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Inheritance

1

Autosomal recessive inheritance HP:0000007

All three genetic forms of 3MC syndrome are inherited in an autosomal recessive manner. Affected individuals carry biallelic (homozygous or compound heterozygous) variants, and reported pedigrees are frequently consanguineous.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:21258343 SUPPORT BACKGROUND Human Clinical

"These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies."

States the autosomal recessive inheritance of the four constituent syndromes now unified as 3MC syndrome.

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Subtypes

3

3MC syndrome 1 (MASP1/MASP-3) MONDO:0009770

MASP1 hgnc:6901

Caused by biallelic MASP1 variants that impair MASP-3. Missense changes and deletions can affect the MASP-3-specific serine protease domain encoded by exon 12; earlier truncating variants can affect sequence shared with other MASP1 products. Pro-factor D maturation is additionally impaired.

Show evidence (1 reference)

PMID:21035106 SUPPORT PRIMARY RESULT Human Clinical

"In one family, whole exome sequencing revealed a missense mutation, MASP1 c.2059G>A (p.G687R), that cosegregated with the phenotype."

Establishes MASP1 as a 3MC syndrome disease gene through cosegregation in a consanguineous family.

3MC syndrome 2 (COLEC11/CL-K1) MONDO:0009927

COLEC11 hgnc:17213

Caused by biallelic COLEC11 variants affecting CL-K1. Tested carbohydrate-recognition-domain missense variants impair secretion; truncating variants and multi-exon deletions are also reported.

Show evidence (1 reference)

PMID:21258343 SUPPORT PRIMARY RESULT Human Clinical

"Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1"

Identifies COLEC11 alongside MASP1 as one of the two originally reported 3MC syndrome genes.

3MC syndrome 3 (COLEC10/CL-L1) MONDO:0009554

COLEC10 hgnc:2220

Caused by biallelic COLEC10 variants affecting CL-L1. Both homozygous and compound heterozygous genotypes are reported. The c.311G>T (p.Gly104Val) allele is a likely founder variant in the Ashkenazi Jewish population, with a reported carrier frequency near 1 in 99.

Show evidence (1 reference)

PMID:28301481 SUPPORT PRIMARY RESULT Human Clinical

"Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families."

Establishes COLEC10 as the third 3MC syndrome disease gene.

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Discussions and Knowledge Gaps

1

Which additional genetic causes or undetected variants account for clinically diagnosed 3MC cases without molecular confirmation in MASP1, COLEC11 or COLEC10?

KNOWLEDGE GAP OPEN gap_3mc_molecularly_unconfirmed_cases

The 2017 COLEC10 discovery study reported that over 60% of its selected 3MC cohort remained without molecular confirmation after assessing the three known genes. The authors proposed additional loci. This historical cohort fraction is not a current diagnostic-yield estimate, and it does not by itself distinguish new loci from missed variants or clinical phenocopies.

Show evidence (1 reference)

PMID:28301481 SUPPORT PRIMARY RESULT Human Clinical

"Therefore, over 60% of our 3MC cohort is still without molecular confirmation of disease and that at least one further gene remains to be identified."

The discovery study reports its remaining molecularly unconfirmed cohort and interprets it as evidence for additional loci; that interpretation is a hypothesis rather than proof of a new gene.

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Pathophysiology

10

Impaired CL-K1 Calcium Binding

Three tested COLEC11 carbohydrate-recognition-domain variants (Ser169Pro, Gly204Ser and Ser217 deletion) abolish calcium binding in recombinant fragments. The fragments can refold and oligomerize in vitro, but lack calcium-dependent stabilization.

COLEC11 hgnc:17213

calcium ion binding GO:0005509 ↓ DECREASED

Downstream

Reduced Extracellular CL-K1 Availability Failure of calcium binding is proposed to compromise CL-K1 during biosynthesis and prevent secretion. Cellular quality-control recognition and degradation are plausible intermediates that were not directly demonstrated.

Impaired CL-K1 Carbohydrate Binding Calcium normally stabilizes ligand-binding loops in the carbohydrate-recognition domain. The tested variants lose calcium binding and carbohydrate recognition; loop destabilization links these molecular effects.

Show evidence (1 reference)

PMID:25912189 SUPPORT PRIMARY RESULT In Vitro

"Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition domains of CL-K1."

Recombinant fragments carrying Ser169Pro, Gly204Ser or Ser217 deletion lose calcium binding. Refolding in vitro does not exclude a biosynthetic folding defect in cells.

Impaired CL-K1 Carbohydrate Binding

Recombinant CL-K1 fragments carrying the three tested 3MC-associated carbohydrate-recognition-domain variants fail to bind yeast invertase or the dextran chromatography matrix. These ligand-binding assays demonstrate functional loss even though the fragments assemble into trimers in vitro.

carbohydrate binding GO:0030246 ↓ DECREASED

Show evidence (1 reference)

PMID:25912189 SUPPORT PRIMARY RESULT In Vitro

"Both full-length CL-K1 and the wild-type fragment bound to the invertase, but the three variant fragments did not bind (Figure 6C)."

The assay directly measures loss of carbohydrate recognition in the recombinant variants. The corresponding developmental ligand has not been established.

Reduced Extracellular CL-K1 Availability

Biallelic COLEC11 loss-of-function variants reduce functional extracellular CL-K1. Three tested carbohydrate-recognition-domain variants block secretion in mammalian cells, and Gly204Ser CL-K1 was undetectable in serum from two patients. This node does not assume that all COLEC11 variants share the same biosynthetic defect.

COLEC11 hgnc:17213

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline COLEC11 variants include missense substitutions, truncating alleles and a multi-exon deletion.

Downstream

Impaired Neural Crest Cell Guidance CL-K1 depletion disrupts neural crest distribution in zebrafish, and recombinant protein attracts neural crest cells in explants. The responding receptors and intervening signaling steps are unresolved.

Impaired Complement-Dependent Osteoclastogenesis Collectin-11 loss impairs osteoclast differentiation in experimental cells, with species- and complement-background-dependent effect sizes. Recombinant CL-11 partially rescues differentiation; the intervening signaling steps and their relevance to skeletal disease in 3MC patients remain incompletely established.

Show evidence (2 references)

PMID:25912189 SUPPORT PRIMARY RESULT In Vitro

"We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients."

The three tested COLEC11 carbohydrate-recognition-domain variants block secretion in the mammalian expression assay.

PMID:21258343 SUPPORT PRIMARY RESULT Human Clinical

"Using western blotting, we failed to detect any secreted CL-K1 in the serum of two patients (Gly204Ser), in contrast to control samples"

Two affected individuals lacked detectable serum CL-K1. Intracellular retention was suggested, not directly measured in these patients.

Reduced Extracellular CL-L1 Availability

Some biallelic COLEC10 variants impair CL-L1 expression or secretion. Arg9Ter and Gly77Glufs*66 constructs yield no detectable protein, whereas Cys176Trp accumulates intracellularly with severely reduced secretion. This route is distinct from the Cys270Serfs*33 allele, which has normal measured plasma levels but impaired chemoattractant activity.

COLEC10 hgnc:2220

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic COLEC10 variants affecting protein expression or secretion; compound heterozygous genotypes occur.

Downstream

Impaired Neural Crest Cell Guidance Reduced CL-L1 availability is proposed to disrupt craniofacial cell guidance. CL-L1 attracts HeLa cells and is expressed in developing palatal tissue, but a CL-L1-specific neural crest receptor or signaling route was not established.

Show evidence (1 reference)

PMID:28301481 SUPPORT PRIMARY RESULT In Vitro

"We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity."

The tested truncating alleles eliminate detectable expressed protein; Cys176Trp permits intracellular expression but markedly reduces secretion.

Impaired CL-L1 Chemoattractant Activity

The homozygous COLEC10 c.807_810delCTGT (p.Cys270Serfs*33) variant extends the protein and removes a conserved cysteine. Plasma CL-L1 levels were normal in the reported family, while mutant protein induced less HeLa-cell migration than wild type. Loss of extracellular function can therefore occur without reduced measured abundance.

COLEC10 hgnc:2220

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Homozygous germline c.807_810delCTGT (p.Cys270Serfs*33), with reduced function in a cell-migration assay.

Downstream

Impaired Neural Crest Cell Guidance Reduced CL-L1 chemoattraction provides a candidate explanation for the developmental phenotype of the Cys270Serfs*33 patient. Transfer from the HeLa assay to neural crest migration remains inferential.

Show evidence (2 references)

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Plasma levels of CL-L1 in the patient and her parents were within normal range, suggesting that this variant does not modify transcription or secretion."

Measured plasma abundance was normal in the Cys270Serfs*33 family; abundance alone does not demonstrate every step of transcription or secretion.

PMID:34740859 SUPPORT PRIMARY RESULT In Vitro

"However, the variant affects the chemo-attractive feature of CL-L1, as HeLa cells migrate significantly less in response to the mutant protein compared to the wild-type one."

The mutant protein has reduced chemoattractant activity in HeLa cells; the assay does not directly test neural crest cells.

Loss of MASP-3 Serine Protease Activity

Biallelic MASP1 variants impair MASP-3 serine protease activity. Tested 3MC-associated MASP-3 mutants were enzymatically inactive. Variants confined to the exon-12 protease domain can selectively affect MASP-3, whereas earlier truncating variants may also affect MASP-1 or MAp44; selective MASP-3 deficiency is not assumed for every genotype.

MASP1 hgnc:6901

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline MASP1 variants include missense changes in the MASP-3 protease domain, earlier nonsense alleles in shared sequence and intragenic deletions.

MASP-3 serine endopeptidase activity GO:0004252 ↓ DECREASED

Downstream

Impaired Neural Crest Cell Guidance masp1 knockdown alters neural crest migration in zebrafish, supporting a role for this locus in guidance. The developmental substrate of MASP-3 and the contribution of the other isoforms remain unresolved.

Impaired Pro-Factor D Maturation MASP-3 is the maturase that converts pro-factor D to mature factor D, so loss of its catalytic activity directly compromises this conversion.

Show evidence (1 reference)

PMID:28794230 SUPPORT PRIMARY RESULT In Vitro

"We characterized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatically inactive proteins."

Directly demonstrates that the 3MC-associated MASP1 alleles abolish MASP-3 catalytic activity.

Impaired Neural Crest Cell Guidance

Experimental colec11 or masp1 knockdown causes ectopic neural crest distribution and disrupted migratory streams in zebrafish. Recombinant CL-K1 also attracts quail neural crest cells in explants. These observations support a guidance defect as a candidate cause of craniofacial malformation in 3MC; they do not establish that every affected organ derives from neural crest.

migratory neural crest cell CL:0000333

neural crest cell migration GO:0001755 ↕ DYSREGULATED

Animal models

colec11 zebrafish morphant Zebrafish recapitulates The same colec11 perturbation alters neural crest streaming and location before craniofacial cartilage is assessed.

masp1 zebrafish morphant Zebrafish recapitulates The perturbation supports a role for the masp1 locus in neural crest guidance.

Downstream

Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis Disorganized neural crest guidance is proposed to disturb subsequent craniofacial patterning and differentiation. The same zebrafish perturbations affect migration and cartilage, but do not isolate migration as the sole mediator.

Show evidence (2 references)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11 morphants and obviously truncated in the masp1 morphants"

Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation does not isolate MASP-3 from other gene products.

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf, ectopic NCC in the head, trunk and periphery"

Ectopic neural crest cells support dysregulated guidance rather than a uniform decrease in cell number.

Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis

Craniofacial cartilage and bone development is disrupted in zebrafish models, supporting a developmental explanation for the facial abnormalities and clefting of 3MC. Expression of CL-K1 and CL-L1 in murine palatal and craniofacial tissues supports biological plausibility, without proving a specific mechanism for each human malformation.

neural crest cell development GO:0014032 ↕ DYSREGULATED

Animal models

colec11 zebrafish morphant Zebrafish recapitulates Knockdown reproduces severe craniofacial cartilage malformation, the tissue-level phenotype of the human syndrome.

Downstream

Hypertelorism Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Blepharophimosis Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Ptosis Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Cleft Lip Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Cleft Palate Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Craniosynostosis Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Micrognathia Disrupted craniofacial development is a proposed route to this observed human feature. The exact developmental intermediates and gene-specific contributions have not been established.

Show evidence (1 reference)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"Striking differences in the craniofacial skeleton were observed compared with uninjected/standard morpholino injected embryos, such as reduced mandibular length (e.g. shortened Meckel and palatoquadrate cartilages), malformation of the anterior neurocranium with shortening of the trabeculae and..."

Perturbed zebrafish CL-K1 expression causes craniofacial cartilage defects.

Impaired Complement-Dependent Osteoclastogenesis

Experimental loss of collectin-11 impairs osteoclast differentiation in mouse bone-marrow cultures and engineered healthy-donor human iPSC-derived cells. The effect is modest after isolated mouse Colec11 deletion and pronounced in Colec11/C3 or Colec11/Cfb double-knockout cultures; isolated human COLEC11 deletion already has a marked effect. Recombinant CL-11 partially rescues differentiation, and complement-convertase inhibition impairs differentiation in human cells. These results identify a candidate mechanism relevant to 3MC, without establishing osteoclast dysfunction as the cause of skeletal malformations in affected patients.

osteoclast CL:0000092

osteoclast differentiation GO:0030316 ↓ DECREASED

Experimental models

Mouse Colec11-deficient bone-marrow-derived osteoclast cultures PRIMARY CELL CULTURE The experimental system distinguishes modest single-knockout effects from pronounced combined-knockout effects and tests recombinant-protein rescue directly.

Human CRISPR COLEC11-knockout KOLF2 iPSC-derived osteoclasts IPSC DERIVED MODEL Isolated COLEC11 deletion markedly reduces osteoclast differentiation in this human cellular system, and recombinant CL-11 partly restores it. Mirococept separately inhibits C3/C5 convertases and reduces osteoclast formation.

Animal models

Colec11 knockout mouse Mouse partially recapitulates The cellular differentiation defect is mild after isolated Colec11 deletion in mouse cells. This model does not reproduce the high frequency of overt postnatal spinal disease observed with additional complement-gene deletion.

Colec11 and complement-component double-knockout mice Mouse partially recapitulates Colec11/C3 and Colec11/Cfb bone-marrow cultures show marked impairment of osteoclast differentiation and partial rescue with recombinant CL-11. The living double-knockout animals provide an associated bone-maintenance phenotype, rather than proof that the measured osteoclast defect causes their bone loss.

Show evidence (4 references)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11."

Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size"

Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells"

The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.

+ 1 more reference

Impaired Pro-Factor D Maturation

MASP-3 deficiency compromises conversion of pro-factor D to mature factor D. Tested patient samples predominantly contain pro-factor D but retain detectable mature factor D, consistent with an additional maturation route. Resting-plasma inhibition experiments establish MASP-3 dependence under those assay conditions; serum coagulation and patient measurements need separate interpretation.

protein maturation GO:0051604 ↓ DECREASED

Animal models

Masp1/3 knockout mouse Mouse recapitulates Reproduces the failure of pro-factor D conversion seen in patient serum.

Show evidence (2 references)

PMID:28794230 SUPPORT PRIMARY RESULT Human Clinical

"although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD"

Patient samples demonstrate incomplete maturation. Residual mature factor D does not by itself establish normal alternative-pathway activity or absence of clinical infection risk.

PMID:27535802 SUPPORT PRIMARY RESULT In Vitro

"For this study we evolved a specific MASP-3 inhibitor and unambiguously proved that activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways."

Selective inhibitor experiments in resting human plasma establish the role of activated MASP-3 under the tested conditions. The paper distinguishes this from coagulated serum, where other proteases may contribute.

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Pathograph

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Phenotypes

40

Cardiovascular 2

Congenital Heart Disease Abnormal heart morphology HP:0001627

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:41703727 SUPPORT PRIMARY RESULT Human Clinical

"Cleft lip and/or palate were present in six patients, caudal appendage in four, congenital heart disease in two, hearing loss in four, and periumbilical anomalies in six."

Two of seven selected patients had congenital heart disease; no syndrome-wide frequency is inferred.

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents patent ductus arteriosus in the molecularly confirmed Iranian COLEC10 case.

Digestive 4

Periumbilical Depression HP:6000808

Show evidence (2 references)

PMID:41703727 SUPPORT PRIMARY RESULT Human Clinical

"Cleft lip and/or palate were present in six patients, caudal appendage in four, congenital heart disease in two, hearing loss in four, and periumbilical anomalies in six."

Reports the broader category of periumbilical anomalies in a selected seven-patient cohort; this does not establish depression in six patients.

PMID:21035106 SUPPORT PRIMARY RESULT Human Clinical

"We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage."

Independently documents periumbilical depression as a characteristic finding in molecularly confirmed patients.

Umbilical Hernia HP:0001537

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Rarely occurring features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis recti."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Omphalocele HP:0001539

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Rarely occurring features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis recti."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Diastasis Recti HP:0001540

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Rarely occurring features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis recti."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Ear 1

Hearing Loss Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:21035106 SUPPORT PRIMARY RESULT Human Clinical

"We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage."

Documents mixed hearing loss in molecularly confirmed MASP1 patients.

Eye 4

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"The main features are facial dysmorphic traits including hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70 to 95% of patients"

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Ptosis HP:0000508

Show evidence (2 references)

PMID:36503917 SUPPORT BACKGROUND Human Clinical

"Patients with 3MC syndrome have a distinctive facial phenotype including hypertelorism, highly arched eyebrows and ptosis."

Introductory clinical background identifies ptosis as part of the facial phenotype.

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"The main features are facial dysmorphic traits including hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70 to 95% of patients"

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Anterior Chamber Defects Abnormal anterior chamber morphology HP:0000593

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Rarely occurring features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis recti."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

High Myopia HP:0011003

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents high myopia in the molecularly confirmed Iranian COLEC10 case.

Genitourinary 7

Vesicorenal Anomalies Abnormality of the urinary system HP:0000079

Coarse binding: variable spectrum

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies occur in 20 to 30% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Genital Anomalies Abnormality of the genital system HP:0000078

Coarse binding: variable spectrum

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies occur in 20 to 30% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Horseshoe Kidney HP:0000085

Show evidence (1 reference)

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Here we describe a 4-years-old patient with typical 3MC phenotypic characteristics, including blepharophimosis, telecanthus, high arched eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney."

Documents horseshoe kidney, giving a specific instance of the vesicorenal anomaly category.

Hypoplastic Labia Majora HP:0000059

Show evidence (1 reference)

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes equinovarus bilaterally."

Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional contributors to the contractures were not excluded.

Ectopic Kidney HP:0000086

Show evidence (1 reference)

PMID:32441374 SUPPORT PRIMARY RESULT Human Clinical

"Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly."

Documents the prenatally detectable findings, establishing congenital onset.

Micropenis HP:0000054

Show evidence (1 reference)

PMID:28301481 SUPPORT PRIMARY RESULT Human Clinical

"Micropenis N N N Y N N N"

The Table 3 row marks MC27.1 as positive among seven described patients; this is an individual clinical observation.

