oa A novel mutation in the MASP1 gene causes autosomal recessive multiple congenital anomaly syndrome

Three patients from two related and consanguineous sibships of Pakistani ethnic origin are affected by a recognizable pattern of multiple congenital anomalies. The clinical picture includes increased inner canthal distance, hypoplastic upper lid with ptosis, blepharophemosis, maxillary hypoplasia, facial asymmetry, cleft lip/palate, high arched palate, irregular dentition, low set ears and low posterior hairline, mild scoliosis and decreased carrying angle of elbow. The apparent clinical characteristics overlap, but do not identify solely, with the individual Malpuech, Michels, Mingarelli or Carnevale syndromes, or what has been collectively referred to as the 3MC syndrome; hence, the referral to the phenotype as Multiple Congenital Anomaly syndrome. The family was studied by homozygosity mapping, and Whole Exome Sequencing of a single affected individual performed on ABI SOLiD4. A novel homozygous mutation [c.G542A] affecting the evolutionary conserved residue p.C181Y was identified at 3q27 in the MASP1 encoding a mannose-associated serine protease 1. The variant was confirmed by Sanger sequencing, segregates with the phenotype in the family and is predicted to be damaging by PolyPhen and SIFT. MASP1 functions as a component of the lectin pathway of complement activation. Mutations in the MASP1 gene and another gene (COLEC11) involved in the same pathway have been associated with human craniofacial malformation indicating an impending role for complement pathway elements in vital developmental processes during embryogenesis. The identified autosomal recessive variant extends further support to this hypothesis.