COLEC10 – 3MC syndrome 3

COLEC10 encodes collectin liver 1 (CL-L1), a lectin complement pathway protein essential for neural crest cell migration and craniofacial morphogenesis. Biallelic pathogenic variants in COLEC10 underlie 3MC syndrome 3, a rare autosomal recessive disorder characterised by facial dysmorphism, craniosynostosis, and multisystem anomalies. Clinical features include telecanthus, blepharoptosis, clinodactyly of the fifth finger, high myopia, long face, micrognathia, patent ductus arteriosus, downslanted palpebral fissures, epicanthus inversus, and dolichocephaly. Inheritance is autosomal recessive, with disease manifesting only in individuals with biallelic loss-of-function variants. Evidence supporting this association includes case reports, segregation analyses, and functional studies. This summary evaluates the strength of the COLEC10–3MC syndrome 3 relationship based on ClinGen criteria.

Genetic evidence comprises four unrelated probands carrying homozygous or compound heterozygous loss-of-function COLEC10 variants. The index case was a 7-year-old Iranian girl with craniosynostosis, dolichocephaly, ptosis, clinodactyly of the fifth finger, high myopia, long face, micrognathia, patent ductus arteriosus, downslanted palpebral fissures, telecanthus, and epicanthus inversus, harbouring the homozygous frameshift deletion c.128_129delCA (p.Thr43AsnfsTer9) (PMID:34636477). Subsequent studies reported a homozygous frameshift c.807_810delCTGT (p.Cys270SerfsTer33) in an Italian patient and additional alleles including nonsense c.25C>T (p.Arg9Ter) and frameshift c.226delA (p.Gly77GlufsTer66) in multiple families (PMID:28301481; PMID:34740859). All variants predict premature truncation, supporting loss-of-function as the disease mechanism. No missense-only pathogenic cases have been described to date.

Segregation analyses confirmed heterozygous carrier status in obligate parents with no additional affected relatives in extended pedigrees. At least two families demonstrated clear cosegregation of biallelic COLEC10 variants with the 3MC phenotype (PMID:34636477; PMID:34740859). Although multiplex sibships have not been reported, the reproducible finding of homozygous variants in unrelated consanguineous kindreds reinforces autosomal recessive inheritance. This fulfills moderate segregation criteria under ClinGen guidelines. No de novo events have been observed.

Functional studies in murine models and cell lines demonstrate a loss-of-function mechanism for CL-L1 variants. CL-L1 is expressed in the basement membrane of the developing palate, congruent with cleft palate and craniosynostosis phenotypes. In vitro assays of c.25C>T (p.Arg9Ter), c.226delA (p.Gly77GlufsTer66) and c.528C>G (p.Cys176Trp) show markedly reduced secretion and impaired assembly of CL-L1/CL-K1 heterocomplexes, disrupting lectin pathway activation (PMID:28301481). Truncated proteins fail to form stable multimers or recruit MASPs effectively. These findings provide strong experimental support for pathogenic loss-of-function.

Further functional evidence comes from the c.807_810delCTGT (p.Cys270SerfsTer33) variant, which, despite normal plasma CL-L1 levels, exhibits significantly reduced chemotactic activity in HeLa cell migration assays, implicating qualitative functional defects in CL-L1–mediated cell signalling (PMID:34740859). The removal of a conserved cysteine likely disrupts disulphide bonding critical for oligomerisation. This highlights that certain truncations can selectively impair functional domains without reducing protein abundance.

Collectively, four probands with biallelic loss-of-function variants, confirmed segregation, and concordant functional defects meet ClinGen criteria for a Strong clinical validity classification. No conflicting evidence has been reported. Inclusion of COLEC10 in diagnostic gene panels facilitates precise molecular diagnosis and informed genetic counselling. Further research may uncover additional alleles in the lectin complement pathway. Key take-home: Biallelic LOF variants in COLEC10 cause 3MC syndrome 3 via impaired CL-L1 secretion and function, supporting its inclusion in clinical testing.

References

• Molecular genetics & genomic medicine • 2021 • Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3. PMID:34636477
• PLoS genetics • 2017 • COLEC10 is mutated in 3MC patients and regulates early craniofacial development. PMID:28301481
• European journal of medical genetics • 2021 • A novel COLEC10 mutation in a child with 3MC syndrome. PMID:34740859

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