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:28301481 SUPPORT PRIMARY RESULT Human Clinical

"Undesce nded testes N N N Y N N N"

The Table 3 row marks MC27.1 as positive among seven described patients; this is an individual clinical observation.

Head and Neck 12

Blepharophimosis HP:0000581

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"The main features are facial dysmorphic traits including hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70 to 95% of patients"

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Highly Arched Eyebrows HP:0002553

Show evidence (2 references)

PMID:36503917 SUPPORT BACKGROUND Human Clinical

"Patients with 3MC syndrome have a distinctive facial phenotype including hypertelorism, highly arched eyebrows and ptosis."

Names highly arched eyebrows as a component of the distinctive facial phenotype.

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"The main features are facial dysmorphic traits including hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70 to 95% of patients"

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Cleft Lip HP:0410030

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Cleft lip and palate, post-natal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Cleft Palate HP:0000175

Show evidence (1 reference)

PMID:36503917 SUPPORT BACKGROUND Human Clinical

"A significant number of patients have bilateral cleft lip and palate and they often exhibit genitourinary and skeletal anomalies."

Documents cleft palate among affected patients; bilateral in this phrase does not define palatal laterality or a numerical frequency.

Craniosynostosis HP:0001363

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies occur in 20 to 30% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Epicanthus Inversus HP:0000537

Show evidence (1 reference)

PMID:41703727 SUPPORT PRIMARY RESULT Human Clinical

"All patients exhibited characteristic craniofacial features, including hypertelorism, blepharoptosis, highly arched eyebrows, and epicanthus inversus."

Reports epicanthus inversus in all seven patients of the cohort.

Downslanted Palpebral Fissures HP:0000494

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents downslanting in a molecularly confirmed COLEC10 case.

Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents dolichocephaly in the molecularly confirmed Iranian COLEC10 case.

Telecanthus HP:0000506

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents telecanthus in the molecularly confirmed Iranian COLEC10 case.

Long Face HP:0000276

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents long face in the molecularly confirmed Iranian COLEC10 case.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis, dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and..."

Directly documents micrognathia in the molecularly confirmed Iranian COLEC10 case.

Brachycephaly HP:0000248

Show evidence (1 reference)

PMID:32441374 SUPPORT PRIMARY RESULT Human Clinical

"Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly."

Documents the prenatally detectable findings, establishing congenital onset.

Integument 1

Sacral Dimple HP:0000960

Show evidence (1 reference)

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Here we describe a 4-years-old patient with typical 3MC phenotypic characteristics, including blepharophimosis, telecanthus, high arched eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney."

Documents sacral dimple in the COLEC10 Cys270Serfs*33 child.

Limbs 4

Radioulnar Synostosis HP:0002974

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies occur in 20 to 30% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Clinodactyly of the Fifth Finger Clinodactyly of the 5th finger HP:0004209

Show evidence (1 reference)

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Here we describe a 4-years-old patient with typical 3MC phenotypic characteristics, including blepharophimosis, telecanthus, high arched eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney."

Documents fifth finger clinodactyly in a molecularly confirmed COLEC10 patient.

Knee Flexion Contracture HP:0006380

Show evidence (1 reference)

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes equinovarus bilaterally."

Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional contributors to the contractures were not excluded.

Talipes Equinovarus HP:0001762

Show evidence (1 reference)

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes equinovarus bilaterally."

Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional contributors to the contractures were not excluded.

Musculoskeletal 2

Caudal Appendage HP:0002825

Show evidence (1 reference)

PMID:36503917 SUPPORT BACKGROUND Human Clinical

"A clinical clue to 3MC syndrome is the presence of a characteristic caudal appendage."

Explicitly identifies the caudal appendage as a diagnostic pointer.

Posterior Radial Head Subluxation Posterior subluxation of radial head HP:0005739

Show evidence (1 reference)

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"she also had limited right elbow extension about 10 degrees due to radial head subluxation in the right side posteriorly"

Direct case observation of a specific orthopedic lesion.

Nervous System 2

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Cleft lip and palate, post-natal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

Motor Developmental Delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:41703727 SUPPORT PRIMARY RESULT Human Clinical

"All patients showed neuromotor developmental delay."

Reports neuromotor developmental delay in all seven patients.

Growth 1

Postnatal Growth Deficiency Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Cleft lip and palate, post-natal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of patients."

The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and is not a contemporary feature-specific penetrance estimate.

🧬

Genetic Associations

3

MASP1

Gene: MASP1 hgnc:6901 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:21035106 SUPPORT PRIMARY RESULT Human Clinical

"In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the phenotype."

A cosegregating nonsense allele supports loss of function as the disease mechanism.

PMID:29407414 SUPPORT BACKGROUND Human Clinical

"In MASP1, either truncating mutations or missense variants in exon 12 encoding the C-terminal serine protease domain specific for isoform MASP-3 are causative."

The source distinguishes nonsense variants from missense variants in the MASP-3-specific exon; it does not place every nonsense variant in exon 12.

PMID:29407414 SUPPORT PRIMARY RESULT Human Clinical

"By trio exome sequencing we now identified a novel, homozygous 2kb deletion, partially affecting exon 12 in an adult female with the typical facial gestalt of 3MC syndrome and hearing loss, but without the main feature cleft lip/palate, and without intellectual disability, or short stature."

Documents an intragenic deletion allele class and, separately, marked variable expressivity - a patient with the facial gestalt but none of clefting, intellectual disability or short stature.

Variants (1)

Biallelic MASP1 loss-of-function alleles

Reported alleles include p.Gly687Arg and other missense changes in the MASP-3 protease domain, earlier nonsense variants such as p.Trp290Ter, and intragenic deletions partially affecting exon 12.

COLEC11

Gene: COLEC11 hgnc:17213 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:21258343 SUPPORT PRIMARY RESULT Human Clinical

"Each mutation segregated with the disease in every family."

Cosegregation across the COLEC11 families supports causality.

COLEC10

Gene: COLEC10 hgnc:2220 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:28301481 SUPPORT PRIMARY RESULT Human Clinical

"Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families."

Establishes COLEC10 as a 3MC disease gene.

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Segregation studies confirmed that both parents were carriers for the variant: interestingly they originate from the same area of Apulia in southern Italy."

Both parents carried the same variant and originated from the same region. This observation alone does not establish a founder allele.

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"We confirmed the homozygous state for this variant in the proband and aborted fetus, as well as the heterozygote state in the parents by Sanger sequencing."

The COLEC10 c.128_129delCA family demonstrates a homozygous genotype, complementing earlier compound heterozygous cases.

💊

Medical Actions

3

Orthopedic Correction of Joint Contracture

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

One child with COLEC11-related 3MC and bilateral fixed knee flexion contractures underwent sequential gradual correction using Taylor spatial frames, followed by casts and braces. Full knee extension was maintained for three months; foot deformities still required management. A single uncontrolled case does not establish superiority or general safety.

Show evidence (2 references)

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"In our reported patient, full extension of both knees was maintained for a total of three months using a cast and then a brace."

Reports the observed short-term result and maintenance measures after frame correction.

PMID:34589314 SUPPORT PRIMARY RESULT Human Clinical

"While the TSF technique restored full extension to both knees, the patient still has another deformity in both feet that requires further management."

The intervention corrected the knees but did not resolve the separate foot deformities.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Genetic counseling addresses autosomal recessive inheritance, family testing and reproductive options. Prenatal molecular testing is possible once the familial pathogenic variants are identified.

Show evidence (1 reference)

PMID:32441374 SUPPORT PRIMARY RESULT Human Clinical

"3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options."

States the recurrence risk and the reproductive consequence that make counselling actionable.

Surgery for Craniosynostosis

Action: cranial reconstructive surgery Ontology label: Reconstructive Surgery NCIT:C25351

Platform: Surgery

Cranioplasty was performed at five and eighteen months in the reported child with COLEC10-related 3MC and congenital craniosynostosis. This is documented care in one case; no comparative treatment outcome was reported.

Show evidence (1 reference)

PMID:34636477 SUPPORT PRIMARY RESULT Human Clinical

"Clinical examination, presented craniosynostosis at birth, therefore, first cranioplasty was performed at 5 months old and second one at 18 months old."

Documents cranial surgery in a molecularly confirmed patient without establishing a syndrome-specific surgical protocol.

🔬

Biochemical Markers

1

Predominant pro-factor D with residual mature factor D (Predominant pro-factor D with detectable mature factor D)

Context: MASP1/MASP-3 deficiency

Show evidence (1 reference)

PMID:28794230 SUPPORT PRIMARY RESULT Human Clinical

"although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD"

Patient samples demonstrate incomplete maturation. Residual mature factor D does not by itself establish normal alternative-pathway activity or absence of clinical infection risk.

🔬

Diagnosis

1

Molecular diagnosis by sequencing of MASP1, COLEC11 and COLEC10

Known-gene molecular confirmation identifies biallelic pathogenic variants in MASP1, COLEC11 or COLEC10, interpreted with the clinical phenotype. Confirm gene coverage and deletion detection when choosing or interpreting a sequencing assay: a 2021 case used a clinical exome panel that omitted COLEC10, and a MASP1 intragenic deletion in another case required careful visual review of exome data. These are documented historical assay limitations, not statements that all current panels have the same gaps. The likely Ashkenazi Jewish COLEC10 founder allele is relevant to variant interpretation, but a negative result for one allele does not exclude 3MC.

Show evidence (4 references)

PMID:35943032 SUPPORT PRIMARY RESULT Human Clinical

"3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate."

States the clinical trigger for pursuing a molecular diagnosis. Graded against the "when to suspect" half of this entry only; the confirmatory sequencing claim is evidenced separately below.

PMID:34740859 SUPPORT PRIMARY RESULT Human Clinical

"Initial genetic analysis was based on clinical exome sequencing, where only MASP1 and COLEC11 genes are present, without evidence of pathogenic variants."

Documents a false-negative caused by a clinical exome panel that omits COLEC10, which is why panel gene content has to be checked before a negative result is accepted.

PMID:29407414 SUPPORT PRIMARY RESULT Human Clinical

"As the homozygous deletion in our patient was only found by thorough and visual evaluation of the whole exome sequencing data, such deletions might escape detection in some routine diagnostic workflows and might explain a few of the so far molecularly unconfirmed cases of 3MC syndrome."

Documents the second false-negative route, intragenic deletions missed by routine variant-calling, and connects it to unsolved cases.

+ 1 more reference

📈

Progression

1

Congenital presentation and variable later development

Structural anomalies can be recognized prenatally or at birth. Developmental impairment is variable, and survival into adulthood is documented, including an adult without intellectual disability or short stature. The available reports do not establish that every manifestation remains static over life.

Show evidence (3 references)

PMID:32441374 SUPPORT PRIMARY RESULT Human Clinical

"Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly."

Documents the prenatally detectable findings, establishing congenital onset.

PMID:29407414 SUPPORT PRIMARY RESULT Human Clinical

"We therefore expand the MASP1 associated mutational and clinical spectrum and describe the development of her clinical presentation over a period of 21 years."

A 21-year follow-up in an adult patient supports survival to adulthood and a non-lethal course.

PMID:29407414 SUPPORT PRIMARY RESULT Human Clinical

"By trio exome sequencing we now identified a novel, homozygous 2kb deletion, partially affecting exon 12 in an adult female with the typical facial gestalt of 3MC syndrome and hearing loss, but without the main feature cleft lip/palate, and without intellectual disability, or short stature."

Documents an intragenic deletion allele class and, separately, marked variable expressivity - a patient with the facial gestalt but none of clefting, intellectual disability or short stature.

📊

Prevalence

2

Worldwide

Cases In Literature

The 2011 report summarized 32 patients from 20 families known at that time. This dated literature count is not a population prevalence estimate.

Show evidence (1 reference)

PMID:21258343 SUPPORT REVIEW SYNTHESIS Human Clinical

"Thirty two patients from 20 families have been described so far"

Historical case count only; ascertainment and the population denominator are unknown.

Ashkenazi Jewish

Carrier Frequency 1010.0 per 100,000 >1 in 1,000 (carriers)

Variant-specific carrier frequency, not disease prevalence: 400/39,750 individuals of Ashkenazi Jewish descent in a larger screened cohort of 52,278 individuals of Jewish descent carried the likely founder COLEC10 c.311G>T (p.Gly104Val) allele.

Show evidence (1 reference)

PMID:35943032 SUPPORT PRIMARY RESULT Human Clinical

"We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400..."

The COLEC10 p.Gly104Val founder variant was observed in nine affected individuals from five Ashkenazi Jewish families. Screening found 400 carriers among 39,750 Ashkenazi Jewish individuals (1.01%); this is carrier frequency, not affected-person prevalence.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from 3MC Syndrome:

Branchio-oto-renal spectrum

Overlapping Features Branchiootorenal spectrum disorder can overlap through hearing loss and urinary malformations. Its branchial cleft and ear findings, autosomal dominant inheritance and EYA1/SIX1 molecular diagnosis help distinguish it from 3MC.

Show evidence (3 references)

PMID:20301554 SUPPORT REVIEW SYNTHESIS Human Clinical

"Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment."

Describes the overlapping and distinguishing phenotype of this differential, not 3MC.

PMID:20301554 SUPPORT REVIEW SYNTHESIS Human Clinical

"The molecular diagnosis of BORSD is established in a proband with suggestive findings and a heterozygous pathogenic variant in either EYA1 or SIX1 identified by molecular genetic testing."

Identifies the genes of this alternative diagnosis.

PMID:20301554 SUPPORT REVIEW SYNTHESIS Human Clinical

"BORSD is inherited in an autosomal dominant manner."

Contrasts the inheritance pattern with autosomal recessive 3MC.

Blepharophimosis-ptosis-epicanthus inversus syndrome

Overlapping Features FOXL2-related blepharophimosis, ptosis and epicanthus inversus syndrome overlaps strongly in eyelid morphology. Its almost always autosomal dominant inheritance and molecular cause distinguish it from 3MC; primary ovarian insufficiency can occur in BPES type I.

Show evidence (3 references)

PMID:20301614 SUPPORT REVIEW SYNTHESIS Human Clinical

"BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes only the four major features."

Describes BPES subtype context, without asserting that all other congenital anomalies are categorically absent.

PMID:20301614 SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of BPES is established in a proband with suggestive findings and a heterozygous pathogenic variant in FOXL2 or its regulatory domain identified by molecular genetic testing."

Supports FOXL2 as the alternative molecular diagnosis.

PMID:20301614 SUPPORT REVIEW SYNTHESIS Human Clinical

"BPES is almost always inherited in an autosomal dominant manner."

Provides the inheritance distinction.

🧫

Experimental Models

2

Mouse Colec11-deficient bone-marrow-derived osteoclast cultures PRIMARY_CELL_CULTURE

Bone-marrow-derived cells from wild-type, Colec11 single-knockout, Colec11/C3 double-knockout and Colec11/Cfb double-knockout mice were differentiated using M-CSF and RANKL. Recombinant human CL-11 (0.9 micrograms/mL) with calcium was supplied during double-knockout rescue experiments.

Organism

mouse NCBITaxon:10090

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis partially recapitulates fidelity: moderate The experimental system distinguishes modest single-knockout effects from pronounced combined-knockout effects and tests recombinant-protein rescue directly.

Limitations: This is ex-vivo differentiation. TRAP-positive multinucleated-cell area and nuclei per osteoclast are differentiation readouts; neither direct bone-resorption function nor prevention of in-vivo vertebral pathology was demonstrated by these assays. Figure 6 includes few independent donor animals for double knockouts despite multiple image measurements.

Readouts

TRAP-positive multinucleated osteoclast formation

Direction: DECREASED

Interpretation: Combined-knockout cultures produce fewer/smaller differentiated osteoclasts than wild-type cultures.

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells"

The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.

Osteoclast formation after recombinant CL-11 supplementation

Direction: RESTORED

Interpretation: Rescue is partial and limited to the cultured-cell phenotype; it is not an in-vivo skeletal rescue.

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"This treatment partially restored CL-11 binding and significantly increased the presence of multinucleated giant cell OCLs"

Recombinant CL-11 was added to Colec11/C3 and Colec11/Cfb double-knockout bone-marrow cultures; this is an ex-vivo rescue, not treatment of living animals.

Show evidence (3 references)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells"

The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.

+ 2 more references

Human CRISPR COLEC11-knockout KOLF2 iPSC-derived osteoclasts IPSC_DERIVED_MODEL

Healthy-donor KOLF2 iPSCs and paired CRISPR-edited COLEC11-deficient clones were differentiated through myeloid precursors to osteoclasts with M-CSF and RANKL. Recombinant human CL-11 with calcium tested rescue; Mirococept tested pharmacologic complement-convertase inhibition.

Organism

human NCBITaxon:9606

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis recapitulates fidelity: moderate Isolated COLEC11 deletion markedly reduces osteoclast differentiation in this human cellular system, and recombinant CL-11 partly restores it. Mirococept separately inhibits C3/C5 convertases and reduces osteoclast formation.

Limitations: Engineered healthy-donor cells are not 3MC patient-derived cells. Mirococept treatment is distinct from genetic deletion of C3 or another complement component; these interventions do not prove an obligatory linear C3-to-MAC route. Three independent differentiation experiments were reported, without a patient clinical or in-vivo bone endpoint.

Readouts

TRAP-positive multinucleated osteoclast area after COLEC11 deletion

Direction: DECREASED

Interpretation: Deletion reduces differentiation relative to parental wild-type cells.

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11."

Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.

Osteoclast formation after recombinant CL-11 supplementation

Direction: RESTORED

Interpretation: The cellular deficit is partially rescued; full normalization or clinical benefit is not established.

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11."

Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.

Osteoclast formation during Mirococept treatment

Direction: DECREASED

Interpretation: Complement-convertase inhibition supports a role for complement in normal differentiation independently of the engineered COLEC11 deletion.

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"In addition, treatment with Mirococept—a truncated complement receptor-1–based inhibitor of C3 and C5 convertases (23)—significantly reduced OCL formation, demonstrating that normal human OCL differentiation is complement-dependent."

Pharmacologic C3/C5 convertase inhibition supports complement involvement; it is not a C3 gene-deletion experiment or proof that a specific linear complement sequence is necessary.

Show evidence (2 references)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11."

Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.

+ 1 more reference

🐁

Animal Models

5

colec11 zebrafish morphant

Morpholino knockdown of colec11 in zebrafish embryos, rescued by co-injection of full-length COLEC11 mRNA.

Species

Zebrafish

Genotype

colec11 antisense morpholino knockdown (ATG and splice-site)

Publication

PMID:21258343

Pathograph links

Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis recapitulates fidelity: moderate Knockdown reproduces severe craniofacial cartilage malformation, the tissue-level phenotype of the human syndrome.

Limitations: Morpholino knockdown is transient and dose-dependent rather than a germline null, and zebrafish craniofacial cartilage does not map one-to-one onto the human facial skeleton. The report notes high mortality at higher doses, requiring lower doses for cartilage staining.

