👪

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 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.

◆

Subtypes

3

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

MASP1 hgnc:6901

Caused by biallelic MASP1 variants, most of which fall in exon 12, the single exon encoding the MASP-3-specific serine protease domain. This is the form in which alternative-pathway pro-factor D maturation is additionally impaired.

Show evidence (1 reference)

PMID:21035106 SUPPORT 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. Missense substitutions can cause cellular retention of CL-K1 so that no protein is secreted, a loss-of-secretion mechanism rather than simple absence of transcript.

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

"Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively)."

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. A founder allele, c.311G>T (p.Gly104Val), segregates in the Ashkenazi Jewish population at a carrier frequency of roughly 1 in 99.

Show evidence (1 reference)

PMID:28301481 SUPPORT 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.

⚙

Pathophysiology

6

Loss of Secreted Collectin CL-K1/CL-L1 Function

Biallelic COLEC11 or COLEC10 variants abolish the function of the secreted collectins CL-K1 and CL-L1, which normally assemble into heteromeric complexes. Pathogenic missense alleles act not only by loss of protein but by impairing secretion — CL-K1 bearing the Gly204Ser substitution is retained intracellularly and is undetectable in patient serum.

COLEC11 hgnc:17213 COLEC10 hgnc:2220

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline COLEC11 or COLEC10 alleles. Reported classes include missense substitutions that block secretion, frameshift and nonsense alleles, a multi-exon deletion, and at least one allele that is secreted normally but chemoattractively inert.

lectin complement pathway activation GO:0001867 ↓ DECREASED

calcium ion binding by the carbohydrate-recognition domain GO:0005509 ↓ DECREASED carbohydrate binding GO:0030246 ↓ DECREASED

Downstream

Impaired Complement-Dependent Osteoclastogenesis CL-11 is required for osteoclast differentiation, acting together with complement. Loss of the collectin impairs osteoclast differentiation directly, and supplementing CL-11 restores it.

Impaired Neural Crest Cell Guidance CL-K1 is the secreted guidance cue itself, so loss of the collectin directly removes the chemoattractant signal that migrating neural crest cells follow.

Show evidence (5 references)

PMID:28301481 SUPPORT In Vitro

"The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1 respectively, form heteromeric complexes."

Establishes that the two collectin gene products act as a physical complex, which is why variants in either produce the same syndrome.

PMID:28301481 SUPPORT 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."

Shows the loss-of-function mechanism operates at the level of expression and secretion of CL-L1.

PMID:21258343 SUPPORT In Vitro

"This suggests that the missense substitution in these patients leads to cellular retention of the protein."

Documents impaired secretion, rather than absent transcript, as the consequence of a pathogenic CL-K1 missense allele.

+ 2 more references

Loss of MASP-3 Serine Protease Activity

Biallelic MASP1 variants clustered in exon 12 — the single exon encoding the serine protease domain unique to the MASP-3 isoform — yield enzymatically inactive protein. MASP1 also encodes MASP-1, which shares the heavy chain but has a distinct protease domain, so the exon-12 clustering is what makes MASP-3 the relevant isoform for 3MC syndrome.

MASP1 hgnc:6901

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline MASP1 alleles, clustered in exon 12. Reported classes are nonsense, missense within the MASP-3 protease domain, and intragenic deletion.

MASP-3 serine endopeptidase activity GO:0004252 ↓ DECREASED

Downstream

Impaired Neural Crest Cell Guidance MASP-3 loss produces the same craniofacial phenotype as collectin loss, and the collectins are MASP-binding partners, but the substrate through which MASP-3 acts on neural crest migration has not been established. One proposed route is processing of IGFBP-5 and consequent modulation of insulin-like growth factor availability during craniofacial development.

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 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

Loss of the secreted collectin guidance cue disrupts the directed migration of neural crest cells during embryogenesis. This is the step that converts a complement-pathway molecular defect into a developmental one, and it explains why the malformed structures in 3MC syndrome are predominantly neural crest derivatives rather than immune tissues.

migratory neural crest cell CL:0000333

neural crest cell migration GO:0001755 ↓ DECREASED

Downstream

Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis Cranial neural crest cells that fail to migrate correctly do not populate the facial primordia and pharyngeal arches, so the skeletal and soft tissue structures they would have formed are malformed.

Show evidence (1 reference)

PMID:35943032 SUPPORT Human Clinical

"Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration."

States the accepted mechanistic model linking collectin loss to the clinical features through neural crest migration.

Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis

Failure of cranial neural crest-derived tissue to form normally produces the craniofacial phenotype: the periorbital gestalt, orofacial clefting, premature suture fusion, and middle/external ear anomalies underlying the hearing loss. Collectin expression in murine embryonic craniofacial cartilage and in the palatal base membrane places the proteins at the right time and place for this role.

neural crest cell development GO:0014032 ↓ DECREASED

Animal models

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

Show evidence (2 references)

PMID:21258343 SUPPORT Model Organism

"CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies."

Places CL-K1 expression in the developing craniofacial tissues affected in the syndrome.

PMID:28301481 SUPPORT Model Organism

"We show COLEC10 is expressed in the base membrane of the palate during murine embryo development."

Places CL-L1 expression at the palatal shelf, the structure whose failure of fusion produces cleft palate.

Impaired Complement-Dependent Osteoclastogenesis

CL-11 is required for osteoclast differentiation and acts in concert with complement to maintain bone. This is a second, non-neural-crest route to skeletal disease in 3MC syndrome, and it is complement-dependent in a way the craniofacial arm is not. The genetic architecture matters and is unusual: CL-11 deletion alone does not produce a skeletal phenotype in mice. Bone loss appears only when collectin deficiency is combined with loss of MASP-2, factor B or C3, so complement acts here as a modifier rather than as the primary lesion.

osteoclast CL:0000092

osteoclast differentiation GO:0030316 ↓ DECREASED

Experimental models

Human iPSC-derived osteoclasts IPSC DERIVED MODEL Reproduces the CL-11 and complement dependence of osteoclast differentiation in human cells, which is what makes the mouse finding relevant to the human disease.

