3MC syndrome has been proposed as a unifying term to integrate the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders of unknown cause comprise a spectrum of developmental features including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability, and genital, limb and vesicorenal anomalies. In a cohort of eleven 3MC families, we identified two mutated genes COLEC11 and MASP1 both of which encode proteins within the lectin complement pathway (CL-K1 and MASP-1 & −3 respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney, and vertebral bodies. Zebrafish morphants develop pigment defects and severe craniofacial abnormalities.

Here, we show that CL-K1 serves as a key guidance cue for neural crest cell migration thus demonstrating for the first time, a role for complement pathway factors in fundamental developmental processes and the origin of 3MC syndrome.

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterized by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of both the time and cost required to screen all 204 coding exons. Here, we report the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci in BBS individuals from inbred and outbred background. In a worldwide cohort of 45 families, we identified, via direct exon sequencing, causative homozygous mutations in 20 families. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.

Despite rapid advances in disease gene identification, the predictive power of the genotype remains limited, in part due to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in patients with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss of function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the 229T-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.