MASP1 Mutations in Patients with Facial, Umbilical, Coccygeal, and Auditory Findings of Carnevale, Malpuech, OSA, and Michels Syndromes

Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis blepharoptosis, epicanthus inversus, periumbil seal defects, and skeletal anomalies are seen in autosomal recessive Carnevale, Malpuech, Michels, and oculo skeletal abdominal (OSA) syndromes The gene or genes responsible for these syndromes were heretofore unknown We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes including facial dysmorphism periumbilical depression mixed hearing loss, radioulnar synostosis and coccygeal appendage Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families In one family, whole exome sequencing revealed a missense mutation, MASP1 c 2059G>A (p G687R) that cosegregated with the phenotype In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c 870G>A (p W290X) that also cosegregated with the phenotype Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries MASP1 encodes mannan binding lectin senne protease 1 The two mutations occur in a MASP1 isoform that has been reported to process IGFBP 5 thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period