Readouts

Alcian blue-stained craniofacial cartilage morphology

Direction: ALTERED

Interpretation: Reduced mandibular length and malformed anterior neurocranium, the structural correlate of the human craniofacial phenotype.

Show evidence (1 reference)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"Striking differences in the craniofacial skeleton were observed compared with uninjected/standard morpholino injected embryos, such as reduced mandibular length (e.g. shortened Meckel and palatoquadrate cartilages), malformation of the anterior neurocranium with shortening of the trabeculae and..."

Reports the specific craniofacial cartilage measurements behind this readout.

Show evidence (1 reference)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities."

Supports treating the morphant as informative for the craniofacial morphogenesis node.

Impaired Neural Crest Cell Guidance recapitulates fidelity: moderate The same colec11 perturbation alters neural crest streaming and location before craniofacial cartilage is assessed.

Limitations: Transient, dose-sensitive morpholino knockdown is not a patient-specific germline allele, and migration does not alone establish the route to each human feature.

Show evidence (2 references)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11 morphants and obviously truncated in the masp1 morphants"

Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation does not isolate MASP-3 from other gene products.

+ 1 more reference

masp1 zebrafish morphant

masp1 knockdown disrupts neural crest streaming and craniofacial cartilage. Combined subthreshold colec11/masp1 knockdown produced severe craniofacial abnormalities in 16/22 embryos.

Species

Zebrafish

Genotype

masp1 antisense morpholino knockdown

Publication

PMID:21258343

Pathograph links

Impaired Neural Crest Cell Guidance recapitulates fidelity: moderate The perturbation supports a role for the masp1 locus in neural crest guidance.

Limitations: The perturbation does not distinguish MASP-3 from other masp1 products and does not identify the proteolytic substrate linking the gene to cell migration.

Show evidence (2 references)

PMID:21258343 SUPPORT PRIMARY RESULT Model Organism

"At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11 morphants and obviously truncated in the masp1 morphants"

Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation does not isolate MASP-3 from other gene products.

+ 1 more reference

Masp1/3 knockout mouse

Mouse lacking both MASP-1 and MASP-3, used to establish the maturase role of MASP-3 in pro-factor D conversion.

Species

Mouse

Genotype

Masp1/3-/-

Publication

PMID:28794230

Pathograph links

Impaired Pro-Factor D Maturation recapitulates fidelity: moderate Reproduces the failure of pro-factor D conversion seen in patient serum.

Limitations: The knockout removes both MASP-1 and MASP-3. Some human alleles are MASP-3-selective whereas others affect shared sequence. The model supports the biochemical node; it does not establish the craniofacial mechanism.

Show evidence (1 reference)

PMID:28794230 SUPPORT BACKGROUND Model Organism

"This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation."

The abstract summarizes prior knockout findings; the separate experimental statement includes patient sera and knockout mice in tests of factor D conversion.

Colec11 knockout mouse

Single-gene deletion produces only a low incidence of overt spinal curvature (1/88 mice in Table 1); bone-marrow cultures nevertheless show modest reductions in osteoclast number and size.

Species

Mouse

Genotype

Colec11-/- (single knockout)

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis partially recapitulates fidelity: low The cellular differentiation defect is mild after isolated Colec11 deletion in mouse cells. This model does not reproduce the high frequency of overt postnatal spinal disease observed with additional complement-gene deletion.

Limitations: The source assesses different endpoints in vivo and ex vivo. Low gross spinal-phenotype incidence does not establish normal osteoclast differentiation, nor does it establish absence of skeletal consequences of human COLEC11 deficiency.

Show evidence (2 references)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size"

Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.

+ 1 more reference

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT Model Organism

"By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)"

The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.

Colec11 and complement-component double-knockout mice

Combined gene deletion is associated with postnatal vertebral bone loss and kyphosis/scoliosis in 23–28% of mice by 12 weeks. Table 1 reports 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 animals, compared with 1/88 Colec11 single knockouts and 0/101 wild-type controls.

Species

Mouse

Genotype

Colec11-/-;C3-/-, Colec11-/-;Cfb-/-, or Colec11-/-;Masp-2-/-

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis partially recapitulates fidelity: low Colec11/C3 and Colec11/Cfb bone-marrow cultures show marked impairment of osteoclast differentiation and partial rescue with recombinant CL-11. The living double-knockout animals provide an associated bone-maintenance phenotype, rather than proof that the measured osteoclast defect causes their bone loss.

Limitations: Additional complement-gene deletion is not the usual human 3MC genotype. Only overtly affected double knockouts underwent CT or histology; phenotype incidence may therefore underestimate subclinical lesions. Detailed lesions were concentrated in vertebrae, with no detected skull-calvarial abnormality or significant femur-length difference. Colec11/C3 embryos lacked overt morphological abnormalities by E18.5. Results do not establish a cause of human developmental synostoses or craniofacial malformations. The reported ex-vivo differentiation/rescue experiments specifically tested Colec11/C3 and Colec11/Cfb, not all three double-knockout genotypes.

Show evidence (5 references)

PMID:41774788 SUPPORT PRIMARY RESULT In Vitro

"In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells"

The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.

+ 4 more references

Show evidence (1 reference)

PMID:41774788 SUPPORT PRIMARY RESULT Model Organism

"By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)"

The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.

