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Intellectual disability

Gene: DYNC1I2

Amber List (moderate evidence)

DYNC1I2 (dynein cytoplasmic 1 intermediate chain 2)
EnsemblGeneIds (GRCh38): ENSG00000077380
EnsemblGeneIds (GRCh37): ENSG00000077380
OMIM: 603331, Gene2Phenotype
DYNC1I2 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis on DYNC1I2, after Ansar et al. (2019 - PMID: 31079899) reported on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants. All reported to have microcephaly and severe intellectual disability.

The three families that were reported on:
A consanguineous Pakistani family affected individuals were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies).
An individual who was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*) variant.
An affected individual was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12).

The authors noted that the identification of a shared missense variant, p.Tyr247Cys, in two unrelated affected individuals with eastern European ancestry. This allele might come from a common ancestral origin, or it could reside in a mutational hotspot.
Functional work was performed on Zebrafish.

It should also be noted that the individual who was heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). That DCAF17 is a Green gene in the ID Panel and SLC25A12 is Amber in the panel.

DYNC1I2 is associated with a relevant phenotype in OMIM but is not in Gene2Phenotype.

As there are not three clear cases of DYNC1I2 solely being linked to ID, classifying as Amber and adding to the watchlist.
Created: 13 Jun 2019, 11:15 a.m. | Last Modified: 17 Jul 2019, 11:20 a.m.
Panel Version: 0.200

Konstantinos Varvagiannis (Other)

I don't know

Ansar et al. (2019 - PMID: 31079899) report on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants.

The phenotype consisted of microcephaly, intellectual disability, cerebral malformations and suggestive facial features. 2/5 individuals, from different families presented seizures.

Affected individuals from a consanguineous Pakistani family were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies). One individual from a futher family was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). Another individual was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*). [NM_001378.2 used as reference].

DYNC1I2 encodes Dynein Cytoplasmic 1 intermediate chain 2, a component of the cytoplasmic dynein 1 complex. This complex is involved in retrograde cargo transport within the cytoplasmic microtubule network. Emerging evidence suggests a critical role of this complex in neurodevelopment and homeostasis (PMIDs cited by the authors: 25374356, 28395088). Mutations in other genes encoding components of the complex (principally DYNC1H1) give rise to neurological disorders, some of which with ID as a principal feature (eg. Mental retardation, autosomal dominant 13 - MIM 614563).

In zebrafish, DYNC1I2 has 2 orthologs - dync1i2a and dync1i2b. The former is suggested to be the functionally relevant DYNC1I2 ortholog as CRISPR-Cas9 dync1i2a disruption and/or suppression with morpholinos resulted in altered craniofacial patterning and reduction in head size (similar to the microcephaly phenotype reported in affected individuals).

In vivo complementation studies suggested a loss of function effect for the p.Tyr247Cys variant, similar to the p.Gln290* one.

Evidence is provided for a role of increased apoptosis, probably secondary to altered cell cycle progression (prolonged mitosis due to abnormal spindle morphology), to explain the reduced head size/microcephaly phenotype.

There is no associated phenotype in OMIM/G2P.

As a result, DYNC1I2 could be considered for inclusion in the ID panel probably as amber (ID reported for 5 individuals from 3 families, severity of ID not specified for all, eg. fam. 2 for whom the deletion was also spanning other genes which might contribute to the phenotype).
Sources: Literature
Created: 24 May 2019, 5:14 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Expert Review
  • Expert Review
Phenotypes
  • Abnormality of nervous system morphology
  • Abnormality of head or neck
  • Microcephaly
  • Intellectual disability
Tags
watchlist
OMIM
603331
Clinvar variants
Variants in DYNC1I2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 2

Added Tag

Catherine Snow (Genomics England)

Tag watchlist tag was added to gene: DYNC1I2.

25 Jul 2019, Gel status: 2

Added New Source, Added New Source, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review was added to DYNC1I2. Source Expert Review Amber was added to DYNC1I2. Added phenotypes Abnormality of head or neck; Microcephaly; Abnormality of nervous system morphology; Intellectual disability for gene: DYNC1I2 Rating Changed from No List (delete) to Amber List (moderate evidence)

24 May 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: DYNC1I2 was added gene: DYNC1I2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DYNC1I2 were set to 31079899 Phenotypes for gene: DYNC1I2 were set to Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck Penetrance for gene: DYNC1I2 were set to Complete Review for gene: DYNC1I2 was set to AMBER