Animal models

Colec11 knockout mouse Mouse fails to recapitulate Collectin loss on its own does not reproduce the skeletal phenotype in mice. This negative result is the reason the osteoclastogenesis node is curated as requiring a second complement hit rather than as a direct consequence of collectin deficiency.

Show evidence (2 references)

PMID:41774788 SUPPORT Model Organism

"combined deficiencies of CL-11 with complement components MASP-2 (lectin pathway), complement factors B, or C3 (alternative pathway amplification) result in marked vertebral bone loss and spinal curvature by 12 wk of age"

Establishes that the skeletal phenotype requires combined collectin and complement deficiency, which is what makes complement a modifier here.

PMID:41774788 SUPPORT Model Organism

"CL-11 and the membrane attack complex (C5b-9) colocalized to OCLs and their precursors in normal bone from embryonic development through to adulthood."

Places CL-11 and terminal complement together at the osteoclast lineage across development, supporting a direct role rather than a bystander association.

Impaired Pro-Factor D Maturation

In the MASP1/MASP-3-deficient form, conversion of pro-factor D to mature factor D in the alternative complement pathway is compromised. Notably this is a biochemical consequence that does not translate into clinical immunodeficiency: 3MC patients retain detectable mature factor D, indicating a MASP-3-independent maturation route, and recurrent infection is not a feature of the syndrome.

alternative complement pathway activation GO:0006957 ↓ 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 Human Clinical

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

Supports impaired but incomplete loss of factor D maturation in patients, which is why this node is a biochemical finding rather than a clinical immunodeficiency. Graded PARTIAL because it establishes residual mature factor D without measuring downstream alternative-pathway competence.

PMID:27535802 SUPPORT 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."

Establishes MASP-3 as the sole physiological pro-factor D activator in resting blood, which is what makes this node a predicted consequence of MASP-3 loss.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

23

Cardiovascular 1

Congenital Heart Disease OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:41703727 SUPPORT 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 congenital heart disease in two of seven patients, which is the OCCASIONAL band.

Ear 1

Hearing Loss FREQUENT Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:21035106 SUPPORT 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 2

Hypertelorism VERY_FREQUENT HP:0000316

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Reports hypertelorism among the core facial traits at 70-95% frequency, mapping to VERY_FREQUENT.

Ptosis VERY_FREQUENT HP:0000508

Show evidence (1 reference)

PMID:36503917 SUPPORT Human Clinical

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

Independent series confirming ptosis as part of the distinctive facial phenotype.

Genitourinary 1

Horseshoe Kidney OCCASIONAL HP:0000085

Show evidence (1 reference)

PMID:34740859 SUPPORT 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.

Head and Neck 5

Highly Arched Eyebrows VERY_FREQUENT HP:0002553

Show evidence (1 reference)

PMID:36503917 SUPPORT 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.

Cleft Lip FREQUENT HP:0410030

Show evidence (1 reference)

PMID:21258343 SUPPORT 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."

Reports cleft lip and palate at 40-68%, mapping to FREQUENT.

Cleft Palate FREQUENT HP:0000175

Show evidence (1 reference)

PMID:36503917 SUPPORT Human Clinical

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

Confirms cleft palate, characteristically bilateral, as a common feature.

Craniosynostosis OCCASIONAL HP:0001363

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Reports craniosynostosis at 20-30%, mapping to OCCASIONAL.

Downslanted Palpebral Fissures FREQUENT HP:0000494

Show evidence (1 reference)

PMID:34589314 SUPPORT Human Clinical

"High-arched brows, ptosis, blepharophimosis, hypertelorism, cleft lip, cleft palate, developmental delay, hearing loss, abdominal wall defect, and urogenital and skeletal abnormalities are all characteristics."

Supports the periorbital gestalt cluster this phenotype belongs to. Graded PARTIAL because the quoted list does not name palpebral fissure slant specifically.

Limbs 1

Radioulnar Synostosis OCCASIONAL HP:0002974

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Reports radioulnar synostosis at 20-30%, mapping to OCCASIONAL.

Nervous System 2

Intellectual Disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:21258343 SUPPORT 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."

Reports cognitive impairment at 40-68%, mapping to FREQUENT.

Global Developmental Delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:41703727 SUPPORT Human Clinical

"All patients showed neuromotor developmental delay."

Reports neuromotor developmental delay in all seven patients.

Growth 1

Postnatal Growth Deficiency FREQUENT Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:21258343 SUPPORT 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."

Reports postnatal growth deficiency at 40-68%, mapping to FREQUENT.

Other 9

Blepharophimosis VERY_FREQUENT HP:0000581

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Reports blepharophimosis among the core facial traits at 70-95% frequency.

Vesicorenal Anomalies OCCASIONAL Vesicoureteral reflux HP:0000076

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Supports vesicorenal anomalies at 20-30%. Graded PARTIAL because the source reports the category "vesicorenal anomalies" rather than vesicoureteral reflux specifically, which is the closest available HPO binding.

Caudal Appendage OCCASIONAL HP:0002825

Show evidence (1 reference)

PMID:36503917 SUPPORT 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.

Periumbilical Depression VERY_FREQUENT HP:6000808

Show evidence (2 references)

PMID:41703727 SUPPORT 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 periumbilical anomalies in six of seven patients, which is why this concept is curated as VERY_FREQUENT and separately from umbilical herniation.

PMID:21035106 SUPPORT 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 or Omphalocele VERY_RARE HP:0001537

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Lists umbilical hernia/omphalocele among the rare features, mapping to VERY_RARE.

Anterior Chamber Defects VERY_RARE Abnormal anterior chamber morphology HP:0000593

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Lists anterior chamber defects among the rare features.

