EP220: Expanding the phenotypic spectrum of COLEC10-related 3MC syndrome: A glimpse into COLEC10-related 3MC syndrome in the Ashkenazi Jewish population

Abstract

3MC syndrome is a clinical entity comprising 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. 3MC syndrome was initially described to be associated with bi-allelic pathogenic variants in the COLEC11 and MASP1 genes. Recently, bi-allelic pathogenic variants in COLEC10 have been described to be associated with 3MC syndrome. Features of COLEC10-related 3MC syndrome included short stature, blepharoptosis and epicanthus inversus, cleft lip/palate, and skeletal anomalies of the digits. The proteins encoded by COLEC11, MASP1, and COLEC10 form an intricate protein network that is important in regulating the lectin complement pathway. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell (NCC) migration. We identified seven individuals from three families of Ashkenazi Jewish descent with homozygosity of the novel c.311G>T (p.Gly104Val) variant in the COLEC10 gene (NM_006438.3) and phenotype consistent with 3MC syndrome. Individuals were retrospectively identified through the Dor Yeshorim screening program based on their genotype of the c.311G>T (p.Gly104Val) variant. The carrier frequency was calculated based on 21,887 individuals of Jewish descent. Samples were obtained anonymously through the Dor Yeshorim screening program between March 2020 and March 2021. Molecular protein modeling was completed. COLEC10 amino acid sequence was obtained, and then predictive protein models from I-Tasser were generated. Using PyMOL Molecular Graphic System 2.3.4 the effect the p.Gly104Val substitution in the COLEC10 protein model was analyzed. Clinical characteristics of the seven identified individuals included variable features of bilateral cleft lip and palate, radioulnar synostosis, short stature, hearing loss, and congenital heart defects. Similar facial features included hypertelorism, ptosis, prominent forehead, semicircular eyebrows, periorbital fullness, and broad nose. All individuals had reported normal intelligence. Carrier screening for the c.311G>T (p.Gly104Val) variant identified 164 heterozygotes out of 16,497 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 101 or 0.99%. There were no heterozygotes identified out of 3,097 individuals of Sephardic Jewish descent and there were 13 heterozygotes out of 2,293 individuals of mixed Ashkenazi and Sephardic Jewish descent. Molecular protein modeling showed that the p.Gly104Val substitution alters local conformation. We identified a novel variant in the COLEC10 gene likely representative of a founder variant in the Ashkenazi Jewish population. Homozygosity of this variant is associated with variable features of 3MC syndrome. Given the observed carrier frequency, the lower than expected number of affected individuals may be due to the extreme phenotypic variability that includes clinically undiagnosed and variable presentations of the syndrome, even within the same family. Molecular protein modeling suggested that the p.Gly104Val variant results in abnormal protein folding. Abnormal protein folding has previously been shown to affect the secretion of the COLEC10 protein, leading to abnormal NCC migration, resulting in the observed craniofacial and skeletal anomalies associated with 3MC syndrome. COLEC10-related 3MC syndrome should be considered in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and palate, and characteristic facial features.