Intellectual disability, autosomal recessive 66

Summary

Intellectual disability, autosomal recessive 66 (MONDO:0032605) is a disease caused by FERRY3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FERRY3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 66
Mondo ID	MONDO:0032605
OMIM	618221
DOID	DOID:0081227
UMLS	C4748732
MedGen	1648460
GARD	0022579
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, autosomal recessive 66 · MRT66

Data availability: 18 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 66

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

18 retrieved; paginated sample, class counts are floors:

9 likely pathogenic, 4 uncertain significance, 3 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1805729	NM_020374.4(FERRY3):c.187G>T (p.Glu63Ter)	FERRY3	Pathogenic	criteria provided, single submitter
183276	NM_020374.4(FERRY3):c.639_640insACAA (p.Gln214fs)	FERRY3	Pathogenic/Likely pathogenic	no assertion criteria provided
3254961	NM_020374.4(FERRY3):c.1043_1044del (p.Thr348fs)	FERRY3	Pathogenic	criteria provided, single submitter
3392491	NM_020374.4(FERRY3):c.499C>T (p.Arg167Ter)	FERRY3	Pathogenic	criteria provided, single submitter
592164	NM_020374.4(FERRY3):c.1360C>T (p.Arg454Ter)	FERRY3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
931775	NM_020374.4(C12orf4):c.1200_1201insGT (p.Lys401fs)	C12orf4	Likely pathogenic	criteria provided, single submitter
977084	NM_020374.4(C12orf4):c.799_1034-429delinsTTATGA	C12orf4	Likely pathogenic	criteria provided, single submitter
977085	NM_020374.4(C12orf4):c.1078C>T (p.Arg360Ter)	C12orf4	Likely pathogenic	criteria provided, single submitter
1708135	NM_020374.4(FERRY3):c.1168_1169delinsC (p.Gly390fs)	FERRY3	Likely pathogenic	criteria provided, single submitter
3367098	NM_020374.4(FERRY3):c.527_528del (p.Lys176fs)	FERRY3	Likely pathogenic	criteria provided, single submitter
4081213	NM_020374.4(FERRY3):c.1003C>T (p.Arg335Ter)	FERRY3	Likely pathogenic	criteria provided, single submitter
4081214	NM_020374.4(FERRY3):c.40_41del (p.Glu14fs)	FERRY3	Likely pathogenic	criteria provided, single submitter
4081215	NM_020374.4(FERRY3):c.38_41del (p.Arg13fs)	FERRY3	Likely pathogenic	criteria provided, single submitter
592163	NM_020374.4(FERRY3):c.983T>C (p.Leu328Pro)	FERRY3	Likely pathogenic	criteria provided, single submitter
1337117	NM_020987.5(ANK3):c.3139G>A (p.Val1047Ile)	ANK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679836	NM_020987.5(ANK3):c.12356T>C (p.Ile4119Thr)	ANK3	Uncertain significance	criteria provided, single submitter
2439608	NM_020374.4(FERRY3):c.766T>C (p.Ser256Pro)	FERRY3	Uncertain significance	criteria provided, single submitter
3893018	NM_020374.4(FERRY3):c.694C>G (p.Gln232Glu)	FERRY3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
FERRY3	Strong	Autosomal recessive	intellectual disability, autosomal recessive 66	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FERRY3	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ANK3	Orphanet:356996	ANK3-related intellectual disability-sleep disturbance syndrome

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
FERRY3	HGNC:1184	ENSG00000047621	Q9NQ89	Ferry endosomal RAB5 effector complex subunit 3	gencc,clinvar
ANK3	HGNC:494	ENSG00000151150	Q12955	Ankyrin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FERRY3	Ferry endosomal RAB5 effector complex subunit 3	Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary).
ANK3	Ankyrin-3	Membrane-cytoskeleton linker.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FERRY3	Other/Unknown	no		Fy-3
ANK3	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
Brodmann (1909) area 23	2
buccal mucosa cell	1
tendon of biceps brachii	1
dorsal motor nucleus of vagus nerve	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FERRY3	280	ubiquitous	marker	tendon of biceps brachii, buccal mucosa cell, Brodmann (1909) area 23
ANK3	298	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK3	6,145
FERRY3	801

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANK3	Q12955	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FERRY3	Q9NQ89	84.04

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	1	368.4×	0.021	ANK3
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	335.9×	0.021	ANK3
ER to Golgi Anterograde Transport	1	132.8×	0.023	ANK3
L1CAM interactions	1	120.2×	0.023	ANK3
COPI-mediated anterograde transport	1	109.8×	0.023	ANK3
Transport to the Golgi and subsequent modification	1	102.9×	0.023	ANK3
Asparagine N-linked glycosylation	1	60.1×	0.033	ANK3
Axon guidance	1	45.1×	0.036	ANK3
Nervous system development	1	42.9×	0.036	ANK3
Membrane Trafficking	1	37.1×	0.037	ANK3
Vesicle-mediated transport	1	34.8×	0.037	ANK3
Post-translational protein modification	1	19.2×	0.061	ANK3
Developmental Biology	1	14.5×	0.074	ANK3
Metabolism of proteins	1	12.4×	0.081	ANK3

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
positive regulation of cell communication by electrical coupling	1	4213.0×	0.002	ANK3
maintenance of protein location in plasma membrane	1	4213.0×	0.002	ANK3
positive regulation of membrane depolarization during cardiac muscle cell action potential	1	4213.0×	0.002	ANK3
membrane assembly	1	2106.5×	0.002	ANK3
protein localization to axon	1	1685.2×	0.002	ANK3
positive regulation of membrane potential	1	1404.3×	0.002	ANK3
negative regulation of delayed rectifier potassium channel activity	1	1404.3×	0.002	ANK3
positive regulation of homotypic cell-cell adhesion	1	1203.7×	0.002	ANK3
cellular response to magnesium ion	1	1203.7×	0.002	ANK3
magnesium ion homeostasis	1	936.2×	0.002	ANK3
regulation of potassium ion transport	1	936.2×	0.002	ANK3
regulation of mast cell degranulation	1	936.2×	0.002	FERRY3
plasma membrane organization	1	443.5×	0.004	ANK3
positive regulation of sodium ion transport	1	421.3×	0.004	ANK3
positive regulation of protein targeting to membrane	1	280.9×	0.005	ANK3
neuromuscular junction development	1	263.3×	0.005	ANK3
Golgi to plasma membrane protein transport	1	263.3×	0.005	ANK3
neuronal action potential	1	240.7×	0.006	ANK3
establishment of protein localization	1	216.1×	0.006	ANK3
mitotic cytokinesis	1	129.6×	0.009	ANK3
axonogenesis	1	80.2×	0.014	ANK3
protein localization to plasma membrane	1	54.4×	0.020	ANK3
positive regulation of gene expression	1	19.4×	0.053	ANK3
signal transduction	1	8.0×	0.121	ANK3

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
FERRY3	0	0
ANK3	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	FERRY3, ANK3

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)
FERRY3	0	—
ANK3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.