MED13L | cardiac anomalies - developmental delay - facial dysmorphism syndrome | Autosomal dominant by Illumina submission information facts

Submitter:

Illumina

Classification:

Definitive

GENCC:100001

Gene:

MED13L

HGNC:22962

Disease:

cardiac anomalies - developmental delay - facial dysmorphism syndrome

MONDO:0014773

Mode Of Inheritance:

Autosomal dominant

HP:0000006

Evaluated Date:

02/14/2020

Evidence/Notes:

The MED13L gene is located on chromosome 12 at 12q24.21 and encodes the mediator complex subunit 13L protein. MED13L is part of the CDK8 module of the Mediator complex, which is required for gene transcription by RNA polymerase II (24550107: Yin & Wang (2014). The MED13L gene was first reported in relation to MED13L-related neurodevelopmental disorder in 2013 (23403903: Asadollahi et al. (2013). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least seven variants have been reported in seven cases from three publications, including two frameshift, three nonsense, one missense, and one in-frame deletion (25712080: Cafiero et al. 2015; 29740699: Snijders Blok et al. 2018; 29959045: Tørring et al. 2019). All variants from these cases were confirmed to have occurred de novo. Considerably more case level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of disease is haploinsufficiency. This gene-disease relationship is supported by the biochemical function of MED13L as a component of the Mediator complex, which is required for gene transcription by RNA polymerase II (24550107: Yin & Wang 2014). Knockdown of the MED13L zebrafish ortholog med13b resulted in craniofacial, brain, and eye abnormalities, and the zebrafish phenotype could be rescued by co-expression of human MED13L (25137640: Utami et al. 2014). Suppression of MED13L with shRNA in ES-derived human neural progenitor cells that were differentiated into neurons demonstrated that MED13L regulates transcription of many genes, including those in the Wnt and FGF pathways that are critical for craniofacial and brain development (25137640: Utami et al. 2014). In summary, MED13L is definitively associated with MED13L-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

PubMed IDs:

25712080 29740699 29959045 24550107 25137640

Assertion Criteria:

Click here to view assertion criteria

https://www.clinicalgenome.org/site/assets/files/3975/gene-disease_validity_standard_operating_procedures_version_7-1.pdf

Submitter Submitted Date:

10/15/2020

Submission Details