Early onset or syndromic epilepsy

Gene: DNM1

Green List (high evidence)

Comment on mode of inheritance: 'Dominant-negative' heterozygous variants in DNM1 are a known cause of a dominant developmental and epileptic encephalopathy. There are now more than 3 unrelated individuals reported in literature with biallelic LoF DNM1 variants and a recessive Developmental and epileptic encephalopathy. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 28 Jul 2026, 2:35 p.m. | Last Modified: 28 Jul 2026, 2:35 p.m.

Panel Version: 9.46

BIALLELIC CASES:
PMID: 41340537 Drackley et al., 2026
24mo female proband with early infantile developmental and epileptic encephalopathy, including a burst suppression pattern with diffuse slowing on interictal EEG, probable tonic seizures, and profound developmental delay, as well as cerebral atrophy, hypotonia, and arthrogryposis. No head circumference measures given. NGS detected comp het DNM1 variants c.194C>A, p.Thr65Asn (de novo) and c.850C>T p.Gln284* (maternally inherited, mother unaffected).

PMID: 37900685 Afsar et al., 2023
Report of a consanguineous Pakistani family. Male proband presented with a neurodevelopmental disorder, mild microcephaly (head circumference: 48.9 cm <1 percentile (−2.8 SD)), moderate to severe ID, speech issues, seizures, epileptic encephalopathy, and hypotonia. WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene.

PMID: 36553519 AlTassan et al., 2022
Female proband presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. Head circumference 46 cm (25th percentile) at 18 months. Parents are consanguineous, Arab ancestry. Clinical WES revealed a homozygous deletion in DNM1 (NM_001288739.1: c.350del, p.Pro117Argfs*14).

PMID: 34172529 Yigit et al., 2022
Report of 2 families, probands affected by DEE. WES detected homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene.
F1 - Lebanese, consanguineous. Female proband presented with multifocal clonic seizures at 15 weeks. At 5yrs, her body weight was 14.35 kg (−2.1 SD); length was 99 cm (−2.4 SD); and OFC was 45.8 cm (−4.4 SD). Lack of verbal understanding and no speech development were noted.
F2 - Arab origins, consanguineous. Female proband presented with infantile spasms (onset around 6mo), severe GDD. At 2 years, she presented with microcephaly, visual disturbance and generalised muscular hypotonia. Mild bilateral optic atrophy observed at 3yrs. At 3yrs 8 mo her weight was 10 kg (−3.7 SD); length was 88 cm (−3.1 SD); and OFC was 45 cm (−4.5 SD).

MONOALLELIC CASES:
PMID: 36413998 Parthasarathy et al., 2022
Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A, 3 individuals harboured p.Arg399Trp, p.Gly401Asp, and p.Pro405Leu missense variants. Importantly, exon 10 is alternatively spliced, with predominantly exon 10a isoform expressed in the brain. Thus, variants in exon 10a result in a more severe phenotype than in exon 10b. Variant p.Pro405Leu, which was the only variant affecting exon 10b isoform, resulted in a less severe neurological presentation (mild DD versus profound DD in all other patients in the cohort).

DNM1 is associated with both AD and AR Developmental and epileptic encephalopathy entities in OMIM (accessed 28th July 2026). The recessive association is classified as Moderate, while dominant disease link is Definitive in ClinGen (Epilepsy GCEP, Feb 2024).

Created: 28 Jul 2026, 2:32 p.m. | Last Modified: 28 Jul 2026, 2:32 p.m.

Panel Version: 9.45

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352; developmental and epileptic encephalopathy, 31B, MONDO:0957248; Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346; developmental and epileptic encephalopathy, 31A, MONDO:0014598; DNM1 early infantile epileptic encephalopathy

Publications

• 34172529
• 36413998
• 36553519
• 37900685
• 41340537

I don't know

Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. Added watchlist tag in anticipation of further biallelic cases emerging.

Created: 7 Jul 2021, 9:38 a.m. | Last Modified: 12 Jul 2022, 10:50 a.m.

Panel Version: 2.543

Yigit et al. 2021 (PMID: 34172529) report two unrelated patients with DEE and homozygous truncating variants (c.97C>T; p.(Gln33*) and c.850C>T; p.(Gln284*), respectively) in the DNM1 gene. All parents were heterozygous carriers but did not show any clinical symptoms indicating a recessive inheritance pattern. No function studies were performed.

Created: 7 Jul 2021, 9:37 a.m. | Last Modified: 7 Jul 2021, 9:37 a.m.

Panel Version: 2.385

Phenotypes
Developmental and epileptic encephalopathy 31, OMIM:616346

Publications

• 34172529

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Missense variants act in dominant negative manner, heterozygous LOF variants are unlikely to cause this phenotype but homozygous LOF mutations could in theory.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 31,616346

Publications

• 25262651
• 27066543

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Checked imprinted gene list.

Created: 17 Dec 2015, 3:24 p.m.

Gene added in expert review of the panel by Richard Scott (Genomics England), Manju Kurian (UCL-Institute of Child Health), Natalie Trump (NHS - Great Ormond Street Hospital), Amy McTague (UCL Institute of Child Health).

Created: 12 Nov 2015, 3:59 p.m.