Expanding the phenotypic spectrum of COLEC10‐Related 3MC syndrome: A glimpse into COLEC10‐Related 3MC syndrome in the Ashkenazi Jewish population

Abstract

Bi-allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi-allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate.

3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum

“…Only one of these patients had bilateral cleft lip and palate. All of the described cases have a similar clinical phenotype to patient 5 with evidence of ptosis, but no hypertelorism or highly arched eyebrows which are almost always present in those affected patients with COLEC11/MASP1 pathogenic genotypes Rabin et al (2022). have very recently identified a founder COLEC10 pathogenic variant among the Ashkenazi Jewish population and many of these patients did have characteristic facies including hypertelorism and highly arched eyebrows but only a minority suffered from additional manifestations of 3MC syndrome.…”

“…The exact incidence and prevalence of 3MC syndrome are unknown, though it is considered to be rare. To date only 58 cases have been reported in the literature; 27 cases with MASP1 variants, 17 cases with COLEC11 variants and 14 cases with COLEC10 variants (Basdemirci et al, 2019;Çakmaklh and Kandur, 2019;Gajek et al, 2020;Lawson et al, 2020;Agaoglu and Akgun Dogan, 2021;Durmaz and Altıner, 2021;Mohammadi et al, 2021;Rabin et al, 2022).…”

“…Mohammadi et al (2021) and Migliorero et al (2021) have identified two female patients with COLEC10 variants. More recently, Rabin et al (2022) have expanded the phenotypic spectrum of COLEC10related 3MC syndrome, describing nine individuals from a Ashkenazi Jewish population with one founder pathogenic variant.…”