Epicanthus Inversus VERY_FREQUENT HP:0000537

Show evidence (1 reference)

PMID:41703727 SUPPORT 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.

Genital Anomalies OCCASIONAL Abnormality of the genital system HP:0000078

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

The same sentence that supports craniosynostosis and radioulnar synostosis names genital anomalies at 20-30%.

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

Show evidence (1 reference)

PMID:34740859 SUPPORT 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.

🧬

Genetic Associations

3

MASP1

Gene: MASP1 hgnc:6901 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:21035106 SUPPORT 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 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."

States the two causative allele classes and confirms the exon 12 / MASP-3 localisation.

PMID:29407414 SUPPORT 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)

MASP1 exon 12 biallelic loss-of-function alleles

Nonsense and missense alleles in exon 12, which encodes the MASP-3-specific serine protease domain, plus intragenic deletions partially affecting that exon. Reported genotypes are homozygous or compound heterozygous and germline.

COLEC11

Gene: COLEC11 hgnc:17213 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:21258343 SUPPORT 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 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 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."

Documents a second, independent COLEC10 founder allele in southern Italy, alongside the Ashkenazi Jewish c.311G>T allele.

PMID:34740859 SUPPORT 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."

Shows a distinct loss-of-function route for this allele: normal plasma levels but impaired chemoattractant activity, so secretion failure is not the only mechanism.

💊

Medical Actions

2

Orthopedic Correction of Joint Contracture

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

Gradual correction of knee flexion contracture using a Taylor spatial frame, followed by bracing to maintain extension. Reported as safe and effective in a molecularly confirmed COLEC11 patient; knee flexion contracture was not previously recognised as part of the syndrome.

Show evidence (1 reference)

PMID:34589314 SUPPORT Human Clinical

"According to our findings, the TSF was the safest, most accurate, stable fixator, and most efficient solution for treating knee flexion contracture, resulting in high patient and family satisfaction."

Reports the outcome of the intervention in a confirmed 3MC patient.

Genetic Counseling

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

Counselling for the autosomal recessive recurrence risk, which is substantial and actionable: a molecularly confirmed diagnosis enables alternative reproductive options and prenatal testing.

Show evidence (1 reference)

PMID:32441374 SUPPORT 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.

🔬

Diagnosis

1

Molecular diagnosis by sequencing of MASP1, COLEC11 and COLEC10

Diagnosis is confirmed by identifying biallelic pathogenic variants in one of the three genes, typically via exome sequencing or a targeted panel. In individuals of Ashkenazi Jewish ancestry, targeted testing for the COLEC10 c.311G>T founder allele is warranted. Two documented false-negative routes matter when a molecular result comes back negative in a clinically convincing case. Some clinical exome panels carry only MASP1 and COLEC11, so a COLEC10 variant is not looked for at all; and intragenic deletions can escape routine variant-calling and be found only on direct inspection of the sequencing data. Both have produced initially unsolved 3MC cases.

Show evidence (3 references)

PMID:35943032 SUPPORT 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 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 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.

📈

Progression

1

Congenital and static

3MC syndrome is a congenital malformation syndrome. The structural anomalies are present at birth, are static rather than progressive, and survival to adulthood is documented. Prenatal detection is possible when fetal ultrasound shows facial clefting together with spinal or renal anomalies.

Show evidence (2 references)

PMID:32441374 SUPPORT 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 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.

📊

Prevalence

2

Worldwide

Cases In Literature Ultra Rare

Thirty-two patients from 20 families had been reported at the time of the 2011 gene discovery; the literature has expanded since but remains small.

Show evidence (1 reference)

PMID:21258343 SUPPORT Human Clinical

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

Gives the reported case count establishing the ultra-rare band.

Ashkenazi Jewish

Carrier Frequency 1010.0 per 100,000 >1 in 1,000

Carrier frequency (not disease prevalence) for the COLEC10 founder allele c.311G>T, 1 in 99 or 1.01%.

Show evidence (1 reference)

PMID:35943032 SUPPORT Human Clinical

"Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%."

Direct measurement of the founder allele carrier frequency.

🔀

Differential Diagnoses

2

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

Branchio-oto-renal spectrum

Overlapping Features Also presents with hearing loss and branchial/ear anomalies, but is autosomal dominant, EYA1/SIX-related, and features renal malformation and branchial fistulae rather than the 3MC periorbital gestalt, clefting and caudal appendage.

Blepharophimosis-ptosis-epicanthus inversus syndrome

Overlapping Features Shares the periorbital gestalt (blepharophimosis, ptosis, epicanthus inversus) but is FOXL2-related, autosomal dominant, and lacks orofacial clefting, growth deficiency and the skeletal synostoses.

🧫

Experimental Models

1

Human iPSC-derived osteoclasts IPSC_DERIVED_MODEL

Osteoclasts differentiated from human induced pluripotent stem cell lines, used to test whether the mouse collectin/complement dependence holds in human cells.

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis recapitulates fidelity: moderate Reproduces the CL-11 and complement dependence of osteoclast differentiation in human cells, which is what makes the mouse finding relevant to the human disease.

Limitations: iPSC-derived osteoclasts in culture lack the bone microenvironment and the mechanical loading that drive remodelling in vivo, and the cells are not 3MC patient-derived, so the system tests the pathway rather than the patient genotype.

Readouts

Osteoclast differentiation from human iPSC lines

Direction: DECREASED

Interpretation: Human confirmation of the collectin/complement requirement measured in the mouse ex vivo assay.

Show evidence (1 reference)

PMID:41774788 SUPPORT In Vitro

"This dependence on CL-11 and complement was recapitulated in human OCLs derived from induced pluripotent stem cell lines."

Reports the human osteoclast differentiation measurement behind this readout.

