Colobomatous microphthalmia-rhizomelic dysplasia syndrome

Summary

Colobomatous microphthalmia-rhizomelic dysplasia syndrome (MONDO:0014380) is a disease caused by MAB21L2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAB21L2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 16

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	colobomatous microphthalmia-rhizomelic dysplasia syndrome
Mondo ID	MONDO:0014380
OMIM	615877
Orphanet	424099
DOID	DOID:0111802
UMLS	C4014540
MedGen	862977
GARD	0017707
Is cancer (heuristic)	no

Also known as: MCOPS14 · MCSKS · microphthalmia, syndromic 14 · microphthalmia, syndromic type 14 · microphthalmia-coloboma-rhizomelic skeletal dysplasia

Data availability: 16 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › colobomatous microphthalmia-rhizomelic dysplasia syndrome

Related subtypes (18): anophthalmia/microphthalmia-esophageal atresia syndrome, COFS syndrome, microphthalmia, syndromic 2, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, microphthalmia, syndromic 1, linear skin defects with multiple congenital anomalies, Matthew-Wood syndrome, MMEP syndrome, microphthalmia with brain and digit anomalies, syndromic microphthalmia type 5, microphthalmia-brain atrophy syndrome, oculoauricular syndrome, microphthalmia, syndromic 11, microphthalmia, syndromic 12, microphthalmia, Lenz type, Behrens Baumann dust syndrome, microphthalmia microtia fetal akinesia, RAB18 deficiency

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

16 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 4 likely pathogenic, 3 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3064182	NM_006439.5(MAB21L2):c.840C>G (p.Tyr280Ter)	LRBA	Pathogenic	criteria provided, single submitter
1299534	NM_006439.5(MAB21L2):c.881C>A (p.Ser294Ter)	MAB21L2	Pathogenic	criteria provided, single submitter
427785	NM_006439.5(MAB21L2):c.151C>G (p.Arg51Gly)	MAB21L2	Pathogenic	criteria provided, multiple submitters, no conflicts
139620	NM_006439.5(MAB21L2):c.152G>A (p.Arg51His)	LRBA	Likely pathogenic	criteria provided, single submitter
139621	NM_006439.5(MAB21L2):c.151C>T (p.Arg51Cys)	LRBA	Likely pathogenic	criteria provided, single submitter
139622	NM_006439.5(MAB21L2):c.145G>A (p.Glu49Lys)	LRBA	Likely pathogenic	criteria provided, single submitter
929565	NM_006439.5(MAB21L2):c.1A>C (p.Met1Leu)	LRBA	Likely pathogenic	criteria provided, single submitter
139623	NM_006439.5(MAB21L2):c.740G>A (p.Arg247Gln)	LRBA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3027346	NM_006439.5(MAB21L2):c.498T>G (p.Tyr166Ter)	LRBA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034276	NM_006439.5(MAB21L2):c.7G>A (p.Ala3Thr)	LRBA	Uncertain significance	criteria provided, single submitter
4079228	NM_006439.5(MAB21L2):c.340G>T (p.Val114Phe)	LRBA	Uncertain significance	criteria provided, single submitter
4531931	NM_006439.5(MAB21L2):c.475_476dup (p.Leu160fs)	LRBA	Uncertain significance	criteria provided, single submitter
4531932	NM_006439.5(MAB21L2):c.697del (p.Gln233fs)	LRBA	Uncertain significance	criteria provided, single submitter
976482	NM_006439.5(MAB21L2):c.287_295del (p.Gly96_Ala98del)	LRBA	Uncertain significance	no assertion criteria provided
988081	NM_006439.5(MAB21L2):c.457G>A (p.Ala153Thr)	LRBA	Uncertain significance	criteria provided, single submitter
931116	NM_006439.5(MAB21L2):c.343G>T (p.Glu115Ter)	MAB21L2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
MAB21L2	Definitive	Autosomal dominant	colobomatous microphthalmia-rhizomelic dysplasia syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAB21L2	Orphanet:424099	Colobomatous microphthalmia-rhizomelic dysplasia syndrome
LRBA	Orphanet:445018	Syndromic autoimmune enteropathy due to LRBA deficiency

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
MAB21L2	HGNC:6758	ENSG00000181541	Q9Y586	Protein mab-21-like 2	gencc,clinvar
LRBA	HGNC:1742	ENSG00000198589	P50851	Lipopolysaccharide-responsive and beige-like anchor protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAB21L2	Protein mab-21-like 2	Required for several aspects of embryonic development including normal development of the eye.
LRBA	Lipopolysaccharide-responsive and beige-like anchor protein	Involved in coupling signal transduction and vesicle trafficking to enable polarized secretion and/or membrane deposition of immune effector molecules.

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)
MAB21L2	Other/Unknown	no		MAB21L/cGLR, Mab-21-like_nuc_Trfase, Mab-21_HhH/H2TH-like
LRBA	Scaffold/PPI	no		BEACH_dom, WD40_rpt, NBEA-like_DUF1088

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
muscle layer of sigmoid colon	1
pigmented layer of retina	1
pons	1
bronchial epithelial cell	1
epithelium of bronchus	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAB21L2	144	broad	marker	muscle layer of sigmoid colon, pons, pigmented layer of retina
LRBA	274	ubiquitous	marker	upper leg skin, bronchial epithelial cell, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRBA	1,331
MAB21L2	1,149

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRBA	P50851	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAB21L2	Q9Y586	95.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
embryonic body morphogenesis	1	1053.2×	0.009	MAB21L2
protein localization to phagophore assembly site	1	495.6×	0.009	LRBA
camera-type eye development	1	179.3×	0.011	MAB21L2
eye development	1	175.5×	0.011	MAB21L2
mitophagy	1	159.0×	0.011	LRBA
intracellular protein localization	1	52.3×	0.025	LRBA
cell population proliferation	1	51.4×	0.025	MAB21L2
nervous system development	1	23.0×	0.048	MAB21L2
positive regulation of cell population proliferation	1	16.8×	0.059	MAB21L2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAB21L2	0	0
LRBA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LRBA	1	Binding:1

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	MAB21L2, LRBA

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)
MAB21L2	0	—
LRBA	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.