Early onset or syndromic epilepsy

Gene: MARK2

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: As reviewed by Zornitza Stark, 31 individuals were reported with intellectual disability/ developmental delay and with monoallelic MARK2 variants. ID/ DD was severe in seven, moderate in two, mild and/or borderline in four and unspecified in 17. In addition, functional evidence is also available.

This gene can therefore be promoted to green rating in the next GMS update.

Created: 14 Nov 2024, 11:59 a.m. | Last Modified: 14 Nov 2024, 11:59 a.m.

Panel Version: 8.28

Comment on phenotypes: This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

Created: 14 Nov 2024, 11:46 a.m. | Last Modified: 14 Nov 2024, 11:46 a.m.

Panel Version: 8.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071

Publications

• 39419027
• 39436150

Green List (high evidence)

31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears).

WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains.

The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD.
Sources: Literature

Created: 11 Nov 2024, 6:09 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder MONDO:0700092

Publications

• 39419027
• 39436150