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Meckel syndrome (MKS) is an embryonic lethal, autosomal recessive disorder characterized by polycystic kidney disease, central nervous system defects, polydactyly and liver fibrosis. This disorder is thought to be associated with defects in primary cilia; therefore, it is classed as a ciliopathy. To date, six genes have been commonly associated with MKS (MKS1,TMEM67,TMEM216,CEP290,CC2D2AandRPGRIP1L). However, mutation screening of these genes revealed two mutated alleles in only just over half of our MKS cohort (46 families), suggesting an even greater level of genetic heterogeneity. To explore the full genetic complexity of MKS, we performed exon-enriched next-generation sequencing of 31 ciliopathy genes in 12 MKS pedigrees usingRainDancemicrodroplet-PCR enrichment andIlluminaGAIIxnext-generation sequencing. In family M456, we detected a splice-donor site change in a novel MKS gene,B9D1. The B9D1 protein is structurally similar to MKS1 and has been shown to be of importance for ciliogenesis inCaenorhabditis elegans. Reverse transcriptase–PCR analysis of fetal RNA revealed, hemizygously, a single smaller mRNA product with a frameshifting exclusion ofB9D1exon 4. ArrayCGH showed that the second mutation was a 1.713 Mbde novodeletion completely deleting theB9D1allele. Immunofluorescence analysis highlighted a significantly lower level of ciliated patient cells compared to controls, confirming a role forB9D1in ciliogenesis. The fetus inherited an additional likely pathogenic novel missense change to a second MKS gene,CEP290; p.R2210C, suggesting oligogenic inheritance in this disorder.

B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis