protocol (Su et al., 2020).

2.3. Literature review

Literature search was performed to identify relevant articles using the terms “DYNC1H1 AND epilepsy”, or “DYNC1H1 AND seizure” up to October 19, 2021, in the following databases: PubMed, Google Scholar, China National Knowledge Infrastructure, and WANFANG DATA.

3. RESULTS

3.1. Case presentation

The female infant, born at 39 weeks, was the first child of a non‐consanguineous Chinese couple. Pregnancy and delivery were uncomplicated. Her birth weight was 2850 g, and her head circumference (HC) was within the normal range. The family history of the infant was negative for epilepsy and other neurological and muscle disorders. Parents had few complaints about the development of this infant during the first 4 months of her life. At the age of 5 months, she presented with epileptic spasms. At that time, the patient was found to have poor head control. Her electroencephalogram (EEG) showed hypsarrhythmia (Figure 1a), confirming the diagnosis of West syndrome. Metabolic screening, including electrolytes and glucose, serum and urine organic acids, and blood amino acid levels were all normal. Brain magnetic resonance imaging (MRI) revealed that the bilateral parieto‐occipital gyri decreased, the flattened cortex and related cortex thickened (oligogyri), and the frontotemporal extracerebral space widened (Figure 2). In addition to oral topiramate (TPM; 12.5 mg a.m. & 25 mg p.m.; weight, 7 kg), she was initially given high‐dose oral prednisone (10 mg qid for the first week and the same dose for the second week after epileptic seizures stopped, then tapering off every week, that is, 10 mg tid, 10 mg bid, 10 mg qd, and 5 mg qd, for a total of 6 weeks), which was followed by seizure‐free for 3 months. At the age of 10 months, wakefulness EEG displayed small occipital sharp waves, while background hypsarrhythmia faded (Figure 1b).

FIGURE 1.

FIGURE 1

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Wakefulness EEG at 5 (a) and 10 months (b). (a) Interictal EEG showed a background of hypsarrhythmia with asymmetrical or asynchronous high‐amplitude, multifocal spike and wave discharges. (b) Interictal EEG showed a normal EEG background with a small amount of sharp and slow waves in right posterior head region, as shown by the arrow

FIGURE 2.

FIGURE 2

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Brain MRI at 5 months. (a, b) Dilated bilateral frontotemporal extracerebral space. (c, d) Bilateral parieto‐occipital gyri are diminished and flattened, and the related cortex is thickened (oligogyri)

However, 3 months after withdrawal of corticosteroids, epileptic spasms in clusters occurred again in this infant. Oral levetiracetam (LEV; 0.125 g bid; weight, 8 kg) was administered as an adjunct to TPM; however, she still had two or three clusters of epileptic spasms per day. At 11 months of age, oral drugs were continued, and the infant began to receive KD treatment (Jiantong, Kinton Medical Food Ltd., Guangzhou, China). After a 3:1 ketogenic ratio of fat to protein plus carbohydrate (in grams), the patient experienced a 50% reduction in seizure frequency, while blood ketone levels were 2.5–3 mmol/L, and blood glucose levels were normal. However, after 529 days of treatment, KD was discontinued when the child was 2 years and 9 months old due to <50% reduction in spasm frequency in subsequent long‐term follow‐up.

At the age of 2 years, seizures decreased significantly in the first week after VNS treatment (PINS Medica, Beijing, China; 30 Hz and 0.5–2.0 mA, 30 s on and 5 min off), but 1 week later, the frequency of seizures returned to the level before VNS treatment. At the last follow‐up, the child had been treated with VNS for nearly 13 months; however, the seizures had not diminished. At the age of 3 years and 2 months, her physical measurements were as follows: height, 89 cm (10th–25th centile), weight, 11 kg (10th–25th centile), and HC, 43 cm (<3rd centile). She was unable to walk independently for up to 5 m, had an unstable gait and easily fell, had hypotonia of her lower extremities, and had severe delays in language skills.

