MED27

protein-coding

mediator complex subunit 27, the group of Mediator complex

Gene summary

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Dec 2011]

Previous symbols:

CRSP8

MANE transcript

NM_004269.4

Inheritance

ClinVar variants

P:8U:42B:8

Top phenotype

Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr9:131,852,928-132,079,867

External References & Databases

Ensembl (ENSG00000160563)

Transcript & Mutation Effects

hg38 • Region Span ~226.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859137

Submitter: PanelApp Australia

neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859137

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0859137

Submitter: ClinGen

The *MED27* gene is located on chromosome 9 at 9q34.13 and encodes a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation (PMID 9989412). *MED27* was first reported in relation to autosomal recessive neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia in 2021 (Meng et al., PMID: 33443317). Eighteen unique variants (13 missense, 1 in-frame deletion, 3 frameshift, and 1 splicing) that have been reported in 32 probands across three publications (PMIDs: 33443317, 37517035, 39296199, SCV003804874.2) are included in this curation. Variants in this gene segregate with disease in families with multiple affected family members. The mechanism of pathogenicity is reported to be loss of function (PMID: 16582438). This gene-disease relationship is also supported by experimental evidence (biochemical, protein interactions and animal models) (PMIDs: 9989412, 37516429, 16582438, 36305825, 30091705, 31613003, 40578305, 40524219). Other genes that code for mediator complex subunits (*MED12*, *MED13*, *MED13L*, *MED17*, *MED25* and *CDK8*) are definitively or strongly associated with conditions involving developmental, language and motor delay, intellectual disability, seizures, cataracts and microcephaly. A knockout zebrafish model showed a reduction in head size and abnormal neurological development (PMID: 16582438). A second knockout zebrafish showed *MED27*’s role in neurogenesis and cerebellar development through motor impairments, reduced GABAergic neurons, failed neurogenesis, and defective progenitor cell differentiation (PMID: 40578305). An additional homozygous mutant zebrafish displayed severe developmental defects, motor deficits, and cerebellar atrophy which are clinical features seen in patients with *MED27* pathogenic variants (PMID: 40524219). Early lethality was observed in *MED27* gene knockouts in mouse, fruit fly and chicken (PMIDs: 36305825, 30091705, 31613003). While these latter three models do not necessarily recapitulate the disease phenotype, the observation that no reported human cases have been homozygous or compound heterozygous for loss-of-function variants suggests that complete loss of function of *MED27* may be embryonically lethal. In summary, there is definitive evidence to support the relationship between *MED27* and autosomal recessive neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on 12/15/2023. It was re-evaluated on 12/03/2025. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of a new case report and two zebrafish knockout models (PMIDs: 39296199, 40524219, 40578305). (SOP Version 11).

neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859137

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaAR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 33443317

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED27 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 27

not providedTotal: 13

Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasiaTotal: 11

not specifiedTotal: 8

Intellectual disabilityTotal: 1

Severe myoclonic epilepsy in infancyTotal: 1

MED27-related disordersTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004269.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	5 clinvar		6
missense	1 clinvar	2 clinvar	31 clinvar	3 clinvar		37
nonsense		2 clinvar	4 clinvar			6
start loss						0
frameshift	1 clinvar	1 clinvar	3 clinvar			5
splice donor/acceptor (+/-2bp)	1 clinvar		3 clinvar			4
Total	3	5	42	8	0	58

Highest pathogenic variant AF is 0.000019222613

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004269.4	RefSeq	NP_004260.2	8	MANE Select
ENST00000292035.10	Ensembl	ENSP00000292035.5	8	MANE Select
NM_001253881.2	RefSeq	NP_001240810.1	7	Standard
NM_001253882.2	RefSeq	NP_001240811.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
Developmental Biology
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

regulation of transcription by RNA polymerase II
transcription initiation from RNA polymerase II promoter
protein ubiquitination
stem cell population maintenance
positive regulation of nucleic acid-templated transcription

Molecular Function

transcription coactivator activity
protein binding
ubiquitin protein ligase activity

Cellular Component

ubiquitin ligase complex
nucleus
nucleoplasm
transcription factor complex
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292035
Coding exons: 8
Length: 219802
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125748
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	131	179	0.734	0.00000971	2029
Missense (PolyPhen)		21	44.504	0.47187		466
Synonymous	0.0300	70	70.3	0.995	0.00000381	599
Loss of Function	1.52	10	16.7	0.599	8.60e-7	190

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. {ECO:0000269|PubMed:10882111, ECO:0000269|PubMed:9989412}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.371
RVIS EVS: -0.47
RVIS percentile EVS: 23.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium