COLEC10 – 3MC syndrome

Autosomal recessive 3MC syndrome presents with craniofacial dysmorphism (blepharophimosis, hypertelorism, highly arched eyebrows, craniosynostosis), cleft lip/palate, radioulnar synostosis, genital anomalies, skeletal defects, growth delay, and hearing impairment. Biallelic variants in COLEC10, encoding collectin-10 (CL-L1), disrupt lectin complement–mediated neural crest cell migration during craniofacial development.

Genetic studies describe 11 unrelated probands from at least seven families carrying COLEC10 variants. A homozygous frameshift c.807_810del (p.Cys270SerfsTer33) was identified in an Apulian patient with classic 3MC features (PMID:34740859). Nine Ashkenazi Jewish individuals from five families share a founder missense variant c.311G>T (p.Gly104Val), presenting with cleft lip/palate, radioulnar synostosis, short stature, and sacral dimple (PMID:35943032). A single-case report of an 11-year-old girl with comorbid ADHD and major depressive disorder further supports COLEC10 involvement (PMID:37463393). PLoS Genetics studies revealed additional homozygous truncating variants c.25C>T (p.Arg9Ter), c.226del (p.Gly77GlufsTer66), and missense c.528C>G (p.Cys176Trp) segregating with 3MC in five families (PMID:28301481).

The variant spectrum comprises two missense alleles and five predicted loss-of-function changes (nonsense and frameshift), including a recurrent Ashkenazi founder p.Gly104Val with a carrier frequency of 1.01% (PMID:35943032). No conflicting pathogenic interpretations have been reported.

Functional assays demonstrate that truncating and missense COLEC10 variants impair CL-L1 secretion, heteromeric CL-10/11 complex formation, and chemoattractive activity. HeLa cell migration toward mutant CL-L1 is significantly reduced (PMID:34740859), and murine embryo studies show COLEC10 expression in the palatal basal membrane is critical for craniofacial morphogenesis (PMID:28301481).

Together, these data support a loss-of-function mechanism for COLEC10 in autosomal recessive 3MC syndrome, integrating multi-family genetic evidence and concordant experimental models to confirm its role in neural crest–derived craniofacial development.

Key Take-home: Biallelic COLEC10 variants underlie autosomal recessive 3MC syndrome and should be included in molecular diagnostics for craniofacial and multisystem dysmorphology.

References

• European journal of medical genetics • 2021 • A novel COLEC10 mutation in a child with 3MC syndrome PMID:34740859
• American journal of medical genetics. Part A • 2022 • Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population PMID:35943032
• Psychiatric genetics • 2023 • A child with Malpuech-Michels-Mingarelli-Carnevale syndrome and ADHD and major depressive disorder PMID:37463393
• PLoS genetics • 2017 • COLEC10 is mutated in 3MC patients and regulates early craniofacial development PMID:28301481

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