3.2. Molecular analysis

When the infant was 14 months old, WES identified a heterozygous variant (NM_001376.4:c.874C>T; p. Arg292Trp) in DYNC1H1 located on chromosome 14q32.31. We submitted this variant to ClinVar (accession SCV001244188). The mutation was absent in the parental DNA and thus arose de novo (Figure 3). In silico analyses using PolyPhen‐2 and Mutation Taster also predicted that the p. Arg292Trp mutation is functionally “probably damaging” (a HumanVar score of 0.986) and “disease causing”, respectively, which was also consistent with the data from the PROVEAN server (http://provean.jcvi.org/protein_batch_submit.php?species=human, PROVEAN score: −4.64, Prediction [cutoff = −2.5]: Deleterious; SIFT score: 0.01, Damaging). In accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines, sequence variants were classified as likely pathogenic.

FIGURE 3.

FIGURE 3

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Sanger sequencing of DYNC1H1 variants in the infant and her healthy parents. (a) The shadow in the electrophoretic pattern shows the site of the mutation. Exome sequencing identified a de novo heterozygous mutation in the DYNC1H1 gene (NM_001376.4: c.874C>T) in exon 5. (b) The amino acid sequence alignment of the DYNC1H1 protein from different species shows that the Arg292 residue is highly conserved during evolution

4. DISCUSSION

Dynein can be divided into two types: axonemal and cytoplasmic. Cytoplasmic dynein is an important motor protein complex in the nervous system and is responsible for the retrograde transport of important substances in axons from the end to the cell body. Cytoplasmic DYNC1H1 is a key subunit of the cytoplasmic dynamic protein complex, and its normal expression is closely related to the development of the nervous system (Eschbach & Dupuis, 2011).

DYNC1H1 mutations have been reported in a series of neurological diseases, including peripheral and central nervous system disorders. Vissers et al. first reported in 2010 that DYHC1H1 mutation was associated with mental retardation in a 2‐year‐old boy. He had mild facial deformities, while his brain MRI was normal (Vissers et al., 2010). In 2013, Poirier et al. reported that 11 patients with a DYHC1H1 mutation had posterior pachygyria and seizures, about half of them had early onset epilepsy, and one proband had Lennox–Gastaut syndrome (LGS) (Poirier et al., 2013). DEE is a group of heterogeneous neurodevelopmental disorders characterized by early onset intractable seizures, abundant EEG epileptiform activity, intellectual disability, or regression. West syndrome and LGS are representative of DEE in both infants and children. To the best of our knowledge, including this reported case, eight infants with DYNC1H1 variants had epileptic spasms (including a pair of twins) (Table 1), and the age of seizure onset was 3–7 months. All of these children had intellectual disability and brain dysplasia, mainly manifesting as gyrus malformations (Table 1). It should be mentioned that a total of three children described autism or autism‐like features in the literature (P7, P39, P54).

DYNC1H1 encodes a large protein (>530 kDA and 4646 amino acid residues), which consists of three main domains. The C‐terminal motor domain region (residues 1846–4646, ~380 kDa) contains six ATPases associated with diverse cellular activities (AAA) and a microtubule‐binding stalk located between AAA4 and AAA5 (Pfister et al., 2006). The N‐terminal region (~160 kDa) is known as the stem domain (tail domain) and contains binding positions for light intermediate and light chains (Figure 4). Previous studies have shown that DYNC1H1 variants have obvious phenotypic heterogeneity and that mutations in different domains or at different locations in the same domain also show different clinical phenotypes. Mutations in the tail domain of DYNC1H1 cause mutations in SMALED1 (Harms et al., 2012) and CMT20 (Weedon et al., 2011). Damage caused by motor domain mutations is mainly caused by MCD and intellectual impairments, such as MRD13 (Poirier et al., 2013; Vissers et al., 2010). Mutations in both tail and motor domains have also been reported to cause SMALED (Fiorillo et al., 2014) and MRD13 (Jamuar et al., 2014).

FIGURE 4.

