Genes in panel
Regions in panel
Prev Next

Intellectual disability

Gene: DNM1L

Amber List (moderate evidence)

DNM1L (dynamin 1 like)
EnsemblGeneIds (GRCh38): ENSG00000087470
EnsemblGeneIds (GRCh37): ENSG00000087470
OMIM: 603850, Gene2Phenotype
DNM1L is in 10 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 unrelated cases with distinct variants, presenting with a relevant phenotype.
Created: 24 Jul 2020, 11:43 a.m. | Last Modified: 24 Jul 2020, 11:43 a.m.
Panel Version: 3.186
Associated with related phenotype in OMIM and 'probable' gene in G2P.

Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients:

PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (6–8%) mosaicism was detected in the maternal sample. The second patient, with diffuse hypotonia, global developmental delay, poor growth, and persistent elevation of lactate, was found to harbour a de novo DNM1L variant (c.1135G>A, p.E379K). However, another de novo change in the PDHA1 gene (c.448G>A, p.G150R) was also found, and the definitive contribution of each variant to the patients phenotype could not be ascertained.

PMID: 27328748 - Compound heterozygous DNM1L variants (c.106A>G, p.Ser36Gly; c.346_347delGA, p.Glu116Lysfs*6) identified in two brothers (3 and 16-years-old) with psychomotor delay, ocular and cerebellar involvement, including mild cognitive impairment in the older brother. Some supporting functional evidence using patient fibroblasts and a yeast model.

PMID: 27301544 - De novo missense variant (c.1217T>C, p.Leu406Ser) identified in a child who presented severe hypotonia, infantile spasms with suppression‐burst and a high level of lactate in CSF. Development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age.

PMID: 26604000 - De novo missense substitution, (c.1085G>A; p.Gly362Asp) identified in a child with refractory epilepsy. Profound global developmental delay was reported, and at the last clinical assessment (age 7 years), he remained nonambulatory with the use of <10 monosyllabic words.

PMID: 26992161 - De novo heterozygous c.1084G>A (p.Gly362Ser) variant. Developmental delay was reported from 6-months of age, and at 2-years-old he was said to not be able to utter any intelligible words.

There are also reports of an identical de novo heterozygous missense variant (p.R403C) in four unrelated individuals who all experienced normal development until a sudden-onset episode of status epilepticus at the age of 4, 5, 10, and 11-years-old, respectively. Subsequently, all presented with rapid neurological regression, diffuse cerebral atrophy and substantial cognitive decline. Functional studies showed the variant confers a dominant negative effect (PMID: 27145208; 30767894; 30711678).
Created: 24 Jul 2020, 11:08 a.m. | Last Modified: 24 Jul 2020, 11:40 a.m.
Panel Version: 3.185

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, 614388; Global developmental delay; Cerebral atrophy; Microcephaly

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.
Sources: Expert list
Created: 1 Feb 2020, 10:10 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388

Mode of pathogenicity
Other

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

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388
Tags
for-review
OMIM
603850
Clinvar variants
Variants in DNM1L
Penetrance
None
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

24 Jul 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: dnm1l has been classified as Amber List (Moderate Evidence).

24 Jul 2020, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: DNM1L.

1 Feb 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set mode of pathogenicity

Zornitza Stark (Australian Genomics)

gene: DNM1L was added gene: DNM1L was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: DNM1L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: DNM1L were set to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388 Mode of pathogenicity for gene: DNM1L was set to Other Review for gene: DNM1L was set to GREEN gene: DNM1L was marked as current diagnostic