Show evidence (1 reference)

PMID:41774788 SUPPORT In Vitro

"This dependence on CL-11 and complement was recapitulated in human OCLs derived from induced pluripotent stem cell lines."

Supports the human system as informative for the osteoclastogenesis node.

🐁

Animal Models

3

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 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 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.

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, whereas human 3MC alleles cluster in the MASP-3-specific exon, so the model is broader than the human genotype. It models the biochemical node only, not the craniofacial phenotype.

Show evidence (1 reference)

PMID:28794230 SUPPORT 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."

Establishes the mouse knockout as the model that first identified the pro-factor D maturation defect.

Colec11 knockout mouse

Single-gene collectin-11 knockout, used as the control arm against which the complement double knockouts were compared.

Species

Mouse

Genotype

Colec11-/- (single knockout)

Publication

PMID:41774788

Pathograph links

Impaired Complement-Dependent Osteoclastogenesis fails to recapitulate fidelity: moderate Collectin loss on its own does not reproduce the skeletal phenotype in mice. This negative result is the reason the osteoclastogenesis node is curated as requiring a second complement hit rather than as a direct consequence of collectin deficiency.

Limitations: A negative result in mouse does not establish that human COLEC11 loss is skeletally silent: humans carry biallelic collectin loss on a different complement background, and the reported 3MC skeletal features (craniosynostosis, radioulnar synostosis) are developmental rather than the remodelling phenotype measured here. The finding constrains the mechanism; it does not transfer the negative to patients.

Show evidence (1 reference)

PMID:41774788 SUPPORT Model Organism

"we demonstrate that CL-11 deletion alone does not produce skeletal abnormalities in mice"

States the negative result directly.

