Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

Summary

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (MONDO:0013351) is a disease caused by MED17 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MED17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 156

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly
Mondo ID	MONDO:0013351
OMIM	613668
Orphanet	402364
DOID	DOID:0111262
UMLS	C3150921
MedGen	462271
GARD	0010995
Is cancer (heuristic)	no

Also known as: postnatal progressive microcephaly, seizures, and brain atrophy

Data availability: 156 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

Related subtypes (18): autoimmune disorder of central nervous system, autonomic nervous system disorder, optic nerve disorder, spinal cord disorder, high pressure neurological syndrome, central nervous system vasculitis, encephalomyelitis, neurodegenerative disease, brain disorder, central nervous system neoplasm, palsy, trigeminal neuralgia, sporadic fetal brain disruption sequence, congenital narrowing of cervical spinal canal, central nervous system infectious disorder, cerebrospinal fluid leak, SPAST-related motor disorder, tinnitus

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

156 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 23 likely pathogenic, 13 pathogenic/likely pathogenic, 13 benign, 11 likely benign, 10 conflicting classifications of pathogenicity, 6 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456927	NM_004268.5(MED17):c.235C>T (p.Gln79Ter)	LOC130006596	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069389	NM_004268.5(MED17):c.565C>T (p.Arg189Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070526	NM_004268.5(MED17):c.1360C>T (p.Arg454Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070708	NM_004268.5(MED17):c.472C>T (p.Gln158Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072022	NM_004268.5(MED17):c.1582C>T (p.Gln528Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448163	NM_004268.5(MED17):c.835C>T (p.Arg279Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460250	NM_004268.5(MED17):c.1405_1433dup (p.Leu478_Ile479insMetPheMetAsnLeuValTer)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18441	NM_004268.5(MED17):c.1112T>C (p.Leu371Pro)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2012767	NM_004268.5(MED17):c.916G>T (p.Glu306Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3003976	NM_004268.5(MED17):c.538C>T (p.Gln180Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688997	NM_004268.5(MED17):c.324_325dup (p.Met109fs)	MED17	Pathogenic	criteria provided, single submitter
849753	NM_004268.5(MED17):c.1444C>T (p.Gln482Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
862218	NM_004268.5(MED17):c.1299_1302del (p.Ala435fs)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
942991	NM_004268.5(MED17):c.589C>T (p.Arg197Ter)	MED17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3067139	NM_021937.5(EEFSEC):c.1751_1752dup (p.Val585fs)	EEFSEC	Likely pathogenic	criteria provided, single submitter
1487568	NM_004268.5(MED17):c.1013-1G>A	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1498075	NM_004268.5(MED17):c.1467-1G>C	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2159503	NM_004268.5(MED17):c.757G>A (p.Gly253Arg)	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2419671	NM_004268.5(MED17):c.1585-1G>T	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2503794	NM_004268.5(MED17):c.604A>T (p.Lys202Ter)	MED17	Likely pathogenic	criteria provided, single submitter
3574123	NM_004268.5(MED17):c.110C>A (p.Ser37Ter)	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574124	NM_004268.5(MED17):c.318_320delinsAA (p.Thr107fs)	MED17	Likely pathogenic	criteria provided, single submitter
3574125	NM_004268.5(MED17):c.873G>A (p.Trp291Ter)	MED17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574126	NM_004268.5(MED17):c.1143+1G>A	MED17	Likely pathogenic	criteria provided, single submitter
3574127	NM_004268.5(MED17):c.1551_1556delinsTTGCT (p.Gln517fs)	MED17	Likely pathogenic	criteria provided, single submitter
4057609	NM_004268.5(MED17):c.924del (p.Phe308fs)	MED17	Likely pathogenic	criteria provided, single submitter
4057639	NM_004268.5(MED17):c.479T>A (p.Leu160Ter)	MED17	Likely pathogenic	criteria provided, single submitter
4081509	NM_004268.5(MED17):c.775-1G>C	MED17	Likely pathogenic	criteria provided, single submitter
4815331	NM_004268.5(MED17):c.1386del (p.His463fs)	MED17	Likely pathogenic	criteria provided, single submitter
4815332	NM_004268.5(MED17):c.1612C>T (p.Gln538Ter)	MED17	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MED17	Strong	Autosomal recessive	infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED17	Orphanet:402364	Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED17	HGNC:2375	ENSG00000042429	Q9NVC6	Mediator of RNA polymerase II transcription subunit 17	gencc,clinvar
EEFSEC	HGNC:24614	ENSG00000132394	P57772	Selenocysteine-specific elongation factor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED17	Mediator of RNA polymerase II transcription subunit 17	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
EEFSEC	Selenocysteine-specific elongation factor	Translation factor required for the incorporation of the rare amino acid selenocysteine encoded by UGA codons.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED17	Other/Unknown	no		Mediator_Med17
EEFSEC	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_B-barrel_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
sural nerve	1
ventricular zone	1
apex of heart	1
gastrocnemius	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED17	199	ubiquitous	marker	sural nerve, ventricular zone, cortical plate
EEFSEC	135	ubiquitous	yes	apex of heart, heart left ventricle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED17	2,747
EEFSEC	2,279

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MED17	Q9NVC6	11
EEFSEC	P57772	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.035	MED17
Selenoamino acid metabolism	1	98.5×	0.035	EEFSEC
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.035	MED17
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.035	MED17
RSV-host interactions	1	78.2×	0.035	MED17
Adipogenesis	1	78.2×	0.035	MED17
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.035	MED17
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.035	MED17
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.035	MED17
Selenocysteine synthesis	1	60.1×	0.035	EEFSEC
Metabolism	2	11.6×	0.035	MED17, EEFSEC
PPARA activates gene expression	1	47.2×	0.040	MED17
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.043	MED17
Epigenetic regulation of gene expression	1	35.7×	0.045	MED17
Metabolism of amino acids and derivatives	1	33.8×	0.045	EEFSEC
Metabolism of lipids	1	15.8×	0.086	MED17
Viral Infection Pathways	1	15.4×	0.086	MED17
Infectious disease	1	12.4×	0.101	MED17
RNA Polymerase II Transcription	1	11.3×	0.105	MED17
Gene expression (Transcription)	1	8.9×	0.125	MED17
Generic Transcription Pathway	1	7.5×	0.140	MED17
Developmental Biology	1	7.2×	0.140	MED17
Disease	1	6.5×	0.147	MED17

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
selenocysteine incorporation	1	936.2×	0.011	EEFSEC
transcription initiation at RNA polymerase II promoter	1	187.2×	0.013	MED17
positive regulation of transcription elongation by RNA polymerase II	1	150.5×	0.013	MED17
RNA polymerase II preinitiation complex assembly	1	135.9×	0.013	MED17
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.013	MED17
somatic stem cell population maintenance	1	123.9×	0.013	MED17
protein ubiquitination	1	20.7×	0.068	MED17
positive regulation of DNA-templated transcription	1	14.0×	0.088	MED17
positive regulation of transcription by RNA polymerase II	1	7.4×	0.144	MED17
regulation of transcription by RNA polymerase II	1	5.8×	0.164	MED17

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MED17	0	0
EEFSEC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MED17, EEFSEC

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MED17	0	—
EEFSEC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.