Majeed syndrome

Summary

Majeed syndrome (MONDO:0012316) is a disease caused by LPIN2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LPIN2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 850
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0001824	Weight loss	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002754	Osteomyelitis	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003025	Metaphyseal irregularity	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0004810	Congenital hypoplastic anemia	Very frequent (80-99%)
HP:0004840	Hypochromic microcytic anemia	Very frequent (80-99%)
HP:0005561	Abnormality of bone marrow cell morphology	Very frequent (80-99%)
HP:0012647	Abnormal inflammatory response	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001061	Acne	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0011001	Increased bone mineral density	Frequent (30-79%)
HP:0100769	Synovitis	Frequent (30-79%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002113	Pulmonary infiltrates	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0002907	Microscopic hematuria	Occasional (5-29%)
HP:0011123	Inflammatory abnormality of the skin	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)
HP:0100820	Glomerulopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Majeed syndrome
Mondo ID	MONDO:0012316
MeSH	C537839
OMIM	609628
Orphanet	77297
DOID	DOID:0061224
ICD-11	1316564349
NCIT	C119058
SNOMED CT	703540008
UMLS	C1864997
MedGen	351273
GARD	0010088
MedDRA	10072223
Is cancer (heuristic)	no

Also known as: CDA and CRMO · chronic recurrent multifocal osteomyelitis, congenital · chronic recurrent multifocal osteomyelitis-congenital dyserythropoietic anemia-neutrophilic dermatosis syndrome · congenital dyserythropoietic anaemia and chronic recurrent multifocal osteomyelitis · congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis · dyserythropoietic anemia, and neutrophilic dermatosis · Majeed syndrome · MJDS

Data availability: 850 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone inflammation disease › osteomyelitis › chronic recurrent multifocal osteomyelitis › Majeed syndrome

Related subtypes (2): sterile multifocal osteomyelitis with periostitis and pustulosis, chronic recurrent multifocal osteomyelitis 3

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

600 retrieved; paginated sample, class counts are floors:

256 likely benign, 234 uncertain significance, 29 conflicting classifications of pathogenicity, 26 benign, 25 benign/likely benign, 15 pathogenic, 12 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012310	NM_001375808.2(LPIN2):c.1691_1694del (p.Arg564fs)	LPIN2	Pathogenic	criteria provided, single submitter
1068791	NM_001375808.2(LPIN2):c.838C>T (p.Arg280Ter)	LPIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069224	NM_001375808.2(LPIN2):c.2342_2346del (p.Lys781fs)	LPIN2	Pathogenic	criteria provided, single submitter
1075334	NM_001375808.2(LPIN2):c.1843G>T (p.Glu615Ter)	LPIN2	Pathogenic	criteria provided, single submitter
1098839	NM_001375808.2(LPIN2):c.696del (p.Thr233fs)	LPIN2	Pathogenic	criteria provided, single submitter
1416971	NM_001375808.2(LPIN2):c.1826dup (p.Ser610fs)	LPIN2	Pathogenic	criteria provided, single submitter
1432195	NM_001375808.2(LPIN2):c.2495_2496dup (p.Asn833Ter)	LPIN2	Pathogenic	criteria provided, single submitter
1452588	NM_001375808.2(LPIN2):c.1160_1163del (p.Lys387fs)	LPIN2	Pathogenic	criteria provided, single submitter
1694293	NM_001375808.2(LPIN2):c.1204_1205dup (p.Asp402fs)	LPIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138125	NM_001375808.2(LPIN2):c.1684C>T (p.Arg562Ter)	LPIN2	Pathogenic	criteria provided, single submitter
21519	NM_001375808.2(LPIN2):c.2327+1G>C	LPIN2	Pathogenic	criteria provided, single submitter
2165430	NM_001375808.2(LPIN2):c.2125A>T (p.Lys709Ter)	LPIN2	Pathogenic	criteria provided, single submitter
234327	NM_001375808.2(LPIN2):c.132_135dup (p.Ser46fs)	LPIN2	Pathogenic	criteria provided, multiple submitters, no conflicts
234338	NM_001375808.2(LPIN2):c.1550G>A (p.Arg517His)	LPIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425962	NC_000018.9:g.(?2656075)(2960838_?)del	LPIN2	Pathogenic	criteria provided, single submitter
2745437	NM_001375808.2(LPIN2):c.475A>T (p.Arg159Ter)	LPIN2	Pathogenic	criteria provided, single submitter
2760513	NM_001375808.2(LPIN2):c.1673G>A (p.Trp558Ter)	LPIN2	Pathogenic	criteria provided, single submitter
2769904	NM_001375808.2(LPIN2):c.689del (p.Pro230fs)	LPIN2	Pathogenic	criteria provided, single submitter
1066630	NC_000018.9:g.(?2921511)(2938055_?)del	LPIN2	Likely pathogenic	criteria provided, single submitter
1066965	NM_001375808.2(LPIN2):c.288+2T>G	LPIN2	Likely pathogenic	criteria provided, single submitter
1474796	NM_001375808.2(LPIN2):c.2443-2A>G	LPIN2	Likely pathogenic	criteria provided, single submitter
1482210	NM_001375808.2(LPIN2):c.822+2T>G	LPIN2	Likely pathogenic	criteria provided, single submitter
1931643	NM_001375808.2(LPIN2):c.698+1G>A	LPIN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2003538	NM_001375808.2(LPIN2):c.699-1G>T	LPIN2	Likely pathogenic	criteria provided, single submitter
2099878	NM_001375808.2(LPIN2):c.699-2A>G	LPIN2	Likely pathogenic	criteria provided, single submitter
2784755	NM_001375808.2(LPIN2):c.289-1G>T	LPIN2	Likely pathogenic	criteria provided, single submitter
2984744	NM_001375808.2(LPIN2):c.1938+1G>A	LPIN2	Likely pathogenic	criteria provided, single submitter
3064410	NM_001375808.2(LPIN2):c.1871del (p.Thr624fs)	LPIN2	Likely pathogenic	criteria provided, single submitter
3628359	NM_001375808.2(LPIN2):c.1269-2A>G	LPIN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3678736	NM_001375808.2(LPIN2):c.698+1del	LPIN2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
LPIN2	Strong	Autosomal recessive	Majeed syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LPIN2	Orphanet:77297	Majeed 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
LPIN2	HGNC:14450	ENSG00000101577	Q92539	Phosphatidate phosphatase LPIN2	gencc,clinvar
MYL12A	HGNC:16701	ENSG00000101608	P19105	Myosin regulatory light chain 12A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LPIN2	Phosphatidate phosphatase LPIN2	Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the endoplasmic reti…
MYL12A	Myosin regulatory light chain 12A	Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation.