{ }

Source YAML

click to show

name: 3MC Syndrome
creation_date: "2026-08-29T00:00:00Z"
description: >-
  3MC syndrome is a rare autosomal recessive developmental disorder that unifies
  four historically separate eponymous conditions — Mingarelli, Malpuech,
  Michels and Carnevale syndromes — under a single molecular etiology. It is
  caused by biallelic loss-of-function variants in genes encoding components of
  the lectin complement pathway: MASP1 (which encodes the MASP-1 and MASP-3
  serine protease isoforms) and the collectins COLEC11 (CL-K1) and COLEC10
  (CL-L1), whose protein products form heteromeric complexes. The cardinal
  presentation is a distinctive craniofacial gestalt — hypertelorism,
  blepharophimosis, blepharoptosis and highly arched eyebrows — accompanied in
  many patients by cleft lip and/or palate, postnatal growth deficiency,
  cognitive impairment and hearing loss, with craniosynostosis, radioulnar
  synostosis and genital or vesicorenal anomalies in a minority. A caudal
  (coccygeal) appendage is an uncommon but strongly suggestive clinical clue.
  The mechanism is developmental rather than immunological: CL-K1 acts as a
  secreted guidance cue (chemoattractant) for migrating neural crest cells, and
  the malformed structures are predominantly those derived from cranial neural
  crest. Although MASP-3 additionally serves as the maturase that converts
  pro-factor D to mature factor D in the alternative complement pathway,
  patients retain detectable mature factor D and clinically significant
  immunodeficiency is not a feature of the syndrome.
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.
has_subtypes:
- name: 3MC1
  display_name: 3MC syndrome 1 (MASP1/MASP-3)
  description: >-
    Caused by biallelic MASP1 variants, most of which fall in exon 12, the
    single exon encoding the MASP-3-specific serine protease domain. This is the
    form in which alternative-pathway 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.
- name: 3MC2
  display_name: 3MC syndrome 2 (COLEC11/CL-K1)
  description: >-
    Caused by biallelic COLEC11 variants. Missense substitutions can cause
    cellular retention of CL-K1 so that no protein is secreted, a
    loss-of-secretion mechanism rather than simple absence of transcript.
  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, both of which encode proteins in the lectin
      complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3,
      respectively).
    explanation: >-
      Identifies COLEC11 alongside MASP1 as one of the two originally reported
      3MC syndrome genes.
- name: 3MC3
  display_name: 3MC syndrome 3 (COLEC10/CL-L1)
  description: >-
    Caused by biallelic COLEC10 variants. A founder allele, c.311G>T
    (p.Gly104Val), segregates in the Ashkenazi Jewish population at a carrier
    frequency of roughly 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.
pathophysiology:
- name: Loss of Secreted Collectin CL-K1/CL-L1 Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic COLEC11 or COLEC10 variants abolish the function of the secreted
    collectins CL-K1 and CL-L1, which normally assemble into heteromeric
    complexes. Pathogenic missense alleles act not only by loss of protein but
    by impairing secretion — CL-K1 bearing the Gly204Ser substitution is
    retained intracellularly and is undetectable in patient serum.
  genes:
  - preferred_term: COLEC11
    term:
      id: hgnc:17213
      label: COLEC11
  - preferred_term: COLEC10
    term:
      id: hgnc:2220
      label: COLEC10
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline COLEC11 or COLEC10 alleles. Reported classes include
      missense substitutions that block secretion, frameshift and nonsense
      alleles, a multi-exon deletion, and at least one allele that is secreted
      normally but chemoattractively inert.
  molecular_functions:
  - preferred_term: calcium ion binding by the carbohydrate-recognition domain
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  - preferred_term: carbohydrate binding
    term:
      id: GO:0030246
      label: carbohydrate binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: lectin complement pathway activation
    term:
      id: GO:0001867
      label: complement activation, lectin pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1
      respectively, form heteromeric complexes.
    explanation: >-
      Establishes that the two collectin gene products act as a physical
      complex, which is why variants in either produce the same syndrome.
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    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: >-
      Shows the loss-of-function mechanism operates at the level of expression
      and secretion of CL-L1.
  - reference: PMID:21258343
    reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This suggests that the missense substitution in these patients leads to
      cellular retention of the protein.
    explanation: >-
      Documents impaired secretion, rather than absent transcript, as the
      consequence of a pathogenic CL-K1 missense allele.
  - 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
    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: >-
      Pins the loss-of-function to failed calcium binding in the
      carbohydrate-recognition domain rather than misfolding, which is the
      molecular reason the protein is not secreted.
  - 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
    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: >-
      States the proposed causal chain from calcium-binding failure to secretion
      failure to disease.
  downstream:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    causal_link_type: DIRECT
    description: >-
      CL-11 is required for osteoclast differentiation, acting together with
      complement. Loss of the collectin impairs osteoclast differentiation
      directly, and supplementing CL-11 restores it.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ex vivo osteoclast (OCL) differentiation from bone marrow-derived cells
        of these double-knockout mice was profoundly impaired but was
        substantially restored by CL-11 supplementation.
      explanation: >-
        The rescue by CL-11 supplementation establishes the dependence of
        osteoclast differentiation on the collectin.
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: DIRECT
    description: >-
      CL-K1 is the secreted guidance cue itself, so loss of the collectin
      directly removes the chemoattractant signal that migrating neural crest
      cells follow.
    evidence:
    - reference: PMID:21258343
      reference_title: Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Finally, we show that CL-K1 serves as a guidance cue for neural crest
        cell migration.
      explanation: >-
        Directly links the collectin to neural crest guidance, the step
        immediately downstream of its loss.
- name: Loss of MASP-3 Serine Protease Activity
  biological_scale: MOLECULAR
  description: >-
    Biallelic MASP1 variants clustered in exon 12 — the single exon encoding the
    serine protease domain unique to the MASP-3 isoform — yield enzymatically
    inactive protein. MASP1 also encodes MASP-1, which shares the heavy chain
    but has a distinct protease domain, so the exon-12 clustering is what makes
    MASP-3 the relevant isoform for 3MC syndrome.
  genes:
  - preferred_term: MASP1
    term:
      id: hgnc:6901
      label: MASP1
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline MASP1 alleles, clustered in exon 12. Reported classes
      are nonsense, missense within the MASP-3 protease domain, and intragenic
      deletion.
  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.
  downstream:
  - target: Impaired Neural Crest Cell Guidance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      MASP-3 loss produces the same craniofacial phenotype as collectin loss,
      and the collectins are MASP-binding partners, but the substrate through
      which MASP-3 acts on neural crest migration has not been established. One
      proposed route is processing of IGFBP-5 and consequent modulation of
      insulin-like growth factor availability during craniofacial development.
    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: >-
        The two mutations occur in a MASP1 isoform that has been reported to
        process IGFBP-5, thereby playing a critical role in insulin growth factor
        availability during craniofacial and muscle development.
      explanation: >-
        Offers a candidate intermediate for the MASP-3 route to craniofacial
        malformation. Graded PARTIAL because the paper reports the IGFBP-5
        substrate relationship as prior knowledge about the isoform rather than
        demonstrating it operates in these patients.
    - 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
      snippet: >-
        It binds to carbohydrates on pathogens to activate the lectin pathway of
        complement and together with its associated serine protease MASP-3
        serves as a guidance cue for neural crest development.
      explanation: >-
        Places MASP-3 with CL-K1 in the same neural crest guidance function,
        which is why loss of either produces the same developmental phenotype.
  - 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.
- name: Impaired Neural Crest Cell Guidance
  biological_scale: CELLULAR
  description: >-
    Loss of the secreted collectin guidance cue disrupts the directed migration
    of neural crest cells during embryogenesis. This is the step that converts a
    complement-pathway molecular defect into a developmental one, and it
    explains why the malformed structures in 3MC syndrome are predominantly
    neural crest derivatives rather than immune tissues.
  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: DECREASED
  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: >-
      Syndromic features seen in 3MC syndrome are thought to be due to
      disruption of the chemoattractant properties that influence neural crest
      cell migration.
    explanation: >-
      States the accepted mechanistic model linking collectin loss to the
      clinical features through neural crest migration.
  downstream:
  - target: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
    causal_link_type: DIRECT
    description: >-
      Cranial neural crest cells that fail to migrate correctly do not populate
      the facial primordia and pharyngeal arches, so the skeletal and soft
      tissue structures they would have formed are malformed.
    evidence:
    - reference: PMID:28301481
      reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main features include facial dysmorphism, craniosynostosis and cleft
        lip/palate; skeletal structures derived from cranial neural crest cells
        (cNCC).
      explanation: >-
        Identifies the malformed structures as cranial neural crest derivatives,
        the tissue-level consequence of the migration defect.
- name: Defective Cranial Neural Crest-Derived Craniofacial Morphogenesis
  biological_scale: TISSUE
  description: >-
    Failure of cranial neural crest-derived tissue to form normally produces the
    craniofacial phenotype: the periorbital gestalt, orofacial clefting,
    premature suture fusion, and middle/external ear anomalies underlying the
    hearing loss. Collectin expression in murine embryonic craniofacial
    cartilage and in the palatal base membrane places the proteins at the right
    time and place for this role.
  biological_processes:
  - preferred_term: neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: DECREASED
  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: >-
      CL-K1 is highly expressed in embryonic murine craniofacial cartilage,
      heart, bronchi, kidney and vertebral bodies.
    explanation: >-
      Places CL-K1 expression in the developing craniofacial tissues affected in
      the syndrome.
  - reference: PMID:28301481
    reference_title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show COLEC10 is expressed in the base membrane of the palate during
      murine embryo development.
    explanation: >-
      Places CL-L1 expression at the palatal shelf, the structure whose failure
      of fusion produces cleft palate.
- name: Impaired Complement-Dependent Osteoclastogenesis
  biological_scale: CELLULAR
  description: >-
    CL-11 is required for osteoclast differentiation and acts in concert with
    complement to maintain bone. This is a second, non-neural-crest route to
    skeletal disease in 3MC syndrome, and it is complement-dependent in a way
    the craniofacial arm is not.