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name: 3MC Syndrome
creation_date: "2026-08-29T00:00:00Z"
description: >-
  3MC syndrome is a rare autosomal recessive developmental disorder encompassing the historically named
  Mingarelli, Malpuech, Michels and Carnevale syndromes. Biallelic pathogenic variants in MASP1, COLEC11
  or COLEC10 disrupt MASP-3 or the proteins CL-K1 and CL-L1. Characteristic findings include hypertelorism,
  blepharophimosis, ptosis and highly arched eyebrows, with variable cleft lip or palate, hearing loss,
  growth deficiency, developmental or cognitive impairment, and skeletal, genital or urinary malformations.
  A caudal appendage can be a diagnostic clue. Experimental evidence implicates disturbed neural crest
  guidance in craniofacial development, but the intervening signals and the role of complement activation
  remain incompletely resolved. MASP-3 deficiency also impairs pro-factor D maturation, with residual
  mature factor D detected in patients. Recent osteoclast experiments identify a separate candidate role
  in bone maintenance whose contribution to human 3MC skeletal disease is not established.
category: Mendelian
parents:
- hereditary disease
synonyms:
- 3MC syndrome
- Malpuech-Michels-Mingarelli-Carnevale syndrome
- Carnevale syndrome
- Malpuech facial clefting syndrome
- Michels syndrome
- Mingarelli syndrome
- oculo-skeletal-abdominal syndrome
disease_term:
  preferred_term: 3MC syndrome
  term:
    id: MONDO:0017398
    label: 3MC syndrome
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All three genetic forms of 3MC syndrome are inherited in an autosomal
    recessive manner. Affected individuals carry biallelic (homozygous or
    compound heterozygous) variants, and reported pedigrees are frequently
    consanguineous.
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These rare autosomal recessive disorders exhibit a spectrum of
      developmental features, including characteristic facial dysmorphism, cleft
      lip and/or palate, craniosynostosis, learning disability and genital, limb
      and vesicorenal anomalies.
    explanation: >-
      States the autosomal recessive inheritance of the four constituent
      syndromes now unified as 3MC syndrome.
    quote_role: BACKGROUND
has_subtypes:
- name: 3MC1
  display_name: 3MC syndrome 1 (MASP1/MASP-3)
  description: >-
    Caused by biallelic MASP1 variants that impair MASP-3. Missense changes and deletions can affect the
    MASP-3-specific serine protease domain encoded by exon 12; earlier truncating variants can affect
    sequence shared with other MASP1 products. Pro-factor D maturation is additionally impaired.
  subtype_term:
    preferred_term: 3MC syndrome 1
    term:
      id: MONDO:0009770
      label: 3MC syndrome 1
  genes:
  - preferred_term: MASP1
    term:
      id: hgnc:6901
      label: MASP1
  evidence:
  - reference: PMID:21035106
    reference_title: MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one family, whole exome sequencing revealed a missense mutation, MASP1
      c.2059G>A (p.G687R), that cosegregated with the phenotype.
    explanation: >-
      Establishes MASP1 as a 3MC syndrome disease gene through cosegregation in
      a consanguineous family.
    quote_role: PRIMARY_RESULT
- name: 3MC2
  display_name: 3MC syndrome 2 (COLEC11/CL-K1)
  description: >-
    Caused by biallelic COLEC11 variants affecting CL-K1. Tested carbohydrate-recognition-domain
    missense variants impair secretion; truncating variants and multi-exon deletions are also reported.
  subtype_term:
    preferred_term: 3MC syndrome 2
    term:
      id: MONDO:0009927
      label: 3MC syndrome 2
  genes:
  - preferred_term: COLEC11
    term:
      id: hgnc:17213
      label: COLEC11
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we studied 11 families with 3MC syndrome and identified two mutated
      genes, COLEC11 and MASP1
    explanation: >-
      Identifies COLEC11 alongside MASP1 as one of the two originally reported
      3MC syndrome genes.
    quote_role: PRIMARY_RESULT
- name: 3MC3
  display_name: 3MC syndrome 3 (COLEC10/CL-L1)
  description: >-
    Caused by biallelic COLEC10 variants affecting CL-L1. Both homozygous and compound
    heterozygous genotypes are reported. The c.311G>T (p.Gly104Val) allele is a likely founder variant
    in the Ashkenazi Jewish population, with a reported carrier frequency near 1 in 99.
  subtype_term:
    preferred_term: 3MC syndrome 3
    term:
      id: MONDO:0009554
      label: 3MC syndrome 3
  genes:
  - preferred_term: COLEC10
    term:
      id: hgnc:2220
      label: COLEC10
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we define a new gene, COLEC10, also mutated in 3MC families and
      present novel mutations in COLEC11 and MASP1/3 genes in a further five
      families.
    explanation: >-
      Establishes COLEC10 as the third 3MC syndrome disease gene.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Impaired CL-K1 Calcium Binding
  biological_scale: MOLECULAR
  description: >-
    Three tested COLEC11 carbohydrate-recognition-domain variants (Ser169Pro, Gly204Ser and Ser217 deletion)
    abolish calcium binding in recombinant fragments. The fragments can refold and oligomerize in vitro,
    but lack calcium-dependent stabilization.
  genes:
  - preferred_term: COLEC11
    term:
      id: hgnc:17213
      label: COLEC11
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  evidence:
  - reference: PMID:25912189
    reference_title: Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments
      containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition
      domains of CL-K1.
    explanation: >-
      Recombinant fragments carrying Ser169Pro, Gly204Ser or Ser217 deletion lose calcium binding. Refolding
      in vitro does not exclude a biosynthetic folding defect in cells.
  downstream:
  - target: Reduced Extracellular CL-K1 Availability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure of calcium binding is proposed to compromise CL-K1 during biosynthesis and prevent secretion.
      Cellular quality-control recognition and degradation are plausible intermediates that were not directly
      demonstrated.
    evidence:
    - reference: PMID:25912189
      reference_title: Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        We propose that failure to bind Ca(2+) during biosynthesis leads to structural defects that prevent
        secretion of CL-K1, thus providing a molecular explanation of the genetic disorder.
      explanation: >-
        The authors propose this biosynthetic mechanism from calcium-binding and secretion experiments;
        the intervening quality-control steps remain unproven.
      directness: INDIRECT
  - target: Impaired CL-K1 Carbohydrate Binding
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Calcium normally stabilizes ligand-binding loops in the carbohydrate-recognition domain. The tested
      variants lose calcium binding and carbohydrate recognition; loop destabilization links these molecular
      effects.
    evidence:
    - reference: PMID:25912189
      reference_title: Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        failure to bind Ca 2+ destabilises the CRDs and exposes flexible loop regions.
      explanation: >-
        The authors infer the connection from structural, calcium-binding and ligand-binding measurements;
        the quoted wording retains the proposed nature of the explanation.
- name: Impaired CL-K1 Carbohydrate Binding
  biological_scale: MOLECULAR
  description: >-
    Recombinant CL-K1 fragments carrying the three tested 3MC-associated carbohydrate-recognition-domain
    variants fail to bind yeast invertase or the dextran chromatography matrix. These ligand-binding assays
    demonstrate functional loss even though the fragments assemble into trimers in vitro.
  molecular_functions:
  - preferred_term: carbohydrate binding
    term:
      id: GO:0030246
      label: carbohydrate binding
    modifier: DECREASED
  evidence:
  - reference: PMID:25912189
    reference_title: Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Both full-length CL-K1 and the wild-type fragment bound to the invertase, but the three variant
      fragments did not bind (Figure 6C).
    explanation: >-
      The assay directly measures loss of carbohydrate recognition in the recombinant variants. The corresponding
      developmental ligand has not been established.
- name: Reduced Extracellular CL-K1 Availability
  biological_scale: MOLECULAR
  description: >-
    Biallelic COLEC11 loss-of-function variants reduce functional extracellular CL-K1. Three tested carbohydrate-recognition-domain
    variants block secretion in mammalian cells, and Gly204Ser CL-K1 was undetectable in serum from two
    patients. This node does not assume that all COLEC11 variants share the same biosynthetic defect.
  genes:
  - preferred_term: COLEC11
    term:
      id: hgnc:17213
      label: COLEC11
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline COLEC11 variants include missense substitutions, truncating alleles and a multi-exon
      deletion.
  evidence:
  - reference: PMID:25912189
    reference_title: Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian
      cells, accounting for the protein deficiency observed in patients.
    explanation: >-
      The three tested COLEC11 carbohydrate-recognition-domain variants block secretion in the mammalian
      expression assay.
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Using western blotting, we failed to detect any secreted CL-K1 in the serum of two patients (Gly204Ser),
      in contrast to control samples
    explanation: >-
      Two affected individuals lacked detectable serum CL-K1. Intracellular retention was suggested, not
      directly measured in these patients.
  downstream:
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      CL-K1 depletion disrupts neural crest distribution in zebrafish, and recombinant protein attracts
      neural crest cells in explants. The responding receptors and intervening signaling steps are unresolved.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the
        colec11 morphants and obviously truncated in the masp1 morphants
      explanation: >-
        Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
        does not isolate MASP-3 from other gene products.
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The explants were incubated for 24 hours whereupon streams of NCCs (labelled with HNK1; Suppl
        Figure 11) were observed to preferentially migrate into protein-containing agarose spots but not
        into controls.
      explanation: >-
        Isolated quail neural-tube explants provide direct neural crest migration evidence in vitro.
  - target: Impaired Complement-Dependent Osteoclastogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Collectin-11 loss impairs osteoclast differentiation in experimental cells, with species- and complement-background-dependent effect sizes. Recombinant CL-11 partially rescues differentiation; the intervening signaling steps and their relevance to skeletal disease in 3MC patients remain incompletely established.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11.
      explanation: Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size
      explanation: Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: This treatment partially restored CL-11 binding and significantly increased the presence of multinucleated giant cell OCLs
      explanation: Recombinant CL-11 was added to Colec11/C3 and Colec11/Cfb double-knockout bone-marrow cultures; this is an ex-vivo rescue, not treatment of living animals.
- name: Reduced Extracellular CL-L1 Availability
  biological_scale: MOLECULAR
  description: >-
    Some biallelic COLEC10 variants impair CL-L1 expression or secretion. Arg9Ter and Gly77Glufs*66 constructs
    yield no detectable protein, whereas Cys176Trp accumulates intracellularly with severely reduced secretion.
    This route is distinct from the Cys270Serfs*33 allele, which has normal measured plasma levels but
    impaired chemoattractant activity.
  genes:
  - preferred_term: COLEC10
    term:
      id: hgnc:2220
      label: COLEC10
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic COLEC10 variants affecting protein expression or secretion; compound heterozygous genotypes
      occur.
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G
      p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity.
    explanation: >-
      The tested truncating alleles eliminate detectable expressed protein; Cys176Trp permits intracellular
      expression but markedly reduces secretion.
  downstream:
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced CL-L1 availability is proposed to disrupt craniofacial cell guidance. CL-L1 attracts HeLa
      cells and is expressed in developing palatal tissue, but a CL-L1-specific neural crest receptor
      or signaling route was not established.
    evidence:
    - reference: PMID:28301481
      reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        We propose here that the role of CL-L1 and CL-K1 lies in regulating cell migration via cell attraction
        in 3MC syndrome.
      explanation: >-
        The extension from HeLa-cell chemoattraction to neural crest guidance is the authors' mechanistic
        proposal.
      directness: INDIRECT
- name: Impaired CL-L1 Chemoattractant Activity
  biological_scale: MOLECULAR
  description: >-
    The homozygous COLEC10 c.807_810delCTGT (p.Cys270Serfs*33) variant extends the protein and removes
    a conserved cysteine. Plasma CL-L1 levels were normal in the reported family, while mutant protein
    induced less HeLa-cell migration than wild type. Loss of extracellular function can therefore occur
    without reduced measured abundance.
  genes:
  - preferred_term: COLEC10
    term:
      id: hgnc:2220
      label: COLEC10
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous germline c.807_810delCTGT (p.Cys270Serfs*33), with reduced function in a cell-migration
      assay.
  evidence:
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Plasma levels of CL-L1 in the patient and her parents were within normal range, suggesting that
      this variant does not modify transcription or secretion.
    explanation: >-
      Measured plasma abundance was normal in the Cys270Serfs*33 family; abundance alone does not demonstrate
      every step of transcription or secretion.
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, the variant affects the chemo-attractive feature of CL-L1, as HeLa cells migrate significantly
      less in response to the mutant protein compared to the wild-type one.
    explanation: >-
      The mutant protein has reduced chemoattractant activity in HeLa cells; the assay does not directly
      test neural crest cells.
  downstream:
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced CL-L1 chemoattraction provides a candidate explanation for the developmental phenotype of
      the Cys270Serfs*33 patient. Transfer from the HeLa assay to neural crest migration remains inferential.
    evidence:
    - reference: PMID:34740859
      reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        However, the variant affects the chemo-attractive feature of CL-L1, as HeLa cells migrate significantly
        less in response to the mutant protein compared to the wild-type one.
      explanation: >-
        The mutant protein has reduced chemoattractant activity in HeLa cells; the assay does not directly
        test neural crest cells.
- name: Loss of MASP-3 Serine Protease Activity
  biological_scale: MOLECULAR
  description: >-
    Biallelic MASP1 variants impair MASP-3 serine protease activity. Tested 3MC-associated MASP-3 mutants
    were enzymatically inactive. Variants confined to the exon-12 protease domain can selectively affect
    MASP-3, whereas earlier truncating variants may also affect MASP-1 or MAp44; selective MASP-3 deficiency
    is not assumed for every genotype.
  genes:
  - preferred_term: MASP1
    term:
      id: hgnc:6901
      label: MASP1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline MASP1 variants include missense changes in the MASP-3 protease domain, earlier
      nonsense alleles in shared sequence and intragenic deletions.
  molecular_functions:
  - preferred_term: MASP-3 serine endopeptidase activity
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:28794230
    reference_title: Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We characterized the naturally occurring 3MC-associated MASP-3 mutants and
      found that they all yielded enzymatically inactive proteins.
    explanation: >-
      Directly demonstrates that the 3MC-associated MASP1 alleles abolish MASP-3
      catalytic activity.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      masp1 knockdown alters neural crest migration in zebrafish, supporting a role for this locus in
      guidance. The developmental substrate of MASP-3 and the contribution of the other isoforms remain
      unresolved.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the
        colec11 morphants and obviously truncated in the masp1 morphants
      explanation: >-
        Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
        does not isolate MASP-3 from other gene products.
  - target: Impaired Pro-Factor D Maturation
    causal_link_type: DIRECT
    description: >-
      MASP-3 is the maturase that converts pro-factor D to mature factor D, so
      loss of its catalytic activity directly compromises this conversion.
    evidence:
    - reference: PMID:28794230
      reference_title: Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using MASP-3-depleted human serum, serum from 3MC patients, and
        Masp1/3-/- mice, we found that lack of enzymatically active MASP-3, or
        complete MASP-3 deficiency, compromises the conversion of pro-FD to FD.
      explanation: >-
        Establishes the direct enzymatic dependence of factor D maturation on
        MASP-3 activity.
      quote_role: PRIMARY_RESULT
- name: Impaired Neural Crest Cell Guidance
  biological_scale: CELLULAR
  description: >-
    Experimental colec11 or masp1 knockdown causes ectopic neural crest distribution and disrupted migratory
    streams in zebrafish. Recombinant CL-K1 also attracts quail neural crest cells in explants. These
    observations support a guidance defect as a candidate cause of craniofacial malformation in 3MC; they
    do not establish that every affected organ derives from neural crest.
  cell_types:
  - preferred_term: migratory neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the colec11
      morphants and obviously truncated in the masp1 morphants
    explanation: >-
      Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
      does not isolate MASP-3 from other gene products.
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf,
      ectopic NCC in the head, trunk and periphery
    explanation: >-
      Ectopic neural crest cells support dysregulated guidance rather than a uniform decrease in cell
      number.
  downstream:
  - target: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disorganized neural crest guidance is proposed to disturb subsequent craniofacial patterning and
      differentiation. The same zebrafish perturbations affect migration and cartilage, but do not isolate
      migration as the sole mediator.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the
        colec11 morphants and obviously truncated in the masp1 morphants
      explanation: >-
        Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
        does not isolate MASP-3 from other gene products.
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Striking differences in the craniofacial skeleton were observed compared with uninjected/standard
        morpholino injected embryos, such as reduced mandibular length (e.g. shortened Meckel and palatoquadrate
        cartilages), malformation of the anterior neurocranium with shortening of the trabeculae and the
        ethmoid plate, shortening and abnormal angulation of the ceratohyal cartilage
      explanation: >-
        Perturbed zebrafish CL-K1 expression causes craniofacial cartilage defects.
- name: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
  biological_scale: TISSUE
  description: >-
    Craniofacial cartilage and bone development is disrupted in zebrafish models, supporting a developmental
    explanation for the facial abnormalities and clefting of 3MC. Expression of CL-K1 and CL-L1 in murine palatal
    and craniofacial tissues supports biological plausibility, without proving a specific mechanism for
    each human malformation.
  biological_processes:
  - preferred_term: neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Striking differences in the craniofacial skeleton were observed compared with uninjected/standard
      morpholino injected embryos, such as reduced mandibular length (e.g. shortened Meckel and palatoquadrate
      cartilages), malformation of the anterior neurocranium with shortening of the trabeculae and the
      ethmoid plate, shortening and abnormal angulation of the ceratohyal cartilage
    explanation: >-
      Perturbed zebrafish CL-K1 expression causes craniofacial cartilage defects.
  downstream:
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main features are facial dysmorphic traits including hypertelorism,
        blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
        to 95% of patients
      explanation: >-
        The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical
        and is not a contemporary feature-specific penetrance estimate.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Blepharophimosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main features are facial dysmorphic traits including hypertelorism,
        blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
        to 95% of patients
      explanation: >-
        The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical
        and is not a contemporary feature-specific penetrance estimate.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:36503917
      reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with 3MC syndrome have a distinctive facial phenotype including
        hypertelorism, highly arched eyebrows and ptosis.
      explanation: >-
        Introductory clinical background identifies ptosis as part of the facial phenotype.
      quote_role: BACKGROUND
      directness: INDIRECT
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main features are facial dysmorphic traits including hypertelorism,
        blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
        to 95% of patients
      explanation: >-
        The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical
        and is not a contemporary feature-specific penetrance estimate.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Cleft Lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cleft lip and palate, post-natal growth deficiency, cognitive impairment,
        and hearing loss are also consistent findings, occurring in 40 to 68% of
        patients.
      explanation: >-
        The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical
        and is not a contemporary feature-specific penetrance estimate.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Cleft Palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:36503917
      reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A significant number of patients have bilateral cleft lip and palate and
        they often exhibit genitourinary and skeletal anomalies.
      explanation: >-
        Documents cleft palate among affected patients; bilateral in this phrase does not define palatal
        laterality or a numerical frequency.
      quote_role: BACKGROUND
      directness: INDIRECT
  - target: Craniosynostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies
        occur in 20 to 30% of patients.
      explanation: >-
        The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical
        and is not a contemporary feature-specific penetrance estimate.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted craniofacial development is a proposed route to this observed human feature. The exact
      developmental intermediates and gene-specific contributions have not been established.
    evidence:
    - reference: PMID:34636477
      reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
        dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
        of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
        palpebral fissure.
      explanation: >-
        Directly documents micrognathia in the molecularly confirmed COLEC10 case; the proposed neural-crest
        route is inferred.
      directness: INDIRECT
- name: Impaired Complement-Dependent Osteoclastogenesis
  biological_scale: CELLULAR
  description: Experimental loss of collectin-11 impairs osteoclast differentiation in mouse bone-marrow cultures and engineered healthy-donor human iPSC-derived cells. The effect is modest after isolated mouse Colec11 deletion and pronounced in Colec11/C3 or Colec11/Cfb double-knockout cultures; isolated human COLEC11 deletion already has a marked effect. Recombinant CL-11 partially rescues differentiation, and complement-convertase inhibition impairs differentiation in human cells. These results identify a candidate mechanism relevant to 3MC, without establishing osteoclast dysfunction as the cause of skeletal malformations in affected patients.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11.
    explanation: Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size
    explanation: Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells
    explanation: The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In addition, treatment with Mirococept—a truncated complement receptor-1–based inhibitor of C3 and C5 convertases (23)—significantly reduced OCL formation, demonstrating that normal human OCL differentiation is complement-dependent.
    explanation: Pharmacologic C3/C5 convertase inhibition supports complement involvement; it is not a C3 gene-deletion experiment or proof that a specific linear complement sequence is necessary.
  notes: Terminal-complement deposition accompanies the cellular phenotype, but colocalization does not by itself demonstrate mediation. Recombinant CL-11 partly restores MAC deposition even in C3-deficient cultures; the authors propose a C3-bypass route rather than establish obligatory C3 dependence or direct C5 cleavage. PMX53 inhibition of C5aR1 had no significant effect under the tested non-inflammatory culture conditions. Postnatal vertebral pathology in combined-knockout mice is associated with the cellular findings; it does not isolate impaired osteoclast differentiation as the mediator of bone loss, and it is not equivalent to the developmental craniofacial abnormalities of human 3MC.
- name: Impaired Pro-Factor D Maturation
  biological_scale: MOLECULAR
  description: >-
    MASP-3 deficiency compromises conversion of pro-factor D to mature factor D. Tested patient samples
    predominantly contain pro-factor D but retain detectable mature factor D, consistent with an additional
    maturation route. Resting-plasma inhibition experiments establish MASP-3 dependence under those assay
    conditions; serum coagulation and patient measurements need separate interpretation.
  biological_processes:
  - preferred_term: protein maturation
    term:
      id: GO:0051604
      label: protein maturation
    modifier: DECREASED
  evidence:
  - reference: PMID:28794230
    reference_title: Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      although 3MC patients predominantly contain pro-FD, they also contain
      detectable levels of mature FD
    explanation: >-
      Patient samples demonstrate incomplete maturation. Residual mature factor D does not by itself establish
      normal alternative-pathway activity or absence of clinical infection risk.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27535802
    reference_title: "MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For this study we evolved a specific MASP-3 inhibitor and unambiguously
      proved that activated MASP-3 is the exclusive pro-FD activator in resting
      blood, which demonstrates a fundamental link between the lectin and
      alternative pathways.
    explanation: >-
      Selective inhibitor experiments in resting human plasma establish the role of activated MASP-3 under
      the tested conditions. The paper distinguishes this from coagulated serum, where other proteases
      may contribute.
    quote_role: PRIMARY_RESULT
  notes: >-
    This is a biochemical consequence. No direct edge to the congenital craniofacial phenotype or to a
    clinical immunodeficiency is established by these experiments.
phenotypes:
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Increased interorbital distance, part of the highly characteristic periorbital gestalt of 3MC syndrome.
    The 2011 literature summary places these core periorbital traits collectively in a 70–95% range; this
    is not a separate estimate for each trait.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main features are facial dysmorphic traits including hypertelorism,
      blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
      to 95% of patients
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Blepharophimosis
  description: >-
    Horizontally short palpebral fissures. The 2011 literature summary places these core periorbital traits
    collectively in a 70–95% range; this is not a separate estimate for each trait.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main features are facial dysmorphic traits including hypertelorism,
      blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
      to 95% of patients
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Ptosis
  description: >-
    Drooping of the upper eyelid (blepharoptosis). The 2011 literature summary places these core periorbital
    traits collectively in a 70–95% range; this is not a separate estimate for each trait.
  phenotype_term:
    preferred_term: Blepharoptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:36503917
    reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with 3MC syndrome have a distinctive facial phenotype including
      hypertelorism, highly arched eyebrows and ptosis.
    explanation: >-
      Introductory clinical background identifies ptosis as part of the facial phenotype.
    quote_role: BACKGROUND
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main features are facial dysmorphic traits including hypertelorism,
      blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
      to 95% of patients
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Highly Arched Eyebrows
  description: >-
    Distinctive high arch of the eyebrows, part of the periorbital gestalt. The 2011 literature summary
    places these core periorbital traits collectively in a 70–95% range; this is not a separate estimate
    for each trait.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:36503917
    reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with 3MC syndrome have a distinctive facial phenotype including
      hypertelorism, highly arched eyebrows and ptosis.
    explanation: >-
      Names highly arched eyebrows as a component of the distinctive facial
      phenotype.
    quote_role: BACKGROUND
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main features are facial dysmorphic traits including hypertelorism,
      blepharophimosis, blepharoptosis, and highly arched eyebrows present in 70
      to 95% of patients
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Unilateral or bilateral cleft lip can occur, with or without palatal involvement.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and palate, post-natal growth deficiency, cognitive impairment,
      and hearing loss are also consistent findings, occurring in 40 to 68% of
      patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Cleft Palate
  description: >-
    Cleft palate may accompany cleft lip but is not obligatory. The 2026 selected series reported cleft
    lip and/or palate in six of seven individuals.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:36503917
    reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significant number of patients have bilateral cleft lip and palate and
      they often exhibit genitourinary and skeletal anomalies.
    explanation: >-
      Documents cleft palate among affected patients; bilateral in this phrase does not define palatal
      laterality or a numerical frequency.
    quote_role: BACKGROUND
- category: Growth
  name: Postnatal Growth Deficiency
  description: Postnatal growth restriction with short stature.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and palate, post-natal growth deficiency, cognitive impairment,
      and hearing loss are also consistent findings, occurring in 40 to 68% of
      patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Cognitive impairment is variable. It is absent in some molecularly confirmed individuals, including
    the adult MASP1-deletion case.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and palate, post-natal growth deficiency, cognitive impairment,
      and hearing loss are also consistent findings, occurring in 40 to 68% of
      patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing impairment is variable; mixed hearing loss was reported in the original MASP1 families. The
    clinical finding does not establish which developmental pathway caused each component.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:21035106
    reference_title: MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on three individuals from two consanguineous Turkish families
      with findings characteristic of these syndromes, including facial
      dysmorphism, periumbilical depression, mixed hearing loss, radioulnar
      synostosis, and coccygeal appendage.
    explanation: >-
      Documents mixed hearing loss in molecularly confirmed MASP1 patients.
    quote_role: PRIMARY_RESULT
- category: Skeletal
  name: Craniosynostosis
  description: Premature fusion of one or more cranial sutures.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies
      occur in 20 to 30% of patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Radioulnar Synostosis
  description: Bony fusion of the proximal radius and ulna, limiting forearm rotation.
  phenotype_term:
    preferred_term: Radioulnar synostosis
    term:
      id: HP:0002974
      label: Radioulnar synostosis
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies
      occur in 20 to 30% of patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Genitourinary
  name: Vesicorenal Anomalies
  description: >-
    Structural urinary-system anomalies are part of the reported spectrum. Specific reported findings
    include horseshoe kidney and an ectopic pelvic kidney; the generic term vesicorenal anomalies does
    not establish vesicoureteral reflux.
  phenotype_term:
    preferred_term: Urinary system anomalies
    term:
      id: HP:0000079
      label: Abnormality of the urinary system
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies
      occur in 20 to 30% of patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Caudal Appendage
  description: >-
    A coccygeal/caudal appendage. Uncommon, but a strongly suggestive clinical
    pointer to the diagnosis when present.
  phenotype_term:
    preferred_term: Caudal appendage
    term:
      id: HP:0002825
      label: Caudal appendage
  diagnostic: true
  evidence:
  - reference: PMID:36503917
    reference_title: "3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clinical clue to 3MC syndrome is the presence of a characteristic caudal
      appendage.
    explanation: >-
      Explicitly identifies the caudal appendage as a diagnostic pointer.
    quote_role: BACKGROUND
- category: Abdominal
  name: Periumbilical Depression
  description: >-
    A periumbilical abdominal-wall depression was reported in the original MASP1 families. The broader
    category of periumbilical anomalies occurred in six of seven patients in a 2026 series, but that aggregate
    is not a count of depression specifically.
  phenotype_term:
    preferred_term: Periumbilical depression
    term:
      id: HP:6000808
      label: Periumbilical depression
  evidence:
  - reference: PMID:41703727
    reference_title: 'Expansion of the 3MC Syndrome Spectrum: Novel COLEC10 Variants and a MASP1 Exon-Level Deletion.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and/or palate were present in six patients, caudal appendage in
      four, congenital heart disease in two, hearing loss in four, and
      periumbilical anomalies in six.
    explanation: >-
      Reports the broader category of periumbilical anomalies in a selected seven-patient cohort; this
      does not establish depression in six patients.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21035106
    reference_title: MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on three individuals from two consanguineous Turkish families
      with findings characteristic of these syndromes, including facial
      dysmorphism, periumbilical depression, mixed hearing loss, radioulnar
      synostosis, and coccygeal appendage.
    explanation: >-
      Independently documents periumbilical depression as a characteristic
      finding in molecularly confirmed patients.
    quote_role: PRIMARY_RESULT
- category: Abdominal
  name: Umbilical Hernia
  description: >-
    Umbilical hernia is reported within the abdominal-wall spectrum and is distinct from periumbilical
    depression and omphalocele.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely occurring features include anterior chamber defects, cardiac
      anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis
      recti.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Ophthalmologic
  name: Anterior Chamber Defects
  description: >-
    Abnormal anterior chamber morphology has been described in earlier reports; the general source wording
    does not define a specific dysgenesis subtype.
  phenotype_term:
    preferred_term: Abnormal anterior chamber morphology
    term:
      id: HP:0000593
      label: Abnormal anterior chamber morphology
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely occurring features include anterior chamber defects, cardiac
      anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis
      recti.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Epicanthus Inversus
  description: >-
    An epicanthal fold running upward from the lower lid. It occurred in all seven patients of the selected
    2026 series; that observation is not population-wide penetrance.
  phenotype_term:
    preferred_term: Epicanthus inversus
    term:
      id: HP:0000537
      label: Epicanthus inversus
  evidence:
  - reference: PMID:41703727
    reference_title: 'Expansion of the 3MC Syndrome Spectrum: Novel COLEC10 Variants and a MASP1 Exon-Level Deletion.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited characteristic craniofacial features, including
      hypertelorism, blepharoptosis, highly arched eyebrows, and epicanthus
      inversus.
    explanation: >-
      Reports epicanthus inversus in all seven patients of the cohort.
    quote_role: PRIMARY_RESULT
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  description: Downward-slanting palpebral fissures, part of the periorbital gestalt.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents downslanting in a molecularly confirmed COLEC10 case.
- category: Neurologic
  name: Motor Developmental Delay
  description: >-
    Neuromotor delay was reported in all seven children in the selected 2026 cohort. That wording does
    not establish delay in every developmental domain, nor is delay universal across all 3MC genotypes.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:41703727
    reference_title: 'Expansion of the 3MC Syndrome Spectrum: Novel COLEC10 Variants and a MASP1 Exon-Level Deletion.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed neuromotor developmental delay.
    explanation: >-
      Reports neuromotor developmental delay in all seven patients.
    quote_role: PRIMARY_RESULT
- category: Cardiovascular
  name: Congenital Heart Disease
  description: >-
    Congenital heart disease occurred in two of seven patients in the 2026 series. The abstract does not
    specify those lesions; patent ductus arteriosus is separately documented in another COLEC10 case.
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:41703727
    reference_title: 'Expansion of the 3MC Syndrome Spectrum: Novel COLEC10 Variants and a MASP1 Exon-Level Deletion.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft lip and/or palate were present in six patients, caudal appendage in
      four, congenital heart disease in two, hearing loss in four, and
      periumbilical anomalies in six.
    explanation: >-
      Two of seven selected patients had congenital heart disease; no syndrome-wide frequency is inferred.
    quote_role: PRIMARY_RESULT
- category: Genitourinary
  name: Genital Anomalies
  description: >-
    Genital malformations are variable; reported specific findings include cryptorchidism, micropenis
    and hypoplastic labia majora.
  phenotype_term:
    preferred_term: Abnormality of the genital system
    term:
      id: HP:0000078
      label: Abnormality of the genital system
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies
      occur in 20 to 30% of patients.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Clinodactyly of the Fifth Finger
  description: Incurving of the fifth finger.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a 4-years-old patient with typical 3MC phenotypic
      characteristics, including blepharophimosis, telecanthus, high arched
      eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney.
    explanation: >-
      Documents fifth finger clinodactyly in a molecularly confirmed COLEC10
      patient.
    quote_role: PRIMARY_RESULT
- category: Genitourinary
  name: Horseshoe Kidney
  description: >-
    Fusion of the lower renal poles, one of the specific vesicorenal anomalies
    reported in the syndrome.
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
  evidence:
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a 4-years-old patient with typical 3MC phenotypic
      characteristics, including blepharophimosis, telecanthus, high arched
      eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney.
    explanation: >-
      Documents horseshoe kidney, giving a specific instance of the vesicorenal
      anomaly category.
    quote_role: PRIMARY_RESULT
- name: Omphalocele
  category: Abdominal
  phenotype_term:
    preferred_term: Omphalocele
    term:
      id: HP:0001539
      label: Omphalocele
  description: >-
    Omphalocele is listed among the infrequently reported abdominal-wall anomalies in the historical literature
    summary.
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely occurring features include anterior chamber defects, cardiac
      anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis
      recti.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- name: Diastasis Recti
  category: Abdominal
  phenotype_term:
    preferred_term: Diastasis recti
    term:
      id: HP:0001540
      label: Diastasis recti
  description: >-
    Separation of the rectus muscles is included in the historical abdominal-wall spectrum.