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)
LPIN2	Other/Unknown	no		Lipin_N, LNS2, LIPIN
MYL12A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_hand_DJBP

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
jejunal mucosa	1
liver	1
right lobe of liver	1
apex of heart	1
hindlimb stylopod muscle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LPIN2	281	ubiquitous	marker	jejunal mucosa, liver, right lobe of liver
MYL12A	240	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYL12A	2,584
LPIN2	1,212

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYL12A	P19105	83.59
LPIN2	Q92539	61.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Synthesis of PE	1	439.2×	0.014	LPIN2
Depolymerization of the Nuclear Lamina	1	380.7×	0.014	LPIN2
Triglyceride biosynthesis	1	335.9×	0.014	LPIN2
Triglyceride metabolism	1	335.9×	0.014	LPIN2
Ephrin signaling	1	285.5×	0.014	MYL12A
Nuclear Envelope Breakdown	1	228.4×	0.014	LPIN2
Synthesis of PC	1	203.9×	0.014	LPIN2
Mitotic Prophase	1	184.2×	0.014	LPIN2
Glycerophospholipid biosynthesis	1	167.9×	0.014	LPIN2
Smooth Muscle Contraction	1	132.8×	0.016	MYL12A
Phospholipid metabolism	1	100.2×	0.019	LPIN2
EPH-Ephrin signaling	1	82.8×	0.021	MYL12A
Muscle contraction	1	38.6×	0.042	MYL12A
M Phase	1	33.0×	0.045	LPIN2
Cell Cycle, Mitotic	1	24.1×	0.057	LPIN2
Axon guidance	1	22.6×	0.057	MYL12A
Nervous system development	1	21.5×	0.057	MYL12A
Cell Cycle	1	18.0×	0.064	LPIN2
Metabolism of lipids	1	15.8×	0.069	LPIN2
Developmental Biology	1	7.2×	0.140	MYL12A
Metabolism	1	5.8×	0.165	LPIN2

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
fatty acid catabolic process	1	648.1×	0.008	LPIN2
triglyceride biosynthetic process	1	366.4×	0.008	LPIN2
platelet aggregation	1	168.5×	0.012	MYL12A
cellular response to insulin stimulus	1	85.1×	0.018	LPIN2
lipid metabolic process	1	45.8×	0.026	LPIN2
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	LPIN2

Therapeutics

Drug target analysis

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

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
MYL12A	1	2
LPIN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MYL12A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYL12A	6	Binding:6

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	MYL12A

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	1	MYL12A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LPIN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LPIN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.