    The genetic architecture matters and is unusual: CL-11 deletion alone does
    not produce a skeletal phenotype in mice. Bone loss appears only when
    collectin deficiency is combined with loss of MASP-2, factor B or C3, so
    complement acts here as a modifier rather than as the primary lesion.
  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: MODEL_ORGANISM
    snippet: >-
      combined deficiencies of CL-11 with complement components MASP-2 (lectin
      pathway), complement factors B, or C3 (alternative pathway amplification)
      result in marked vertebral bone loss and spinal curvature by 12 wk of age
    explanation: >-
      Establishes that the skeletal phenotype requires combined collectin and
      complement deficiency, which is what makes complement a modifier here.
  - reference: PMID:41774788
    reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CL-11 and the membrane attack complex (C5b-9) colocalized to OCLs and
      their precursors in normal bone from embryonic development through to
      adulthood.
    explanation: >-
      Places CL-11 and terminal complement together at the osteoclast lineage
      across development, supporting a direct role rather than a bystander
      association.
  notes: >-
    Curated as a distinct route to skeletal disease, separate from the neural
    crest arm. Do not merge the two: the craniofacial malformations follow from
    a migration-guidance defect during embryogenesis, whereas this node is a
    complement-dependent bone-remodelling defect that continues postnatally and
    requires a second complement hit to manifest.
- name: Impaired Pro-Factor D Maturation
  biological_scale: MOLECULAR
  description: >-
    In the MASP1/MASP-3-deficient form, conversion of pro-factor D to mature
    factor D in the alternative complement pathway is compromised. Notably this
    is a biochemical consequence that does not translate into clinical
    immunodeficiency: 3MC patients retain detectable mature factor D, indicating
    a MASP-3-independent maturation route, and recurrent infection is not a
    feature of the syndrome.
  biological_processes:
  - preferred_term: alternative complement pathway activation
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    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: >-
      Supports impaired but incomplete loss of factor D maturation in patients,
      which is why this node is a biochemical finding rather than a clinical
      immunodeficiency. Graded PARTIAL because it establishes residual mature
      factor D without measuring downstream alternative-pathway competence.
  - 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: >-
      Establishes MASP-3 as the sole physiological pro-factor D activator in
      resting blood, which is what makes this node a predicted consequence of
      MASP-3 loss.
  notes: >-
    Curated deliberately as a node with no *immunological* clinical consequence.
    Do not attach an immunodeficiency phenotype to it without evidence of
    recurrent infection in 3MC patients; the cited work shows residual mature
    factor D.