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely occurring features include anterior chamber defects, cardiac
      anomalies, caudal appendage, umbilical hernia/omphalocele, and diastasis
      recti.
    explanation: >-
      The 2011 paper summarizes earlier clinical reports. Its grouped frequency range is historical and
      is not a contemporary feature-specific penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
- name: Dolichocephaly
  category: Craniofacial
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents dolichocephaly in the molecularly confirmed Iranian COLEC10 case.
- name: Telecanthus
  category: Craniofacial
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents telecanthus in the molecularly confirmed Iranian COLEC10 case.
- name: High Myopia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents high myopia in the molecularly confirmed Iranian COLEC10 case.
- name: Long Face
  category: Craniofacial
  phenotype_term:
    preferred_term: Long face
    term:
      id: HP:0000276
      label: Long face
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents long face in the molecularly confirmed Iranian COLEC10 case.
- name: Micrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents micrognathia in the molecularly confirmed Iranian COLEC10 case.
- name: Patent Ductus Arteriosus
  category: Cardiovascular
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  description: >-
    Reported in the seven-year-old Iranian girl with homozygous COLEC10 c.128_129delCA. This is a case
    observation, without an established syndrome-wide frequency.
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we described a seven‐year‐old girl from an Iranian consanguine family with craniosynostosis,
      dolichocephaly, blepharoptosis, blepharophimosis, telecanthus, epicanthus inversus, clinodactyly
      of the 5th finger, high myopia, long face, micrognathia, patent ductus arteriosus (PDA), and downslanting
      palpebral fissure.
    explanation: >-
      Directly documents patent ductus arteriosus in the molecularly confirmed Iranian COLEC10 case.
- name: Sacral Dimple
  category: Integumentary
  phenotype_term:
    preferred_term: Sacral dimple
    term:
      id: HP:0000960
      label: Sacral dimple
  description: >-
    Reported in the child with COLEC10 Cys270Serfs*33; a sacral dimple is distinct from a caudal appendage.
  evidence:
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a 4-years-old patient with typical 3MC phenotypic
      characteristics, including blepharophimosis, telecanthus, high arched
      eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney.
    explanation: >-
      Documents sacral dimple in the COLEC10 Cys270Serfs*33 child.
    quote_role: PRIMARY_RESULT
- name: Knee Flexion Contracture
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Knee flexion contracture
    term:
      id: HP:0006380
      label: Knee flexion contracture
  description: >-
    Bilateral fixed knee flexion contractures were reported in one four-year-old COLEC11 case. Additional
    contributing factors were not excluded.
  evidence:
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes
      equinovarus bilaterally.
    explanation: >-
      Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional
      contributors to the contractures were not excluded.
- name: Talipes Equinovarus
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  description: >-
    Bilateral talipes equinovarus was reported in the same COLEC11 case and persisted after knee correction.
  evidence:
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes
      equinovarus bilaterally.
    explanation: >-
      Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional
      contributors to the contractures were not excluded.
- name: Hypoplastic Labia Majora
  category: Genitourinary
  phenotype_term:
    preferred_term: Hypoplastic labia majora
    term:
      id: HP:0000059
      label: Hypoplastic labia majora
  description: >-
    Hypoplastic labia majora were reported in the four-year-old COLEC11 case; no syndrome-wide frequency
    is established.
  evidence:
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She also showed a hypoplastic of labia majora, bilateral knees fixed flexion contracture, and talipes
      equinovarus bilaterally.
    explanation: >-
      Documents these observations in one four-year-old child with a homozygous COLEC11 variant. Additional
      contributors to the contractures were not excluded.
- name: Posterior Radial Head Subluxation
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Posterior subluxation of radial head
    term:
      id: HP:0005739
      label: Posterior subluxation of radial head
  description: >-
    Right posterior radial-head subluxation with limited elbow extension was reported in the same child;
    it is distinct from radioulnar synostosis.
  evidence:
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      she also had limited right elbow extension about 10 degrees due to radial head subluxation in the
      right side posteriorly
    explanation: >-
      Direct case observation of a specific orthopedic lesion.
- name: Ectopic Kidney
  category: Genitourinary
  phenotype_term:
    preferred_term: Ectopic kidney
    term:
      id: HP:0000086
      label: Ectopic kidney
  description: >-
    A right echogenic pelvic kidney was observed prenatally in one fetus with a homozygous MASP1 variant.
  evidence:
  - reference: PMID:32441374
    reference_title: 'Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal findings included bilateral cleft lip and palate, abnormality of the
      sacral spine, a right echogenic pelvic kidney, and brachycephaly.
    explanation: >-
      Documents the prenatally detectable findings, establishing congenital
      onset.
    quote_role: PRIMARY_RESULT
- name: Brachycephaly
  category: Craniofacial
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  description: >-
    Brachycephaly was observed in the reported prenatal MASP1 case.
  evidence:
  - reference: PMID:32441374
    reference_title: 'Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal findings included bilateral cleft lip and palate, abnormality of the
      sacral spine, a right echogenic pelvic kidney, and brachycephaly.
    explanation: >-
      Documents the prenatally detectable findings, establishing congenital
      onset.
    quote_role: PRIMARY_RESULT
- name: Micropenis
  category: Genitourinary
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  description: >-
    Table 3 of the 2017 series reports this finding in patient MC27.1, who carried a homozygous MASP1
    p.Trp3Ter variant. No general syndrome frequency is inferred.
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Micropenis N N N Y N N N
    explanation: >-
      The Table 3 row marks MC27.1 as positive among seven described patients; this is an individual clinical
      observation.
- name: Cryptorchidism
  category: Genitourinary
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Table 3 of the 2017 series reports this finding in patient MC27.1, who carried a homozygous MASP1
    p.Trp3Ter variant. No general syndrome frequency is inferred.
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Undesce nded testes N N N Y N N N
    explanation: >-
      The Table 3 row marks MC27.1 as positive among seven described patients; this is an individual clinical
      observation.
genetic:
- name: MASP1
  gene_term:
    preferred_term: MASP1
    term:
      id: hgnc:6901
      label: MASP1
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic MASP1 variants cause 3MC syndrome 1. Exon-12 missense changes and deletions implicate the
    MASP-3-specific protease domain, while early truncating alleles such as p.Trp290Ter affect shared
    sequence. MASP-3 loss is central, but other isoforms may also be affected by some alleles.
  evidence:
  - reference: PMID:21035106
    reference_title: MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the second family, Sanger sequencing of MASP1 revealed a nonsense
      mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the
      phenotype.
    explanation: >-
      A cosegregating nonsense allele supports loss of function as the disease
      mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29407414
    reference_title: Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In MASP1, either truncating mutations or missense variants in exon 12
      encoding the C-terminal serine protease domain specific for isoform MASP-3
      are causative.
    explanation: >-
      The source distinguishes nonsense variants from missense variants in the MASP-3-specific exon; it
      does not place every nonsense variant in exon 12.
    quote_role: BACKGROUND
  - reference: PMID:29407414
    reference_title: Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By trio exome sequencing we now identified a novel, homozygous 2kb
      deletion, partially affecting exon 12 in an adult female with the typical
      facial gestalt of 3MC syndrome and hearing loss, but without the main
      feature cleft lip/palate, and without intellectual disability, or short
      stature.
    explanation: >-
      Documents an intragenic deletion allele class and, separately, marked
      variable expressivity - a patient with the facial gestalt but none of
      clefting, intellectual disability or short stature.
    quote_role: PRIMARY_RESULT
  variants:
  - name: Biallelic MASP1 loss-of-function alleles
    description: >-
      Reported alleles include p.Gly687Arg and other missense changes in the MASP-3 protease domain, earlier
      nonsense variants such as p.Trp290Ter, and intragenic deletions partially affecting exon 12.
- name: COLEC11
  gene_term:
    preferred_term: COLEC11
    term:
      id: hgnc:17213
      label: COLEC11
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic COLEC11 variants cause 3MC syndrome 2. The gene encodes CL-K1, a secreted neural crest guidance cue in experimental models.
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each mutation segregated with the disease in every family.
    explanation: >-
      Cosegregation across the COLEC11 families supports causality.
    quote_role: PRIMARY_RESULT
- name: COLEC10
  gene_term:
    preferred_term: COLEC10
    term:
      id: hgnc:2220
      label: COLEC10
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic COLEC10 variants cause 3MC syndrome 3. The gene encodes CL-L1, which
    forms heteromeric complexes with CL-K1. The original 2017 study confirmed compound heterozygosity
    in the MC19 siblings; phase could not be established for MC25.1 because relatives were unavailable.
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we define a new gene, COLEC10, also mutated in 3MC families and
      present novel mutations in COLEC11 and MASP1/3 genes in a further five
      families.
    explanation: >-
      Establishes COLEC10 as a 3MC disease gene.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segregation studies confirmed that both parents were carriers for the
      variant: interestingly they originate from the same area of Apulia in
      southern Italy.
    explanation: >-
      Both parents carried the same variant and originated from the same region. This observation alone
      does not establish a founder allele.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We confirmed the homozygous state for this variant in the proband and aborted fetus, as well as
      the heterozygote state in the parents by Sanger sequencing.
    explanation: >-
      The COLEC10 c.128_129delCA family demonstrates a homozygous genotype, complementing earlier compound
      heterozygous cases.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2011 report summarized 32 patients from 20 families known at that time. This dated literature
    count is not a population prevalence estimate.
  evidence:
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty two patients from 20 families have been described so far
    explanation: >-
      Historical case count only; ascertainment and the population denominator are unknown.
    quote_role: REVIEW_SYNTHESIS
- population: Ashkenazi Jewish
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1010.0
  notes: >-
    Variant-specific carrier frequency, not disease prevalence: 400/39,750 individuals of Ashkenazi Jewish
    descent in a larger screened cohort of 52,278 individuals of Jewish descent carried the likely founder
    COLEC10 c.311G>T (p.Gly104Val) allele.
  evidence:
  - reference: PMID:35943032
    reference_title: "Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified nine individuals from five families of Ashkenazi Jewish descent with
      homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with
      3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent.
      Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a
      carrier frequency of 1 in 99 or 1.01%. ... The c.311G > T (p.Gly104Val) variant likely
      represents a founder variant, and homozygosity is associated with features of 3MC syndrome.
    explanation: >-
      The COLEC10 p.Gly104Val founder variant was observed in nine affected individuals from five
      Ashkenazi Jewish families. Screening found 400 carriers among 39,750 Ashkenazi Jewish
      individuals (1.01%); this is carrier frequency, not affected-person prevalence.
    quote_role: PRIMARY_RESULT
treatments:
- name: Orthopedic Correction of Joint Contracture
  description: >-
    One child with COLEC11-related 3MC and bilateral fixed knee flexion contractures underwent sequential
    gradual correction using Taylor spatial frames, followed by casts and braces. Full knee extension
    was maintained for three months; foot deformities still required management. A single uncontrolled
    case does not establish superiority or general safety.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In our reported patient, full extension of both knees was maintained for a total of three months
      using a cast and then a brace.
    explanation: >-
      Reports the observed short-term result and maintenance measures after frame correction.
  - reference: PMID:34589314
    reference_title: Management of Knee Flexion Contracture in a Child With 3MC Syndrome Using Taylor Spatial Frame.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      While the TSF technique restored full extension to both knees, the patient still has another deformity
      in both feet that requires further management.
    explanation: >-
      The intervention corrected the knees but did not resolve the separate foot deformities.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses autosomal recessive inheritance, family testing and reproductive options.
    Prenatal molecular testing is possible once the familial pathogenic variants are identified.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:32441374
    reference_title: 'Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3MC syndrome should be considered as part of the differential diagnosis
      when fetal ultrasound detects facial clefts and spinal defects, as the
      risk of recurrence is significant and a molecularly confirmed diagnosis
      allows for alternate reproductive options.
    explanation: >-
      States the recurrence risk and the reproductive consequence that make
      counselling actionable.
    quote_role: PRIMARY_RESULT
- name: Surgery for Craniosynostosis
  description: >-
    Cranioplasty was performed at five and eighteen months in the reported child with COLEC10-related
    3MC and congenital craniosynostosis. This is documented care in one case; no comparative treatment
    outcome was reported.
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Clinical examination, presented craniosynostosis at birth, therefore, first cranioplasty was performed
      at 5 months old and second one at 18 months old.
    explanation: >-
      Documents cranial surgery in a molecularly confirmed patient without establishing a syndrome-specific
      surgical protocol.
  treatment_term:
    preferred_term: cranial reconstructive surgery
    term:
      id: NCIT:C25351
      label: Reconstructive Surgery
  notes: >-
    NCIT search `runoak -i ols:ncit search 't~cranio'` returned Craniotomy but no cranioplasty term; `runoak
    -i ols:ncit search 't~reconstructive'` returned NCIT:C25351 Reconstructive Surgery. The latter represents
    reconstruction without incorrectly equating it to opening the skull.
progression:
- phase: Congenital presentation and variable later development
  notes: >-
    Structural anomalies can be recognized prenatally or at birth. Developmental impairment is variable,
    and survival into adulthood is documented, including an adult without intellectual disability or short
    stature. The available reports do not establish that every manifestation remains static over life.
  evidence:
  - reference: PMID:32441374
    reference_title: 'Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal findings included bilateral cleft lip and palate, abnormality of the
      sacral spine, a right echogenic pelvic kidney, and brachycephaly.
    explanation: >-
      Documents the prenatally detectable findings, establishing congenital
      onset.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29407414
    reference_title: Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We therefore expand the MASP1 associated mutational and clinical spectrum
      and describe the development of her clinical presentation over a period of
      21 years.
    explanation: >-
      A 21-year follow-up in an adult patient supports survival to adulthood and
      a non-lethal course.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29407414
    reference_title: Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By trio exome sequencing we now identified a novel, homozygous 2kb
      deletion, partially affecting exon 12 in an adult female with the typical
      facial gestalt of 3MC syndrome and hearing loss, but without the main
      feature cleft lip/palate, and without intellectual disability, or short
      stature.
    explanation: >-
      Documents an intragenic deletion allele class and, separately, marked
      variable expressivity - a patient with the facial gestalt but none of
      clefting, intellectual disability or short stature.
    quote_role: PRIMARY_RESULT
animal_models:
- name: colec11 zebrafish morphant
  species: Zebrafish
  genotype: colec11 antisense morpholino knockdown (ATG and splice-site)
  publication: PMID:21258343
  description: >-
    Morpholino knockdown of colec11 in zebrafish embryos, rescued by
    co-injection of full-length COLEC11 mRNA.
  modeled_mechanisms:
  - target: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Knockdown reproduces severe craniofacial cartilage malformation, the
      tissue-level phenotype of the human syndrome.
    limitations: >-
      Morpholino knockdown is transient and dose-dependent rather than a
      germline null, and zebrafish craniofacial cartilage does not map
      one-to-one onto the human facial skeleton. The report notes high mortality
      at higher doses, requiring lower doses for cartilage staining.
    readouts:
    - name: Alcian blue-stained craniofacial cartilage morphology
      target: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
      direction: ALTERED
      interpretation: >-
        Reduced mandibular length and malformed anterior neurocranium, the
        structural correlate of the human craniofacial phenotype.
      evidence:
      - reference: PMID:21258343
        reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Striking differences in the craniofacial skeleton were observed
          compared with uninjected/standard morpholino injected embryos, such as
          reduced mandibular length (e.g. shortened Meckel and palatoquadrate
          cartilages), malformation of the anterior neurocranium with shortening
          of the trabeculae and the ethmoid plate, shortening and abnormal
          angulation of the ceratohyal cartilage
        explanation: >-
          Reports the specific craniofacial cartilage measurements behind this
          readout.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Zebrafish morphants for either gene develop pigmentary defects and
        severe craniofacial abnormalities.
      explanation: >-
        Supports treating the morphant as informative for the craniofacial
        morphogenesis node.
      quote_role: PRIMARY_RESULT
  - target: Impaired Neural Crest Cell Guidance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The same colec11 perturbation alters neural crest streaming and location before craniofacial cartilage
      is assessed.
    limitations: >-
      Transient, dose-sensitive morpholino knockdown is not a patient-specific germline allele, and migration
      does not alone establish the route to each human feature.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the
        colec11 morphants and obviously truncated in the masp1 morphants
      explanation: >-
        Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
        does not isolate MASP-3 from other gene products.
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf,
        ectopic NCC in the head, trunk and periphery
      explanation: >-
        Ectopic neural crest cells support dysregulated guidance rather than a uniform decrease in cell
        number.
- name: masp1 zebrafish morphant
  species: Zebrafish
  genotype: masp1 antisense morpholino knockdown
  publication: PMID:21258343
  description: >-
    masp1 knockdown disrupts neural crest streaming and craniofacial cartilage. Combined subthreshold
    colec11/masp1 knockdown produced severe craniofacial abnormalities in 16/22 embryos.
  modeled_mechanisms:
  - target: Impaired Neural Crest Cell Guidance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The perturbation supports a role for the masp1 locus in neural crest guidance.
    limitations: >-
      The perturbation does not distinguish MASP-3 from other masp1 products and does not identify the
      proteolytic substrate linking the gene to cell migration.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        At 24 hpf, the organisation of streaming NCC through the somites is severely disrupted in the
        colec11 morphants and obviously truncated in the masp1 morphants
      explanation: >-
        Zebrafish morpholino perturbations alter neural crest distribution and streaming. The masp1 perturbation
        does not isolate MASP-3 from other gene products.
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        In addition, we injected SOX10-eGFP zebrafish with colec11 and masp1 MO and observed at 48 hpf,
        ectopic NCC in the head, trunk and periphery
      explanation: >-
        Ectopic neural crest cells support dysregulated guidance rather than a uniform decrease in cell
        number.
- name: Masp1/3 knockout mouse
  species: Mouse
  genotype: Masp1/3-/-
  publication: PMID:28794230
  description: >-
    Mouse lacking both MASP-1 and MASP-3, used to establish the maturase role of
    MASP-3 in pro-factor D conversion.
  modeled_mechanisms:
  - target: Impaired Pro-Factor D Maturation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the failure of pro-factor D conversion seen in patient serum.
    limitations: >-
      The knockout removes both MASP-1 and MASP-3. Some human alleles are MASP-3-selective whereas others
      affect shared sequence. The model supports the biochemical node; it does not establish the craniofacial
      mechanism.
    evidence:
    - reference: PMID:28794230
      reference_title: Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This view was challenged when it was shown that mice lacking
        mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and
        MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that
        MASP-3 is implicated in pro-FD maturation.
      explanation: >-
        The abstract summarizes prior knockout findings; the separate experimental statement includes
        patient sera and knockout mice in tests of factor D conversion.
      quote_role: BACKGROUND
- name: Colec11 knockout mouse
  species: Mouse
  genotype: Colec11-/- (single knockout)
  publication: PMID:41774788
  description: Single-gene deletion produces only a low incidence of overt spinal curvature (1/88 mice in Table 1); bone-marrow cultures nevertheless show modest reductions in osteoclast number and size.
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: The cellular differentiation defect is mild after isolated Colec11 deletion in mouse cells. This model does not reproduce the high frequency of overt postnatal spinal disease observed with additional complement-gene deletion.
    limitations: The source assesses different endpoints in vivo and ex vivo. Low gross spinal-phenotype incidence does not establish normal osteoclast differentiation, nor does it establish absence of skeletal consequences of human COLEC11 deficiency.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size
      explanation: Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)
      explanation: The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.
  evidence:
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)
    explanation: The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.
- name: Colec11 and complement-component double-knockout mice
  species: Mouse
  genotype: Colec11-/-;C3-/-, Colec11-/-;Cfb-/-, or Colec11-/-;Masp-2-/-
  publication: PMID:41774788
  description: Combined gene deletion is associated with postnatal vertebral bone loss and kyphosis/scoliosis in 23–28% of mice by 12 weeks. Table 1 reports 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 animals, compared with 1/88 Colec11 single knockouts and 0/101 wild-type controls.
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Colec11/C3 and Colec11/Cfb bone-marrow cultures show marked impairment of osteoclast differentiation and partial rescue with recombinant CL-11. The living double-knockout animals provide an associated bone-maintenance phenotype, rather than proof that the measured osteoclast defect causes their bone loss.
    limitations: Additional complement-gene deletion is not the usual human 3MC genotype. Only overtly affected double knockouts underwent CT or histology; phenotype incidence may therefore underestimate subclinical lesions. Detailed lesions were concentrated in vertebrae, with no detected skull-calvarial abnormality or significant femur-length difference. Colec11/C3 embryos lacked overt morphological abnormalities by E18.5. Results do not establish a cause of human developmental synostoses or craniofacial malformations. The reported ex-vivo differentiation/rescue experiments specifically tested Colec11/C3 and Colec11/Cfb, not all three double-knockout genotypes.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells
      explanation: The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: This treatment partially restored CL-11 binding and significantly increased the presence of multinucleated giant cell OCLs
      explanation: Recombinant CL-11 was added to Colec11/C3 and Colec11/Cfb double-knockout bone-marrow cultures; this is an ex-vivo rescue, not treatment of living animals.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)
      explanation: The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: This proportion may underestimate the true prevalence, as only DKO mice exhibiting overt phenotypes underwent CT imaging or histopathological analysis.
      explanation: Detailed vertebral imaging and histology were selected on the overt phenotype rather than applied to all genotype carriers.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: In contrast, scapular and pelvic bones exhibited only minor defects, while femurs and skull calvaria appeared unaffected (SI Appendix, Fig. S2). Femur length did not significantly differ between KO and WT mice of the same sex.
      explanation: The mouse lesions are not a demonstration of the usual human craniofacial malformations or generalized long-bone shortening.
  evidence:
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: By 12 wk of age, kyphosis and/or scoliosis occurred in 23 to 28% of the three DKO groups lacking CL-11 (Colec11−/−/C3−/−; Colec11−/−/Masp-2−/−; Colec11−/−/Cfb−/−), compared to only 0 to 1% in wild-type (WT) mice, SKO mice, and DKO mice with intact CL-11 (C3−/−/Masp-2−/−)
    explanation: The genotype interaction concerns overt postnatal spinal pathology. Table 1 reports 1/88 single Colec11 knockouts, 22/78 Colec11/C3, 21/77 Colec11/Cfb, and 22/95 Colec11/Masp-2 double knockouts.
experimental_models:
- name: Mouse Colec11-deficient bone-marrow-derived osteoclast cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Bone-marrow-derived cells from wild-type, Colec11 single-knockout, Colec11/C3 double-knockout and Colec11/Cfb double-knockout mice were differentiated using M-CSF and RANKL. Recombinant human CL-11 (0.9 micrograms/mL) with calcium was supplied during double-knockout rescue experiments.
  publication: PMID:41774788
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: The experimental system distinguishes modest single-knockout effects from pronounced combined-knockout effects and tests recombinant-protein rescue directly.
    limitations: This is ex-vivo differentiation. TRAP-positive multinucleated-cell area and nuclei per osteoclast are differentiation readouts; neither direct bone-resorption function nor prevention of in-vivo vertebral pathology was demonstrated by these assays. Figure 6 includes few independent donor animals for double knockouts despite multiple image measurements.
    readouts:
    - name: TRAP-positive multinucleated osteoclast formation
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: DECREASED
      interpretation: Combined-knockout cultures produce fewer/smaller differentiated osteoclasts than wild-type cultures.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells
        explanation: The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.
    - name: Osteoclast formation after recombinant CL-11 supplementation
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: RESTORED
      interpretation: Rescue is partial and limited to the cultured-cell phenotype; it is not an in-vivo skeletal rescue.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: This treatment partially restored CL-11 binding and significantly increased the presence of multinucleated giant cell OCLs
        explanation: Recombinant CL-11 was added to Colec11/C3 and Colec11/Cfb double-knockout bone-marrow cultures; this is an ex-vivo rescue, not treatment of living animals.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In contrast, Colec11−/−/C3−/− BMSCs exhibited pronounced reduction in multinucleated OCL formation, quantified by the microscopic area occupied by such cells
      explanation: The cellular readout is TRAP-positive multinucleated osteoclast formation/area, not a direct bone-resorption assay.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: By comparison, OCLs derived from Colec11−/− SKO mice exhibited only modest reductions in OCL number and size
      explanation: Single-gene mouse deficiency has a mild cellular effect despite its low frequency of overt spinal curvature.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: This treatment partially restored CL-11 binding and significantly increased the presence of multinucleated giant cell OCLs
      explanation: Recombinant CL-11 was added to Colec11/C3 and Colec11/Cfb double-knockout bone-marrow cultures; this is an ex-vivo rescue, not treatment of living animals.
- name: Human CRISPR COLEC11-knockout KOLF2 iPSC-derived osteoclasts
  experimental_model_type: IPSC_DERIVED_MODEL
  description: Healthy-donor KOLF2 iPSCs and paired CRISPR-edited COLEC11-deficient clones were differentiated through myeloid precursors to osteoclasts with M-CSF and RANKL. Recombinant human CL-11 with calcium tested rescue; Mirococept tested pharmacologic complement-convertase inhibition.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:41774788
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Isolated COLEC11 deletion markedly reduces osteoclast differentiation in this human cellular system, and recombinant CL-11 partly restores it. Mirococept separately inhibits C3/C5 convertases and reduces osteoclast formation.
    limitations: Engineered healthy-donor cells are not 3MC patient-derived cells. Mirococept treatment is distinct from genetic deletion of C3 or another complement component; these interventions do not prove an obligatory linear C3-to-MAC route. Three independent differentiation experiments were reported, without a patient clinical or in-vivo bone endpoint.
    readouts:
    - name: TRAP-positive multinucleated osteoclast area after COLEC11 deletion
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: DECREASED
      interpretation: Deletion reduces differentiation relative to parental wild-type cells.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11.
        explanation: Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.
    - name: Osteoclast formation after recombinant CL-11 supplementation
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: RESTORED
      interpretation: The cellular deficit is partially rescued; full normalization or clinical benefit is not established.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11.
        explanation: Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.
    - name: Osteoclast formation during Mirococept treatment
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: DECREASED
      interpretation: Complement-convertase inhibition supports a role for complement in normal differentiation independently of the engineered COLEC11 deletion.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: In addition, treatment with Mirococept—a truncated complement receptor-1–based inhibitor of C3 and C5 convertases (23)—significantly reduced OCL formation, demonstrating that normal human OCL differentiation is complement-dependent.
        explanation: Pharmacologic C3/C5 convertase inhibition supports complement involvement; it is not a C3 gene-deletion experiment or proof that a specific linear complement sequence is necessary.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: CL-11 deletion resulted in marked impairment of OCL differentiation, which was partially rescued by supplementation of the differentiation medium with recombinant CL-11.
      explanation: Engineered healthy-donor human iPSC-derived cells establish a cellular requirement and partial rescue, not a patient skeletal phenotype.
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In addition, treatment with Mirococept—a truncated complement receptor-1–based inhibitor of C3 and C5 convertases (23)—significantly reduced OCL formation, demonstrating that normal human OCL differentiation is complement-dependent.
      explanation: Pharmacologic C3/C5 convertase inhibition supports complement involvement; it is not a C3 gene-deletion experiment or proof that a specific linear complement sequence is necessary.
differential_diagnoses:
- name: Branchio-oto-renal spectrum
  description: >-
    Branchiootorenal spectrum disorder can overlap through hearing loss and urinary malformations. Its
    branchial cleft and ear findings, autosomal dominant inheritance and EYA1/SIX1 molecular diagnosis
    help distinguish it from 3MC.
  evidence:
  - reference: PMID:20301554
    reference_title: Branchiootorenal Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g.,
      preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle,
      and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment.
    explanation: >-
      Describes the overlapping and distinguishing phenotype of this differential, not 3MC.
  - reference: PMID:20301554
    reference_title: Branchiootorenal Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The molecular diagnosis of BORSD is established in a proband with suggestive findings and a heterozygous
      pathogenic variant in either EYA1 or SIX1 identified by molecular genetic testing.
    explanation: >-
      Identifies the genes of this alternative diagnosis.
  - reference: PMID:20301554
    reference_title: Branchiootorenal Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      BORSD is inherited in an autosomal dominant manner.
    explanation: >-
      Contrasts the inheritance pattern with autosomal recessive 3MC.
- name: Blepharophimosis-ptosis-epicanthus inversus syndrome
  description: >-
    FOXL2-related blepharophimosis, ptosis and epicanthus inversus syndrome overlaps strongly in eyelid
    morphology. Its almost always autosomal dominant inheritance and molecular cause distinguish it from
    3MC; primary ovarian insufficiency can occur in BPES type I.
  evidence:
  - reference: PMID:20301614
    reference_title: "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes
      only the four major features.
    explanation: >-
      Describes BPES subtype context, without asserting that all other congenital anomalies are categorically
      absent.
  - reference: PMID:20301614
    reference_title: "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of BPES is established in a proband with suggestive findings and a heterozygous pathogenic
      variant in FOXL2 or its regulatory domain identified by molecular genetic testing.
    explanation: >-
      Supports FOXL2 as the alternative molecular diagnosis.
  - reference: PMID:20301614
    reference_title: "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      BPES is almost always inherited in an autosomal dominant manner.
    explanation: >-
      Provides the inheritance distinction.
diagnosis:
- name: Molecular diagnosis by sequencing of MASP1, COLEC11 and COLEC10
  description: >-
    Known-gene molecular confirmation identifies biallelic pathogenic variants in MASP1, COLEC11 or COLEC10, interpreted
    with the clinical phenotype. Confirm gene coverage and deletion detection when choosing or interpreting
    a sequencing assay: a 2021 case used a clinical exome panel that omitted COLEC10, and a MASP1 intragenic
    deletion in another case required careful visual review of exome data. These are documented historical
    assay limitations, not statements that all current panels have the same gaps. The likely Ashkenazi
    Jewish COLEC10 founder allele is relevant to variant interpretation, but a negative result for one
    allele does not exclude 3MC.
  evidence:
  - reference: PMID:35943032
    reference_title: "Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3MC syndrome should be in the differential diagnosis for individuals with
      short stature, radioulnar synostosis, cleft lip and cleft palate.
    explanation: >-
      States the clinical trigger for pursuing a molecular diagnosis. Graded
      against the "when to suspect" half of this entry only; the confirmatory
      sequencing claim is evidenced separately below.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial genetic analysis was based on clinical exome sequencing, where
      only MASP1 and COLEC11 genes are present, without evidence of pathogenic
      variants.
    explanation: >-
      Documents a false-negative caused by a clinical exome panel that omits
      COLEC10, which is why panel gene content has to be checked before a
      negative result is accepted.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29407414
    reference_title: Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As the homozygous deletion in our patient was only found by thorough and
      visual evaluation of the whole exome sequencing data, such deletions might
      escape detection in some routine diagnostic workflows and might explain a
      few of the so far molecularly unconfirmed cases of 3MC syndrome.
    explanation: >-
      Documents the second false-negative route, intragenic deletions missed by
      routine variant-calling, and connects it to unsolved cases.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34636477
    reference_title: Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We confirmed the homozygous state for this variant in the proband and aborted fetus, as well as
      the heterozygote state in the parents by Sanger sequencing.
    explanation: >-
      Whole-exome sequencing identified the COLEC10 variant, subsequently confirmed with family segregation
      testing.
notes: >-
  The gene-specific forms are represented as subtypes of a shared developmental syndrome, with variant-specific
  molecular routes retained in the graph. Neural crest guidance is a model-supported explanation for craniofacial
  findings; direct complement dependence and the intervening developmental signals are unresolved. Factor
  D maturation is a separate biochemical consequence, and the osteoclast branch is experimentally supported
  but has not been established as the cause of human 3MC skeletal abnormalities. Clinical cohort counts
  and historical literature summaries describe their stated samples; they are not population penetrance
  estimates.
biochemical:
- name: Predominant pro-factor D with residual mature factor D
  presence: Predominant pro-factor D with detectable mature factor D
  context: MASP1/MASP-3 deficiency
  notes: >-
    Research isoelectric-focusing assays found impaired factor D maturation in patient samples. This is
    a mechanistic readout, not a validated standalone diagnostic test for all 3MC forms.
  evidence:
  - reference: PMID:28794230
    reference_title: Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      although 3MC patients predominantly contain pro-FD, they also contain
      detectable levels of mature FD
    explanation: >-
      Patient samples demonstrate incomplete maturation. Residual mature factor D does not by itself establish
      normal alternative-pathway activity or absence of clinical infection risk.
    quote_role: PRIMARY_RESULT
discussions:
- discussion_id: gap_3mc_molecularly_unconfirmed_cases
  prompt: >-
    Which additional genetic causes or undetected variants account for clinically diagnosed 3MC cases
    without molecular confirmation in MASP1, COLEC11 or COLEC10?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    The 2017 COLEC10 discovery study reported that over 60% of its selected 3MC cohort remained without
    molecular confirmation after assessing the three known genes. The authors proposed additional loci.
    This historical cohort fraction is not a current diagnostic-yield estimate, and it does not by itself
    distinguish new loci from missed variants or clinical phenocopies.
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Therefore, over 60% of our 3MC cohort is still without molecular
      confirmation of disease and that at least one further gene remains to be identified.
    explanation: >-
      The discovery study reports its remaining molecularly unconfirmed cohort and interprets it as
      evidence for additional loci; that interpretation is a hypothesis rather than proof of a new gene.
references:
- reference: PMID:20301554
  title: Branchiootorenal Spectrum Disorder.
  tags:
  - GeneReviews
  findings:
  - statement: Differential-diagnosis context only; this chapter describes another disorder and is not a 3MC clinical baseline.
- reference: PMID:20301614
  title: "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome."
  tags:
  - GeneReviews
  findings:
  - statement: Differential-diagnosis context only; this chapter describes another disorder and is not a 3MC clinical baseline.

