COLEC11 – 3MC syndrome

3MC syndrome is a rare autosomal recessive developmental disorder characterized by facial dysmorphism (blepharophimosis, hypertelorism), craniosynostosis, cleft lip/palate, genital anomalies and limb defects. Pathogenic variants in COLEC11, which encodes collectin-K1 (CL-11) in the lectin complement pathway, are established causes of 3MC syndrome alongside MASP1 and COLEC10. The gene–disease relationship has been corroborated by multiple families worldwide and functional studies demonstrating loss of CL-11 activity.

In a cohort of 11 unrelated families (11 probands) with 3MC syndrome, biallelic COLEC11 variants segregated with disease under autosomal recessive inheritance (PMID:21258343). Segregation analysis in two consanguineous families revealed two affected siblings sharing a homozygous C-terminal COLEC11 deletion (PMID:27356087). An additional sporadic case further supports the association (PMID:37463393).

The variant spectrum in COLEC11 includes five predicted loss-of-function alleles (frameshifts: c.45del (p.Phe16fs), c.309del (p.Gly104fs), c.648_650del (p.Ser217del); C-terminal deletions) and two missense substitutions (c.610G>A (p.Gly204Ser), c.505T>C (p.Ser169Pro)) affecting protein secretion and carbohydrate recognition (PMID:21258343). These variants are absent or extremely rare in population databases, consistent with a recessive mechanism.

Functional assays demonstrate that disease-associated CL-11 mutants fail to bind Ca2+ and are not secreted from mammalian cells, leading to protein deficiency in patient serum (PMID:25912189). Zebrafish morphants lacking colec11 phenocopy human craniofacial defects, confirming a critical role in neural crest cell migration and craniofacial development (PMID:21258343).

No studies have convincingly refuted the COLEC11–3MC link, and reported animal models and in vitro data consistently recapitulate human phenotypes. Additional deep-intronic or hypomorphic alleles may yet be uncovered, but current evidence reaches the ClinGen cap for genetic and experimental data.

Key Take-home: Biallelic COLEC11 variants result in loss of collectin-K1 function and causally underlie 3MC syndrome, supporting genetic testing and functional assays for diagnosis and counseling.

References

• Nature Genetics • 2011 • Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome PMID:21258343
• The Cleft palate-craniofacial journal • 2017 • Familial Recurrence of 3MC Syndrome in Consanguineous Families: A Clinical and Molecular Diagnostic Approach With Review of the Literature PMID:27356087
• Psychiatric genetics • 2023 • A child with Malpuech-Michels-Mingarelli-Carnevale syndrome and ADHD and major depressive disorder PMID:37463393
• BMC Biology • 2015 • Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome PMID:25912189

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