    This is not the same as saying the complement axis is inert. In mice,
    combined loss of CL-11 with factor B or C3 produces vertebral bone loss that
    neither lesion causes alone (PMID:41774788), so alternative-pathway
    components act as modifiers of the skeletal phenotype. See Impaired
    Complement-Dependent Osteoclastogenesis. What the human literature does not
    support is an infectious-susceptibility phenotype.
phenotypes:
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Increased interorbital distance, part of the highly characteristic
    periorbital gestalt of 3MC syndrome.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: VERY_FREQUENT
  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: >-
      Reports hypertelorism among the core facial traits at 70-95% frequency,
      mapping to VERY_FREQUENT.
- category: Craniofacial
  name: Blepharophimosis
  description: Horizontally short palpebral fissures.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  frequency: VERY_FREQUENT
  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: >-
      Reports blepharophimosis among the core facial traits at 70-95% frequency.
- category: Craniofacial
  name: Ptosis
  description: Drooping of the upper eyelid (blepharoptosis).
  phenotype_term:
    preferred_term: Blepharoptosis
    term:
      id: HP:0000508
      label: Ptosis
  frequency: VERY_FREQUENT
  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: >-
      Independent series confirming ptosis as part of the distinctive facial
      phenotype.
- category: Craniofacial
  name: Highly Arched Eyebrows
  description: Distinctive high arch of the eyebrows, part of the periorbital gestalt.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  frequency: VERY_FREQUENT
  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.
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Orofacial clefting, frequently bilateral, reflecting failure of neural
    crest-derived facial prominences to fuse.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  frequency: FREQUENT
  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: >-
      Reports cleft lip and palate at 40-68%, mapping to FREQUENT.
- category: Craniofacial
  name: Cleft Palate
  description: Failure of palatal shelf fusion, often accompanying cleft lip.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  frequency: FREQUENT
  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: >-
      Confirms cleft palate, characteristically bilateral, as a common feature.
- 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
  frequency: FREQUENT
  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: >-
      Reports postnatal growth deficiency at 40-68%, mapping to FREQUENT.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Cognitive impairment, generally mild to moderate, described in older
    literature as learning disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  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: >-
      Reports cognitive impairment at 40-68%, mapping to FREQUENT.
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing impairment, reported as mixed conductive and sensorineural, in
    keeping with the neural crest contribution to middle and external ear
    structures.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: FREQUENT
  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.
- category: Skeletal
  name: Craniosynostosis
  description: Premature fusion of one or more cranial sutures.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  frequency: OCCASIONAL
  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: >-
      Reports craniosynostosis at 20-30%, mapping to OCCASIONAL.
- 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
  frequency: OCCASIONAL
  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: >-
      Reports radioulnar synostosis at 20-30%, mapping to OCCASIONAL.
- category: Genitourinary
  name: Vesicorenal Anomalies
  description: >-
    Structural anomalies of the urinary tract, including vesicoureteral reflux.
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  frequency: OCCASIONAL
  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: >-
      Supports vesicorenal anomalies at 20-30%. Graded PARTIAL because the
      source reports the category "vesicorenal anomalies" rather than
      vesicoureteral reflux specifically, which is the closest available HPO
      binding.
- 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
  frequency: OCCASIONAL
  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.
- category: Abdominal
  name: Periumbilical Depression
  description: >-
    A depression of the periumbilical abdominal wall. Common, and distinct from
    frank umbilical herniation.
  phenotype_term:
    preferred_term: Periumbilical depression
    term:
      id: HP:6000808
      label: Periumbilical depression
  frequency: VERY_FREQUENT
  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 periumbilical anomalies in six of seven patients, which is why
      this concept is curated as VERY_FREQUENT and separately from umbilical
      herniation.
  - 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.
- category: Abdominal
  name: Umbilical Hernia or Omphalocele
  description: >-
    Frank herniation through the umbilical ring. Rare, and to be distinguished
    from the common periumbilical depression above.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  frequency: VERY_RARE
  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: >-
      Lists umbilical hernia/omphalocele among the rare features, mapping to
      VERY_RARE.
- category: Ophthalmologic
  name: Anterior Chamber Defects
  description: Anterior segment dysgenesis affecting the anterior chamber of the eye.
  phenotype_term:
    preferred_term: Abnormal anterior chamber morphology
    term:
      id: HP:0000593
      label: Abnormal anterior chamber morphology
  frequency: VERY_RARE
  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: >-
      Lists anterior chamber defects among the rare features.
- category: Craniofacial
  name: Epicanthus Inversus
  description: >-
    Epicanthal fold running from the lower lid upward, completing the
    characteristic periorbital gestalt.
  phenotype_term:
    preferred_term: Epicanthus inversus
    term:
      id: HP:0000537
      label: Epicanthus inversus
  frequency: VERY_FREQUENT
  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.
- 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
  frequency: FREQUENT
  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
    snippet: >-
      High-arched brows, ptosis, blepharophimosis, hypertelorism, cleft lip,
      cleft palate, developmental delay, hearing loss, abdominal wall defect,
      and urogenital and skeletal abnormalities are all characteristics.
    explanation: >-
      Supports the periorbital gestalt cluster this phenotype belongs to. Graded
      PARTIAL because the quoted list does not name palpebral fissure slant
      specifically.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Neuromotor developmental delay, reported in every patient of the largest
    recent cohort. Distinct from the cognitive impairment already curated, and
    apparent earlier.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  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.
- category: Cardiovascular
  name: Congenital Heart Disease
  description: Congenital cardiac malformation.
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: OCCASIONAL
  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 congenital heart disease in two of seven patients, which is the
      OCCASIONAL band.
- category: Genitourinary
  name: Genital Anomalies
  description: >-
    Structural anomalies of the external or internal genitalia, reported
    alongside the vesicorenal anomalies at the same frequency.
  phenotype_term:
    preferred_term: Abnormality of the genital system
    term:
      id: HP:0000078
      label: Abnormality of the genital system
  frequency: OCCASIONAL
  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 same sentence that supports craniosynostosis and radioulnar synostosis
      names genital anomalies at 20-30%.
- 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
  frequency: OCCASIONAL
  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.
- 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
  frequency: OCCASIONAL
  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.
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. Pathogenic alleles cluster in
    exon 12, which encodes the serine protease domain specific to the MASP-3
    isoform, so the syndrome is attributable to MASP-3 rather than MASP-1 loss.
  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.
  - 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: >-
      States the two causative allele classes and confirms the exon 12 / MASP-3
      localisation.
  - 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.
  variants:
  - name: MASP1 exon 12 biallelic loss-of-function alleles
    description: >-
      Nonsense and missense alleles in exon 12, which encodes the
      MASP-3-specific serine protease domain, plus intragenic deletions
      partially affecting that exon. Reported genotypes are homozygous or
      compound heterozygous and germline.
- 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 collectin
    kidney 1 (CL-K1), the secreted neural crest guidance cue.
  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.
- 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 collectin
    liver 1 (CL-L1), which forms heteromeric complexes with CL-K1.
  case_fractions:
  - population: Ashkenazi Jewish carrier screening cohort
    notes: >-
      Not a case fraction among 3MC patients but a population carrier frequency
      for the founder allele c.311G>T (p.Gly104Val); recorded here because it is
      the only quantitative population genetic estimate available for any 3MC
      gene.