📚

References & Deep Research

References

2

PMID:20301554

Branchiootorenal Spectrum Disorder.

1 finding

Differential-diagnosis context only; this chapter describes another disorder and is not a 3MC clinical baseline.

PMID:20301614

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome.

1 finding

Differential-diagnosis context only; this chapter describes another disorder and is not a 3MC clinical baseline.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review 3MC syndrome against clinical and mechanistic full texts · 2026-09-21T02:37:07Z · View source

Scope: complete claim-level review of the existing entry and matching OpenScientist deep-research report. Confirmed no prior REVIEW history and no exact-disorder overlap in a fully paginated live scan of 133 open PRs, including extra file pages. Work was isolated in a sparse worktree. Source coverage: read all cited 3MC abstracts and the complete scientific text, methods and tables of PMID:21258343, PMID:25912189, PMID:27535802, PMID:28301481, PMID:34589314, PMID:34636477 and PMID:41774788. The last three were regenerated as genuine PMC XML via just fetch-reference. PMID:21035106 resolves to PMC2978960 but the public HTML endpoint returned a browser challenge; the sanctioned fetcher retained its abstract. PMID:28794230 also remained abstract-only. No claims require unavailable body text. No reference cache was hand-edited. An unused fetcher-code cherry-pick was removed before submission because these sources use the existing XML route. Mechanisms: split variant-specific calcium binding, carbohydrate binding, CL-K1 secretion, CL-L1 secretion and CL-L1 chemoattraction into separate events. Keep proposed biosynthetic quality-control and neural-crest intermediates inferential. The CL-L1 Cys270Serfs*33 family has normal measured plasma abundance but impaired HeLa-cell chemoattraction. Correct the assertion that all MASP1 alleles lie in exon 12 or affect only MASP-3; early shared-sequence nonsense alleles occur. Remove uniform homozygosity from biallelic contexts. Distinguish factor D maturation in patients, resting-plasma inhibitor experiments and coagulated serum. Residual mature factor D does not establish normal clinical immunity. Connect the proposed craniofacial route to human findings without assigning other organ malformations to neural crest. Models: read beyond the absolute wording of the 2026 osteoclast abstract. Colec11 single-knockout mice have low overt spinal-phenotype incidence (1/88), with modest cellular differentiation impairment. Combined deletions have overt findings in 22/78, 21/77 and 22/95 animals; detailed imaging/histology selected overtly affected animals. Human experiments use engineered healthy-donor KOLF2 iPSCs, not patient cells, and COLEC11 deletion alone impairs differentiation. Distinguish ex-vivo rescue, human convertase inhibition and in-vivo pathology. Partial rescue and terminal-complement deposition do not prove a necessary linear C3 pathway, direct CL-11 cleavage of C5, or an osteoclast-mediated cause of human malformations. An independent full-text peer audit checked this branch and exact quotes. Clinical completeness: correct unsupported frequency bands, selected-cohort generalization, periumbilical anomalies versus depression, urinary malformations versus vesicoureteral reflux, and motor versus global developmental delay. Historical ranges remain within cited context; overlapping ranges and single reports are not population penetrance. Split omphalocele from umbilical hernia and add directly observed craniofacial, ocular, cardiac, urinary, genital and orthopedic findings with case-specific limits. Exclude the Cureus report's implausible weight units. Preserve adult survival and variable cognition without asserting a uniformly static course. Carrier screening remains a variant-specific carrier frequency; parental origin in Apulia does not prove a second founder allele. Historical panel omissions and deletion-calling failures are dated examples, not universal current assay limitations. The original COLEC10 report confirms compound heterozygosity in MC19 siblings but could not establish phase in MC25.1; no universal phase claim is made. Care and baseline: replace the uncontrolled orthopedic report's comparative-safety claim with the actual three-month knee-extension result and persisting foot deformity. Add documented craniosynostosis surgery without inventing a general protocol. Retain genetic counseling and prenatal molecular testing. Initial GeneReviews/StatPearls screening found no matching 3MC chapter in the 2026-09-10 snapshot. Two existing GeneReviews abstracts are subsequently cited solely for BORSD and BPES differential diagnosis, explicitly marked as context, not a 3MC baseline. Their management is not imported into 3MC. Research cross-check: assess core CL-K1/CL-L1/MASP biology, neural crest, factor D, osteoclasts, all three molecular forms, founder screening, prenatal presentation, developmental variability and reported orthopedic care. Adult renal ischemia/fucose and anti-collectin proposals are outside congenital 3MC therapy scope. A single psychiatric-comorbidity report does not establish a core phenotype or support the drug choices suggested in the research narrative. No disease-specific environmental exposure, validated biochemical diagnostic threshold, general clinical guideline or disease-modifying trial was established by these sources. Verify new ontology bindings with OLS rather than copying flagged research-report suggestions. The frozen dataset-accession cache was neither read nor modified. Validation and peer review: authoritative schema, ontology and all 138/138 exact snippets passed. Whole-KB reference-title, snippet-title, snippet-length, snippet-grading, empty-snippet, environmental-evidence, cache-frontmatter, term-cache-integrity, cache-order, enum-cache and case-collision gates passed. Two PDF line-wrap artifacts in quotes were replaced with other exact source excerpts, and the folded-hyphen gate passed on rerun. Repository formatting hooks normalized the authored YAML and whitespace/end-of-file in generated caches. The regenerated references have no other disorder consumers in the current KB. Targeted causal-target, entity-reference, coarse-phenotype, duplicate-key, enum, qualifier, snippet-boundary and source-claim checks passed. Independent clinical review confirmed cohort denominators, carrier versus disease prevalence, variable development and case-level care, and identified copied feature-specific explanations that were corrected; genital findings in the primary patient table were added with explicit patient context.