FIGURE 4

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Schematic representation of human DYNC1H1 and mutations in patients with seizures or epilepsy. The DYNC1H1 mutation sites in patients with seizures were found in both motor domain and tail domain, mainly clustering in and around the stalk region of the motor domain, the junction area of motor and tail domain, and the N‐terminal region of the tail domain

In this case, the c.874C>T mutation is located in the tail domain of DYNC1H1, near the N‐terminus, which is a de novo missense mutation. The phenotypes of this case mostly consisted of brain malformations, global developmental delays, and seizures. Compared with an adult case reported by Benson et al., both patients had intellectual disability, abnormal MRIs, and early onset epilepsy, while there were no epileptic spasms or hypsarrhythmia EEG background in Benson's case (Benson et al., 2020). As shown in Figure 4, the DYNC1H1 mutation sites in patients with seizures were found in both the motor and tail domains, mainly clustering in and around the stalk region of the motor domain, junction area of the motor and tail domain, and N‐terminal region of the tail domain. In addition, this patient had decreased muscle strength of her lower limbs, and she was unable to achieve independent walking at the age of 2 years, which was, to a certain extent, similar to the phenotypes of spinal muscular atrophy, lower extremity‐predominant 1 caused by a DYNC1H1 mutation.

Epileptic spasms are often accompanied by hypsarrhythmia on EEG, and the use of standard first‐line drugs, such as ACTH, vigabatrin, and prednisolone, may provide the greatest benefit in terms of seizures, EEG changes, and long‐term prognosis in children (Knupp et al., 2016). Regarding the seizure treatments in these 55 patients, 27 had no information available in the literature, 13 were reported as refractory epilepsy, seven were reported as controlled seizures, eight cases mentioned specific treatment drugs, and all were drug‐resistant epilepsy (P20, P41, P42/43, P44, P53, P54, P55, see Table 2). Five of these eight patients were diagnosed with epileptic spasms, and one with LGS. Similar to Li′s case report (Li et al., 2019), seizures were reduced by more than 50% after introduction of KD in our case (8 months follow‐up for Li′s case, and 33 months in this study). Although combined with oral ASMs, KD, and VNS, our case still had at least one cluster of spasms per day and global development delay, including physical growth, motor, and language skills. These results indicate that the existing encephalopathy in this infant, due to a DYNC1H1 mutation, was not only caused by epileptic spasms, but also by the developmental consequences of the gene variant itself, known as one type of DEE.

TABLE 2.

Treatments in DYNC1H1 mutation patients with epileptic encephalopathy

ID Seizure onset Seizure type Drugs Seizure < 50%
P20 3 m Spasms Prednisolone, VGB NA
P41 NA Spasms PB, LEV, CZP, VPA NA
P42/43 7 m Spasms LEV, TPM, VPA Vigabatrin
P44 1 y5 m LGS LEV, VPA, RUF LEV + KD
P55 5 m Spasms Prednisolone, TPM LEV + KD + VNS
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Abbreviations: CZP, clonazepam; KD, ketogenic diet; LEV, levetiracetam; LGS, Lennox–Gastaut syndrome; m, month; NA, not available; PB, phenobarbital; RUF, rufinamide; TPM, topiramate; VGB, vigabatrin; VNS, vagus nerve stimulation; VPA, valproate; y, year.

In summary, DYNC1H1 mutations can cause lesions in the central and peripheral nervous systems with various heterogeneous manifestations. Mutations in both the motor and tail domains of DYNC1H1 can cause cortical developmental malformations and refractory seizures. Epileptic spasms were resistant to multiple treatments (ASMs, corticosteroids, KD, and VNS) in this p.Arg292Trp mutation patient. Refractory epilepsy, developmental retardation, and brain malformations are core symptoms of DYNC1H1‐related DEE.

CONFLICT OF INTEREST

None.

AUTHOR CONTRIBUTIONS

TS prepared the original draft, YY did literature searching, YY, QH, YL revised the manuscript, TS and SX edited the final manuscript. All authors have read and approved the final manuscript.

ETHICAL APPROVAL

This study was approved by the ethics committee of the Tongji Hospital of Huazhong University of Science and Technology.

PATIENT CONSENT STATEMENT

The parents agreed to the publication of the WES results and some of the data related to the medical history and signed an informed consent form.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

None.

ACKNOWLEDGMENTS

The authors would like to thank the patients and their parents for their participation in this study. The authors thank Ms. Xinyi Hu from the University of Geneva, Switzerland for English language editing. This study was funded by the National Natural Science Foundation of China (Grant No. 81804188).

Su, T.,, Yan, Y.,, Hu, Q.,, Liu, Y., & Xu, S. (2022). De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations. Molecular Genetics & Genomic Medicine, 10, e1874. 10.1002/mgg3.1874

Tangfeng Su and Yu Yan contributed equally to this work.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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