    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: >-
        Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi
        Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%.
      explanation: >-
        Quantifies the founder allele carrier frequency in the Ashkenazi Jewish
        population.
  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.
  - 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: >-
      Documents a second, independent COLEC10 founder allele in southern Italy,
      alongside the Ashkenazi Jewish c.311G>T allele.
  - reference: PMID:34740859
    reference_title: A novel COLEC10 mutation in a child with 3MC syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    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: >-
      Shows a distinct loss-of-function route for this allele: normal plasma
      levels but impaired chemoattractant activity, so secretion failure is not
      the only mechanism.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Thirty-two patients from 20 families had been reported at the time of the
    2011 gene discovery; the literature has expanded since but remains small.
  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: >-
      Gives the reported case count establishing the ultra-rare band.
- population: Ashkenazi Jewish
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1010.0
  notes: >-
    Carrier frequency (not disease prevalence) for the COLEC10 founder allele
    c.311G>T, 1 in 99 or 1.01%.
  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: >-
      Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi
      Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%.
    explanation: >-
      Direct measurement of the founder allele carrier frequency.
treatments:
- name: Orthopedic Correction of Joint Contracture
  description: >-
    Gradual correction of knee flexion contracture using a Taylor spatial frame,
    followed by bracing to maintain extension. Reported as safe and effective in
    a molecularly confirmed COLEC11 patient; knee flexion contracture was not
    previously recognised as part of the syndrome.
  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
    snippet: >-
      According to our findings, the TSF was the safest, most accurate, stable
      fixator, and most efficient solution for treating knee flexion
      contracture, resulting in high patient and family satisfaction.
    explanation: >-
      Reports the outcome of the intervention in a confirmed 3MC patient.
- name: Genetic Counseling
  description: >-
    Counselling for the autosomal recessive recurrence risk, which is
    substantial and actionable: a molecularly confirmed diagnosis enables
    alternative reproductive options and prenatal testing.
  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.
  notes: >-
    There is no disease-modifying therapy for 3MC syndrome. Management is
    symptomatic and surgical - orofacial cleft repair, correction of ptosis and
    blepharophimosis, craniosynostosis surgery where present, orthopedic
    correction of contractures, and audiologic rehabilitation for the hearing
    loss. Only the interventions with a citable 3MC-specific report are curated
    as treatments here; the rest are standard management of the individual
    malformations rather than of the syndrome.
progression:
- phase: Congenital and static
  notes: >-
    3MC syndrome is a congenital malformation syndrome. The structural
    anomalies are present at birth, are static rather than progressive, and
    survival to adulthood is documented. Prenatal detection is possible when
    fetal ultrasound shows facial clefting together with spinal or renal
    anomalies.
  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.
  - 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.
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.
    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.
- 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, whereas human 3MC alleles
      cluster in the MASP-3-specific exon, so the model is broader than the
      human genotype. It models the biochemical node only, not the craniofacial
      phenotype.
    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: >-
        Establishes the mouse knockout as the model that first identified the
        pro-factor D maturation defect.
- name: Colec11 knockout mouse
  species: Mouse
  genotype: Colec11-/- (single knockout)
  publication: PMID:41774788
  description: >-
    Single-gene collectin-11 knockout, used as the control arm against which the
    complement double knockouts were compared.
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    description: >-
      Collectin loss on its own does not reproduce the skeletal phenotype in
      mice. This negative result is the reason the osteoclastogenesis node is
      curated as requiring a second complement hit rather than as a direct
      consequence of collectin deficiency.
    limitations: >-
      A negative result in mouse does not establish that human COLEC11 loss is
      skeletally silent: humans carry biallelic collectin loss on a different
      complement background, and the reported 3MC skeletal features
      (craniosynostosis, radioulnar synostosis) are developmental rather than
      the remodelling phenotype measured here. The finding constrains the
      mechanism; it does not transfer the negative to patients.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we demonstrate that CL-11 deletion alone does not produce skeletal
        abnormalities in mice
      explanation: >-
        States the negative result directly.
experimental_models:
- name: Human iPSC-derived osteoclasts
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Osteoclasts differentiated from human induced pluripotent stem cell lines,
    used to test whether the mouse collectin/complement dependence holds in
    human cells.
  publication: PMID:41774788
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Osteoclastogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the CL-11 and complement dependence of osteoclast
      differentiation in human cells, which is what makes the mouse finding
      relevant to the human disease.
    limitations: >-
      iPSC-derived osteoclasts in culture lack the bone microenvironment and the
      mechanical loading that drive remodelling in vivo, and the cells are not
      3MC patient-derived, so the system tests the pathway rather than the
      patient genotype.
    readouts:
    - name: Osteoclast differentiation from human iPSC lines
      target: Impaired Complement-Dependent Osteoclastogenesis
      direction: DECREASED
      interpretation: >-
        Human confirmation of the collectin/complement requirement measured in
        the mouse ex vivo assay.
      evidence:
      - reference: PMID:41774788
        reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          This dependence on CL-11 and complement was recapitulated in human
          OCLs derived from induced pluripotent stem cell lines.
        explanation: >-
          Reports the human osteoclast differentiation measurement behind this
          readout.
    evidence:
    - reference: PMID:41774788
      reference_title: Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This dependence on CL-11 and complement was recapitulated in human
        OCLs derived from induced pluripotent stem cell lines.
      explanation: >-
        Supports the human system as informative for the osteoclastogenesis
        node.
differential_diagnoses:
- name: Branchio-oto-renal spectrum
  description: >-
    Also presents with hearing loss and branchial/ear anomalies, but is
    autosomal dominant, EYA1/SIX-related, and features renal malformation and
    branchial fistulae rather than the 3MC periorbital gestalt, clefting and
    caudal appendage.
- name: Blepharophimosis-ptosis-epicanthus inversus syndrome
  description: >-
    Shares the periorbital gestalt (blepharophimosis, ptosis, epicanthus
    inversus) but is FOXL2-related, autosomal dominant, and lacks orofacial
    clefting, growth deficiency and the skeletal synostoses.
diagnosis:
- name: Molecular diagnosis by sequencing of MASP1, COLEC11 and COLEC10
  description: >-
    Diagnosis is confirmed by identifying biallelic pathogenic variants in one
    of the three genes, typically via exome sequencing or a targeted panel. In
    individuals of Ashkenazi Jewish ancestry, targeted testing for the COLEC10
    c.311G>T founder allele is warranted.

    Two documented false-negative routes matter when a molecular result comes
    back negative in a clinically convincing case. Some clinical exome panels
    carry only MASP1 and COLEC11, so a COLEC10 variant is not looked for at all;
    and intragenic deletions can escape routine variant-calling and be found
    only on direct inspection of the sequencing data. Both have produced
    initially unsolved 3MC cases.
  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.
  - 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.
  - 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.
notes: >-
  Curated as a single Disease entry rather than three per-gene entries. The
  three genetic forms are clinically indistinguishable and their protein
  products act in one pathway — CL-K1 and CL-L1 form heteromeric complexes, and
  MASP-3 is the collectin-associated protease — so one pathograph covers all
  three. Per-gene detail is carried in has_subtypes and genetic.

  The entry deliberately keeps the alternative-complement-pathway consequence
  (impaired pro-factor D maturation) as a terminal node with no clinical
  sequela. This is the most likely place for a future curator to overreach: the
  gene names invite an immunodeficiency narrative that the clinical literature
  does not support.

📚

References & Deep Research

Deep Research

1

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.

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

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