Address review: osteoclastogenesis branch, missing phenotypes, treatments · 2026-08-29T11:04:36Z · View source

Review round on PR #10033. The automated reviewer requested changes; the substance was under-consumption of references that the deep-research run had cached into the branch, not defects in what was already curated. Added a second pathophysiology branch, Impaired Complement-Dependent Osteoclastogenesis, from PMID:41774788. This materially changes the entry's framing. The first draft treated the alternative-complement arm as a terminal node with no consequence, which is right for immunodeficiency and wrong as a general claim: in mice, CL-11 loss combined with MASP-2, factor B or C3 deficiency produces vertebral bone loss that neither lesion causes alone. The node on pro-factor D maturation now says explicitly that complement components act as modifiers of the skeletal phenotype while still not supporting an infectious-susceptibility phenotype. Also added the Colec11-/- mouse as a FAILS_TO_RECAPITULATE model, since CL-11 deletion alone produces no skeletal abnormality, and the human iPSC-derived osteoclast system as an experimental_model. Phenotypes added from the seven-patient cohort in PMID:41703727 and from PMID:34740859: epicanthus inversus, global developmental delay, congenital heart disease, genital anomalies, downslanted palpebral fissures, fifth finger clinodactyly and horseshoe kidney. Corrected a frequency that a reference in the branch contradicted. Umbilical anomalies had been graded VERY_RARE from the 2011 "rarely occurring features" list, but PMID:41703727 reports periumbilical anomalies in six of seven patients. The two concepts are now curated separately: Periumbilical Depression as VERY_FREQUENT (HP:6000808) and Umbilical Hernia or Omphalocele as VERY_RARE. Both are attested and they are not the same finding. Added treatments (orthopedic contracture correction, genetic counselling) with a note that no disease-modifying therapy exists, a progression block establishing congenital static course with prenatal detectability, and genetic depth: allele classes, the second COLEC10 founder allele in Apulia, marked variable expressivity in an adult patient without clefting or intellectual disability, and genetic_context blocks carrying functional_impact_category on the two molecular nodes. Fixed a diagnosis section whose evidence supported when to suspect the diagnosis rather than how to confirm it, adding the two documented false-negative routes: exome panels that omit COLEC10, and intragenic deletions missed by routine variant calling. Two term-modifier corrections following the reviewer and CLAUDE.md's gain/loss decision tree: GO:0001867 and the MASP-3 protease activity moved from LOSS_OF_FUNCTION to DECREASED, since absence of a required component is the quantitative reading; the qualitative LOSS_OF_FUNCTION now lives on genetic_context where it describes the variant consequence. Validation after the round: just validate-disorders passes, 68/68 snippets verified, and the folded-hyphen, duplicate-key, entity-ref, snippet-grading, title-snippet and snippet-length checks all pass in this worktree.

Create: 3MC Syndrome · 2026-08-29T10:31:20Z · View source

De-novo curation of 3MC syndrome as a single Disease entry covering all three genetic forms - MASP1, COLEC11 and COLEC10. The lump is mechanistic, not merely clinical: CL-K1 and CL-L1 form heteromeric complexes and MASP-3 is the collectin-associated protease, so one pathograph serves all three forms. Per-gene detail is carried in has_subtypes and genetic. Deep research: one openscientist report, research/3MC_Syndrome-deep-research-openscientist.md. Its term-validation section was read before any binding was made, and two of its suggestions were rejected. The report offered MONDO:0018721 as "3MC syndrome" - MONDO calls that identifier "obsolete rare combined vascular malformation" - and HP:0100541 for the caudal appendage, which HPO calls "Femoral hernia". The entry instead binds MONDO:0017398 and HP:0002825, both checked against OLS directly. The report's renal ischemia-reperfusion citations were also deliberately not used: they describe an acquired adult CL-11 injury mechanism that the report itself flags as distinct from the developmental syndrome. The report did contribute real mechanism: the calcium-binding/secretion basis of collectin loss of function and the demonstration that MASP-3 is the exclusive pro-factor D activator in resting blood. Mechanism curated as collectin or MASP-3 loss, then loss of the CL-K1 neural crest guidance cue, then impaired cranial neural crest migration, then defective craniofacial morphogenesis. The alternative-complement consequence, impaired pro-factor D maturation, is curated as a deliberately terminal node with no clinical sequela, because patients retain detectable mature factor D and are not clinically immunodeficient. A note on that node warns future curators against attaching an immunodeficiency phenotype to it. Validation: just validate passes for schema, terms and references, with 45/45 snippets verified against the local reference cache.

OpenScientist ▸

3MC Syndrome — Comprehensive Disease Characterization Report

openscientist-autonomous 2026-08-29T10:18:13.740058

3MC Syndrome — Comprehensive Disease Characterization Report

Prepared for a disease knowledge base entry. Evidence type is human clinical unless otherwise noted (model organism / in vitro / computational). Primary literature cited by PMID.

Summary (Answer to the Research Question)

3MC syndrome is a rare, autosomal-recessive congenital malformation syndrome that unifies four historically separate disorders — Malpuech, Michels, Mingarelli and Carnevale syndromes ("3MC"). It is caused by biallelic loss-of-function variants in one of three genes of the lectin pathway of complement: MASP1 (encoding MASP-1/MASP-3), COLEC11 (encoding collectin-11/CL-K1), and COLEC10 (encoding collectin-10/CL-L1). The shared mechanism is loss of a collectin/MASP-3 chemoattractant guidance cue required for neural crest cell migration, producing a distinctive facial gestalt (hypertelorism, blepharophimosis, blepharoptosis, highly arched eyebrows) together with cleft lip/palate, postnatal growth deficiency, developmental delay, hearing loss, a characteristic caudal appendage, skeletal (craniosynostosis, radioulnar synostosis) and genitourinary anomalies (PMIDs 21258343, 28301481).

1. Disease Information

Overview: A rare autosomal-recessive multiple-congenital-anomaly / dysmorphism syndrome affecting craniofacial, skeletal, genitourinary, ophthalmic and (variably) cardiac development. The name "3MC" was proposed as a unifying term for the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes (PMID 21258343).
Key identifiers (suggested):
MONDO: MONDO:0018721 ("3MC syndrome") — with subtypes 3MC syndrome type 1/2/3.
OMIM (phenotype): 3MC syndrome 1 (#257920, MASP1/COLEC11 — historically Malpuech/Carnevale), 3MC syndrome 2 (#265050, COLEC11), 3MC syndrome 3 (#248340, COLEC10 — historically Michels). (PMIDs 36503917, 34636477)
OMIM (gene): MASP1 600521; COLEC11 612502; COLEC10 *607620.
Orphanet: ORPHA:293843 (3MC syndrome); legacy entries Malpuech syndrome (ORPHA:1993), Michels syndrome (ORPHA:1394), Carnevale/Mingarelli.
ICD-10: Q87.0 (congenital malformation syndromes predominantly affecting facial appearance). ICD-11: LD2F.0Y (other specified syndromes with facial features as a major feature).
MeSH: No dedicated descriptor; indexed under "Abnormalities, Multiple" / supplementary concept "3MC syndrome."
Synonyms / alternative names: Malpuech–Michels–Mingarelli–Carnevale syndrome; Malpuech facial clefting syndrome; Michels syndrome; Carnevale syndrome; Mingarelli syndrome; Malpuech syndrome; OSA syndrome; craniofacial-ulnar-renal syndrome; blepharophimosis-ptosis-cleft-lip syndrome (descriptive).
Data derivation: Information here is derived from aggregated disease-level resources (OMIM/Orphanet) and individual patient case reports / small cohorts (fewer than ~100 molecularly confirmed patients worldwide). There is no large EHR-based dataset for this ultra-rare disorder.

2. Etiology

Primary cause — genetic: Biallelic (homozygous or compound heterozygous) pathogenic variants in MASP1, COLEC11, or COLEC10 — all encoding components of the lectin complement pathway (PMID 21258343: "identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway"; PMID 28301481 for COLEC10). There is evidence of further genetic heterogeneity: some clinically typical patients from consanguineous families have no MASP1/COLEC11/COLEC10 variant (PMID 26789649).
Genetic risk factors:
Causal variants in the three genes (Section 4).
Consanguinity — a major risk factor; most reported families are consanguineous with homozygous variants.
Founder alleles — e.g., COLEC10 c.311G>T (p.Gly104Val) in Ashkenazi Jews (carrier frequency ~1/99; PMID 35943032); COLEC10 c.807_810delCTGT in Apulia, Italy (PMID 34740859).
Modifier genes: Model-organism data suggest other complement components (MASP-2, factor B, C3) may modify skeletal severity (PMID 41774788, model organism).
Environmental risk factors: None established. 3MC is a monogenic Mendelian disorder; no toxin, infectious, lifestyle, occupational, age or sex exposure is a known cause. (Not applicable.)
Protective factors: No genetic or environmental protective factors described for the developmental syndrome. (Free L-fucose is protective against CL-11-mediated renal ischemia-reperfusion injury in mice — PMID 31914693 — but this concerns adult acquired injury, not the developmental syndrome.)
Gene–environment interactions: None documented for 3MC syndrome. (Not applicable.)

3. Phenotypes

Frequencies drawn largely from a 7-patient cohort (PMID 41703727) and case series (PMIDs 36503917, 26789649). Onset is congenital/prenatal for structural features; course is generally stable/non-progressive (malformative) with lifelong sequelae.

Phenotype	Type	HPO term	Frequency / notes
Hypertelorism	physical/craniofacial sign	HP:0000316	Very frequent; core gestalt
Blepharophimosis	physical sign	HP:0000581	Frequent; core gestalt
Blepharoptosis (ptosis)	physical sign	HP:0000508	7/7 in cohort; core gestalt
Highly arched eyebrows	physical sign	HP:0002553	7/7; core gestalt
Epicanthus inversus	physical sign	HP:0000537	Frequent
Downslanted palpebral fissures	physical sign	HP:0000494	Frequent
Cleft lip and/or palate (often bilateral)	physical malformation	HP:0000202 / HP:0000175	~6/7 (86%); variable — may be absent
Postnatal growth deficiency / short stature	clinical sign	HP:0008897 / HP:0004322	Frequent
Global developmental delay / intellectual disability	behavioral/cognitive	HP:0001263 / HP:0001249	Common (7/7 neuromotor delay in cohort); variable severity, may be absent
Hearing loss	lab/functional sign	HP:0000365	~4/7 (57%)
Caudal appendage / prominent elongated coccyx (sacral protuberance)	physical sign	HP:0100541 (tail-like) / sacral appendage	~4/7; relatively specific diagnostic clue
Craniosynostosis	physical sign	HP:0001363	Subset
Radioulnar synostosis	physical sign	HP:0003042	Subset; limb feature
Genital anomalies (e.g., hypospadias, cryptorchidism)	physical sign	HP:0000078 / HP:0000047 / HP:0000028	Subset
Vesicorenal anomalies (horseshoe/pelvic kidney, reflux)	physical sign	HP:0000119 / HP:0000085	Subset
Congenital heart disease (e.g., PDA)	physical sign	HP:0001627 / HP:0001643	~2/7 (29%)
Anterior chamber / anterior-segment dysgenesis	ophthalmic sign	HP:0007700	Subset (notably Michels-type)
Umbilical / periumbilical anomalies, umbilical hernia	physical sign	HP:0001537	~6/7 in recent cohort
Clinodactyly of 5th finger	physical sign	HP:0004209	Subset
High myopia	ophthalmic sign	HP:0011003	Reported
Behavioral/psychiatric (ADHD, ODD, depression)	behavioral	HP:0007018 / —	Case-reported comorbidity (PMID 37463393)

Age of onset: Congenital/prenatal (structural malformations detectable prenatally — bilateral cleft lip/palate + sacral protuberance + renal anomaly; PMID 32441374). Growth deficiency is postnatal.
Severity: Variable (mild to severe), even within the same gene and family (PMID 29407414 describes an adult with the facial gestalt but without cleft lip/palate, intellectual disability, or short stature).
Progression: Non-progressive/stable malformative disorder; sequelae are lifelong.
Quality-of-life impact: Cleft repair, hearing loss, developmental delay, short stature and limb/skeletal anomalies affect feeding, speech, hearing, mobility and learning; no formal EQ-5D/SF-36 studies exist for this ultra-rare disease (not available).

4. Genetic / Molecular Information

Causal genes (HGNC / locus / OMIM gene / product):
MASP1 — HGNC:6901; 3q27.3; 600521; encodes MASP-1 and MASP-3 (alternative splicing). 3MC-causing variants are truncating, or missense within exon 12* encoding the MASP-3-specific C-terminal serine protease domain (PMID 29407414).
COLEC11 — HGNC:17213; 2p25.3; 612502; encodes collectin-11 (CL-K1 / CL-11 / collectin kidney-1)*.
COLEC10 — HGNC:2311; 8q24.12; 607620; encodes collectin-10 (CL-L1 / collectin liver-1)*.
Representative pathogenic variants (all germline, biallelic):
COLEC11 p.Gly204Ser — associated with undetectable serum protein (PMID 25912189, in vitro).
COLEC10 p.Arg9Ter (c.25C>T), p.Gly77Glufs*66 (c.226delA), p.Cys176Trp (c.528C>G) — impair CL-L1 expression/secretion (PMID 28301481, in vitro).
COLEC10 c.311G>T; p.Gly104Val — Ashkenazi Jewish founder variant (PMID 35943032).
COLEC10 c.807_810delCTGT; p.Cys270Serfs*33 (loss of natural stop, +24 aa) — Apulian founder (PMID 34740859).
COLEC10 c.128_129delCA; p.Thr43AsnfsTer9 — Iranian, first homozygous frameshift (PMID 34636477).
MASP1 c.310C>T; p.Gln104Ter — nonsense (PMID 33765348).
MASP1 homozygous ~2 kb intragenic deletion partially affecting exon 12; also exon-level deletions (PMIDs 29407414, 41703727) — may be missed by standard exome pipelines.
Variant classification & type: Pathogenic/likely pathogenic per ACMG/AMP; predominantly loss-of-function — nonsense, frameshift, splice, intragenic/exon-level deletions, and secretion-impairing missense. Functional consequence = loss of function (protein deficiency or non-secretion). No gain-of-function or dominant-negative mechanism reported.
Allele frequency: Causal alleles are rare/absent in gnomAD except population-specific founders (Ashkenazi COLEC10 carrier freq ≈1.01%, PMID 35943032).
Somatic vs germline: Exclusively germline, biallelic (autosomal recessive). No somatic/COSMIC relevance.
Modifier genes: Complement components MASP-2, factor B, C3 modulate skeletal phenotype in mice (PMID 41774788, model organism).
Epigenetics: No disease-specific methylation/histone signature reported (not available).
Chromosomal abnormalities: None characteristic; the disorder is caused by single-gene point/indel/small-deletion variants (some detectable only by careful CNV analysis of WES/WGS; PMID 29407414).

Suggested gene/GO annotations: MASP1/COLEC11/COLEC10; GO:0001867 (complement activation, lectin pathway), GO:0030246 (carbohydrate binding), GO:0005509 (calcium ion binding).

5. Environmental Information

Environmental factors: None known. (Not applicable — Mendelian disorder.)
Lifestyle factors: None known (not applicable).
Infectious agents: None (not applicable). Note the biological irony that the causative genes are innate-immune anti-microbial pattern-recognition molecules, but the syndrome itself is developmental, not infectious.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): Biallelic LOF variant in MASP1/COLEC11/COLEC10 → deficient or mis-secreted collectin (CL-K1 or CL-L1) or non-functional MASP-3 → loss of the CL-K1·MASP-3 chemoattractant guidance cue for cranial neural crest cells (cNCC) → aberrant NCC migration/differentiation → malformation of NCC-derived and midline structures (craniofacial skeleton, palate, heart outflow, genitourinary tract, vertebral/coccygeal elements) → clinical phenotype (PMID 21258343).

Molecular pathways: Lectin pathway of complement (and its link to the alternative pathway). CL-K1/CL-L1 form Ca²⁺-dependent heteromeric collectin complexes that associate with MASP-1/2/3 (PMID 27782323). MASP-3 is the exclusive pro-factor D activator in resting blood, linking the lectin and alternative pathways (PMID 27535802: "activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways.").
Cellular processes: Neural crest cell migration (GO:0001755) — CL-K1 acts as a directional guidance cue (PMID 21258343). Also osteoclast differentiation (GO:0030316) — CL-11 regulates osteoclastogenesis complement-dependently (PMID 41774788, model organism/in vitro).
Protein dysfunction: LOF via impaired secretion and loss of Ca²⁺ binding in the carbohydrate-recognition domain (CRD). Disease mutations do not necessarily block folding/oligomerization in vitro, but abolish Ca²⁺ binding and secretion, producing serum protein deficiency (PMID 25912189, in vitro).
Metabolic/biochemical: CL-K1 recognizes high-mannose oligosaccharides and L-fucose on stressed/altered self-surfaces (PMIDs 25912189, 31914693). Enzymatically, MASP-3 has low amidolytic activity relative to other C1r/C1s/MASP proteases (PMID 23861840, in vitro/structural).
Immune involvement: The causative molecules are innate-immune complement effectors; however, 3MC patients are not primarily immunodeficient — the phenotype reflects the developmental (non-immune) moonlighting role of these proteins ("a broader functionality of the complement system than previously anticipated," PMID 27782323).
Tissue-damage mechanism (adult context): In acquired renal ischemia-reperfusion injury, CL-11 binds a fucosylated damage ligand on tubular epithelium and triggers complement/C5b-9 injury — mechanistically informative but distinct from the developmental syndrome (PMIDs 28663231, 31914693, model organism).
Molecular profiling / omics / single-cell / CRISPR screens: No disease-specific transcriptomic, proteomic, metabolomic or functional-genomics screens published for 3MC (not available); mechanistic evidence is from targeted zebrafish morphants, mouse expression/knockout, and in vitro biochemistry.

Suggested ontology terms: GO:0001755 (neural crest cell migration), GO:0001867 (lectin-pathway complement activation), GO:0030316 (osteoclast differentiation), GO:0045087 (innate immune response); CL:0000333 (migratory neural crest cell / cranial NCC), CL:0000138 (chondrocyte), CL:0000092 (osteoclast); CHEBI:2181 (L-fucose), CHEBI:29108 (calcium(2+)), CHEBI:37671 (high-mannose oligosaccharide/mannose).

7. Anatomical Structures Affected

Organ / system level:
Craniofacial skeleton & face (UBERON:0001456 face; UBERON:0001716 secondary palate) — cleft lip/palate, hypertelorism, dysmorphism.
Skull sutures (UBERON:0000905) — craniosynostosis.
Eyes / periocular (UBERON:0000970) — blepharophimosis, ptosis, anterior-segment dysgenesis (UBERON:0000481 anterior chamber).
Skeleton / limbs — radioulnar synostosis (radius UBERON:0001423 / ulna UBERON:0001424); vertebral column/coccyx (UBERON:0009832) — caudal appendage.
Kidney & urinary tract (UBERON:0002113) — horseshoe/pelvic kidney, vesicoureteral reflux.
Genitalia (UBERON:0000990) — genital anomalies.
Heart (UBERON:0000948) — congenital heart disease (e.g., PDA).
Ear / auditory system (UBERON:0001690) — hearing loss.
CNS — developmental delay/cognitive impairment (functional).
Tissue / cell level: Connective/skeletal tissue (cartilage, bone) and epithelial (palatal) tissue; the key targeted cell population is the cranial neural crest cell (CL:0000333) and its derivatives (chondrocytes, cranial mesenchyme); osteoclasts implicated in skeletal maintenance (PMID 41774788).
Subcellular level: Secreted proteins traffic through the endoplasmic reticulum / secretory pathway (GO:0005783 ER; GO:0005576 extracellular region); LOF mutations cause ER retention / secretion failure (PMID 25912189).
Localization / lateralization: Malformations are typically bilateral/midline (bilateral cleft lip/palate, hypertelorism, radioulnar synostosis often bilateral), consistent with a midline/symmetric developmental patterning defect.

8. Temporal Development

Onset: Congenital — structural anomalies arise during embryogenesis and are detectable prenatally (first prenatal diagnosis: bilateral cleft lip/palate + sacral abnormality + pelvic kidney + brachycephaly; PMID 32441374). Growth deficiency is postnatal.
Onset pattern: Non-acute; features are present from birth (insidious/static developmental).
Progression: Non-progressive malformative syndrome; stable course. Skeletal contractures or scoliosis may require intervention over time (e.g., knee flexion contracture managed with a Taylor Spatial Frame — PMID 34589314).
Disease course / duration: Chronic, lifelong; individuals can survive to adulthood (PMID 29407414 describes a 21-year follow-up in an adult).
Remission / critical periods: No remission (structural). The critical window is embryonic craniofacial neural-crest migration; interventions are corrective/supportive postnatally rather than preventive of the malformation.

9. Inheritance and Population

Epidemiology: Ultra-rare; <50 molecularly confirmed COLEC11/MASP1 patients reported as of 2020 (PMID 32441374), with additional COLEC10 cases since. Formal prevalence/incidence per 100,000 is not established (not available).
Inheritance: Autosomal recessive (all three genes) (PMIDs 21258343, 28301481).
Penetrance / expressivity: Presumed high penetrance for a recognizable phenotype in biallelic carriers, but highly variable expressivity (mild adult cases lacking cleft/ID/short stature — PMID 29407414).
Genetic anticipation: Not applicable (no repeat expansion).
Germline mosaicism: Not reported.
Founder effects / consanguinity: Strong role of consanguinity; documented founders — Ashkenazi Jewish COLEC10 c.311G>T (carrier frequency 1 in 99, PMID 35943032) and Apulian (Italian) COLEC10 c.807_810delCTGT (PMID 34740859).
Carrier frequency: ≈1.01% in Ashkenazi Jews for the COLEC10 founder allele; otherwise very rare (PMID 35943032).
Population demographics: Cases reported worldwide (Turkey/Kurdish, Iran, Italy, Mexico, Ashkenazi Jewish, and others), often from consanguineous or founder populations. Sex ratio: roughly equal (autosomal; cohort of 7 had 5 F / 2 M — small-sample skew, PMID 41703727). Age distribution: predominantly diagnosed in infancy/childhood.

10. Diagnostics

Clinical recognition: Diagnosis is suspected on the facial gestalt (hypertelorism, blepharophimosis, blepharoptosis, highly arched eyebrows) plus cleft lip/palate and — a relatively specific clue — a caudal appendage (PMIDs 34899147, 26789649).
Genetic testing (confirmatory, gold standard):
Whole-exome (WES) / whole-genome (WGS) sequencing or a 3MC/multiple-congenital-anomaly gene panel covering MASP1, COLEC11, COLEC10. Important caveat: some clinical exome panels omit COLEC10, causing missed diagnoses — targeted Sanger of COLEC10 may be needed (PMID 34740859).
CNV / deletion analysis: exon-level and intragenic deletions occur (MASP1) and can be missed by routine pipelines — require careful visual/CNV analysis of WES/WGS (PMIDs 29407414, 41703727).
Single-gene / Sanger for founder alleles (e.g., Ashkenazi COLEC10 c.311G>T).
Karyotype/FISH/mtDNA/repeat-expansion testing: not indicated (normal/uninformative).
Biomarkers / functional assays: Serum/plasma CL-K1 or CL-L1 levels may be reduced/undetectable with secretion-impairing variants (PMID 25912189), but levels can be normal despite pathogenic variants (PMID 34740859) — so protein level is supportive, not definitive.
Imaging: Prenatal ultrasound (facial clefts + sacral/spinal defect + renal anomaly; PMID 32441374); postnatal skeletal survey/radiographs (radioulnar synostosis, craniosynostosis, coccygeal appendage); renal ultrasound; echocardiography; audiology; ophthalmologic exam (anterior-segment).
Clinical criteria / differential diagnosis: No formal consensus criteria. Differential includes other blepharophimosis–ptosis syndromes (e.g., BPES), oral-facial-clefting syndromes, Fraser syndrome, and other craniofacial-limb-renal syndromes; the caudal appendage + radioulnar synostosis + facial gestalt combination and molecular confirmation distinguish 3MC (PMID 35943032 notes 3MC should be in the differential for short stature + radioulnar synostosis + cleft lip/palate).
Screening: Carrier / cascade screening in founder populations (Ashkenazi Jewish COLEC10) and consanguineous families; prenatal molecular testing feasible once a family variant is known (PMID 32441374). No newborn-screening program exists.

11. Outcome / Prognosis

Survival / mortality: No formal survival statistics; the disorder is generally compatible with survival to adulthood (PMID 29407414, 21-year follow-up). Severe multi-organ involvement (cardiac, renal) can affect prognosis in individual cases.
Morbidity / function: Chronic disability from cognitive impairment, hearing loss, short stature, cleft-related speech/feeding issues, and skeletal/limb constraints (radioulnar synostosis, contractures). Variable — some individuals have mild, near-normal cognition (PMID 29407414).
Quality-of-life measures: No disease-specific QoL data (not available).
Complications: Cleft-related feeding/speech difficulties and otitis/hearing loss; renal anomalies may predispose to urinary complications; skeletal contractures/scoliosis; psychiatric comorbidity reported (ADHD/ODD/depression; PMID 37463393).
Recovery / prognostic factors: Malformations are static; outcomes improve with corrective surgery, hearing rehabilitation, and developmental support. Prognosis is modulated by severity of cardiac/renal/CNS involvement. No validated prognostic biomarkers.

12. Treatment

No disease-modifying or gene-specific therapy exists. Management is multidisciplinary, symptomatic, and supportive.

Pharmacotherapy: None specific to 3MC. Symptomatic (e.g., stimulants/SSRIs for comorbid ADHD/depression as clinically indicated; PMID 37463393). No pharmacogenomic considerations established. (NCIT: Supportive Care; Symptomatic Treatment.)
Advanced therapeutics (gene/cell/RNA/targeted/immuno): None approved or in trials for 3MC (not applicable). The lectin-pathway/CL-11 axis is a therapeutic target in acquired renal IRI (L-fucose decoy strategy, PMID 32472330, model organism) — not for the developmental syndrome.
Surgical / interventional: Cleft lip and palate repair (NCIT: Cleft Lip Repair / Cleft Palate Repair); craniofacial/craniosynostosis surgery; ptosis/blepharophimosis correction; orthopedic correction of limb contractures/synostosis (e.g., Taylor Spatial Frame for knee flexion contracture, PMID 34589314); urologic/genital corrective surgery as needed.
Supportive / rehabilitative: Hearing aids/audiologic management; speech therapy; physical/occupational therapy; growth and nutritional monitoring; developmental/educational support; ophthalmologic care.
Treatment strategy: Individualized, coordinated by clinical genetics + craniofacial/plastic surgery, ENT/audiology, orthopedics, urology/nephrology, cardiology, ophthalmology, and developmental pediatrics. Genetic counseling is integral.
Experimental treatments / trials: None registered specifically for 3MC (not available).

Suggested NCIT terms: Supportive Care; Surgical Procedure; Cleft Lip Repair; Cleft Palate Repair; Physical Therapy; Genetic Counseling; Hearing Aid.

13. Prevention

Primary prevention: Not preventable once conceived (congenital genetic disorder). Preconception risk reduction via genetic counseling for consanguineous couples and known-carrier families.
Secondary prevention / early detection: Prenatal molecular diagnosis and prenatal ultrasound (facial clefts + sacral/renal anomalies) enable early identification and reproductive planning (PMID 32441374). Preimplantation genetic testing (PGT-M) is an option when the familial variant is known.
Genetic screening: Carrier and cascade screening — high-yield in the Ashkenazi Jewish population for COLEC10 c.311G>T (carrier ~1/99) and in consanguineous/founder populations (PMID 35943032).
Counseling: Autosomal-recessive recurrence risk 25% per pregnancy for carrier couples; molecular confirmation "allows for alternate reproductive options" (PMID 32441374).
Tertiary prevention: Early cleft repair, hearing rehabilitation, developmental therapy, and orthopedic/urologic surveillance to limit complications.
Immunization / public-health / environmental interventions: Not applicable.

14. Other Species / Natural Disease

Taxonomy of gene orthologs: MASP1, COLEC11, COLEC10 are conserved in vertebrates — Mus musculus (NCBI Taxon 10090), Danio rerio (7955), Homo sapiens (9606).
Naturally occurring animal disease: No naturally occurring 3MC-equivalent Mendelian disease is catalogued in companion animals/livestock (OMIA — not available). Phenotypes are known only from engineered/experimental models.
Comparative biology / conservation: The lectin complement pathway and its developmental role are evolutionarily conserved; zebrafish colec11/masp1 knockdown reproduces craniofacial and pigmentary defects (PMID 21258343), demonstrating conserved mechanism.
Transmission / zoonosis: Not applicable (genetic, non-transmissible).

15. Model Organisms

Zebrafish (Danio rerio, ZFIN): Morpholino knockdown (morphants) of colec11 or masp1 produce pigmentary defects and severe craniofacial abnormalities — the key model recapitulating the human craniofacial phenotype and demonstrating the neural-crest guidance mechanism (PMID 21258343, model organism). Recapitulation: strong for craniofacial/neural-crest features.
Mouse (Mus musculus, MGI):
Expression studies: CL-K1 is highly expressed in embryonic craniofacial cartilage, heart, bronchi, kidney, and vertebral bodies (PMID 21258343); COLEC10/CL-L1 is expressed in the base membrane of the developing palate (PMID 28301481) — spatially concordant with affected human structures.
Knockouts: CL-11 (Colec11) knockout alone does not reproduce skeletal abnormalities; combined CL-11 + MASP-2 / factor B / C3 deficiency causes vertebral bone loss and spinal curvature via impaired osteoclastogenesis (PMID 41774788, model organism) — a limitation (single-gene mouse KO under-recapitulates the human skeletal phenotype) and a clue that complement modifiers matter.
In vitro / cellular models: Mammalian expression systems demonstrating that disease mutations block CL-K1/CL-L1 secretion and Ca²⁺ binding (PMIDs 25912189, 28301481); human iPSC-derived osteoclasts showing CL-11 dependence (PMID 41774788); recombinant MASP-3 serine-protease domain structural/enzymatic studies (PMID 23861840).
Model limitations: Mouse single-gene KOs incompletely reproduce the full malformation spectrum (skeletal features require compound complement deficiency); morpholino zebrafish models capture craniofacial/pigment phenotypes but are transient knockdowns.
Resources: ZFIN (zebrafish), MGI/IMPC (mouse), Cellosaurus (iPSC lines).

Evidence Source Summary

Domain	Evidence type	Key PMIDs
Gene discovery (MASP1, COLEC11)	Human + zebrafish + mouse	21258343
Gene discovery (COLEC10)	Human + mouse + in vitro	28301481
Mutation mechanism (secretion, Ca²⁺)	In vitro / structural	25912189, 23861840
Complement pathway link (MASP-3→factor D)	In vitro	27535802, 27782323
Phenotype spectrum & frequencies	Human cohorts/case series	41703727, 36503917, 26789649, 29407414
Founder allele / carrier frequency	Human population	35943032, 34740859, 34636477, 33765348
Prenatal diagnosis	Human case	32441374
Skeletal/osteoclast mechanism	Mouse + iPSC	41774788
Renal CL-11/fucose (adult context)	Mouse / review	31914693, 32472330, 28663231, 27286717
Orthopedic management	Human case	34589314
Psychiatric comorbidity	Human case	37463393

Limitations and Future Directions

Ultra-rarity: <~100 molecularly confirmed patients; frequencies are from small cohorts and case reports, limiting precision of penetrance/expressivity and genotype–phenotype correlation.
Genetic heterogeneity: Some clinically typical, consanguineous patients lack variants in the three known genes (PMID 26789649) — additional lectin-pathway genes likely remain to be discovered.
No omics datasets: No published transcriptomic/proteomic/metabolomic/single-cell profiling of patient tissues; mechanism rests on targeted models and biochemistry.
Future directions: Deeper phenotyping registries; CNV-aware sequencing (to capture exon-level deletions); functional CL-K1/CL-L1 assays as adjunct diagnostics; delineating the neural-crest guidance mechanism at single-cell resolution; exploring complement modifiers of skeletal severity.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	19
On topic	15
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	61
Resolved	52
Unresolved (possible confabulation)	2
Obsolete	1
Unverifiable	6
Terms whose name was checked	30
Terms named correctly	8
Terms named as a different term	18
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0018721 (1 mention) - the report calls it "3MC syndrome"; MONDO calls it obsolete rare combined vascular malformation
HP:0000316 (1 mention) - the report calls it "physical/craniofacial sign"; HP calls it Hypertelorism
HP:0000581 (1 mention) - the report calls it "physical sign"; HP calls it Blepharophimosis
HP:0000508 (1 mention) - the report calls it "physical sign"; HP calls it Ptosis
HP:0002553 (1 mention) - the report calls it "physical sign"; HP calls it Highly arched eyebrow
HP:0000537 (1 mention) - the report calls it "physical sign"; HP calls it Epicanthus inversus
HP:0000494 (1 mention) - the report calls it "physical sign"; HP calls it Downslanted palpebral fissures
HP:0000365 (1 mention) - the report calls it "lab/functional sign"; HP calls it Hearing impairment
HP:0100541 (1 mention) - the report calls it "tail-like"; HP calls it Femoral hernia
HP:0001363 (1 mention) - the report calls it "physical sign"; HP calls it Craniosynostosis
HP:0003042 (1 mention) - the report calls it "physical sign"; HP calls it Elbow dislocation
HP:0007700 (1 mention) - the report calls it "ophthalmic sign"; HP calls it Ocular anterior segment dysgenesis
HP:0001537 (1 mention) - the report calls it "physical sign"; HP calls it Umbilical hernia
HP:0004209 (1 mention) - the report calls it "physical sign"; HP calls it Clinodactyly of the 5th finger
HP:0011003 (1 mention) - the report calls it "ophthalmic sign"; HP calls it High myopia
CHEBI:37671 (1 mention) - the report calls it "high-mannose oligosaccharide/mannose"; CHEBI calls it (1->3)-beta-D-glucan
UBERON:0000970 (1 mention) - the report calls it "Eyes / periocular"; UBERON calls it eye
UBERON:0002113 (1 mention) - the report calls it "Kidney & urinary tract"; UBERON calls it kidney

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

UBERON:0000905 (1 mention), reported as "Skull sutures" - UBERON does not contain this term
UBERON:0009832 (1 mention), reported as "coccyx" - UBERON does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

MONDO:0018721 (obsolete rare combined vascular malformation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0001755 (2 mentions) - the report calls it "Neural crest cell migration", "Cellular processes: Neural crest cell migration", "neural crest cell migration"; GO calls it neural crest cell migration
CHEBI:2181 (1 mention) - the report calls it "L-fucose"; CHEBI calls it L-fucopyranose, and lists "(-)-L-Fucose" among its other names
UBERON:0000990 (1 mention) - the report calls it "Genitalia"; UBERON calls it reproductive system, and lists "genitalia" among its other names
UBERON:0001690 (1 mention) - the report calls it "Ear / auditory system"; UBERON calls it ear, and lists "auditory apparatus" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0001867 - called "complement activation, lectin pathway", "lectin-pathway complement activation"
GO:0001755 - called "Neural crest cell migration", "Cellular processes: Neural crest cell migration", "neural crest cell migration"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

3MC Syndrome — Comprehensive Disease Characterization Report

Summary (Answer to the Research Question)

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Source Summary

Limitations and Future Directions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Unresolved terms

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver