ORPHA: 564;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p11.2 | ?Meckel syndrome 9 | 614209 | Autosomal recessive | 3 | B9D1 | 614144 |
A number sign (#) is used with this entry because of evidence that Meckel syndrome-9 (MKS9) can be caused by compound heterozygous mutation in the B9D1 gene (614144) on chromosome 17p11.2. One such family has been reported.
Meckel syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia (summary by Hopp et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
Hopp et al. (2011) reported a fetus with Meckel syndrome who was found by ultrasound at 13 weeks' gestation to have posterior encephalocele and abnormal posterior fossa, bilaterally enlarged multicystic dysplastic kidneys, and no bladder. Polydactyly was not noted, but the fetus had bilateral clubfeet and shortened limbs. By 16 weeks, the cystic kidneys were grossly enlarged, distorting the abdomen and compressing the diaphragm. The baby was born at 35 weeks, and survived 1.75 hours. Examination at birth indicated an enlarged abdomen, an irregular-shaped posterior encephalocele, bilateral clubfeet and ambiguous genitalia. The parents were nonconsanguineous.
Hopp et al. (2011) performed exon-enriched next-generation sequencing of 31 ciliopathy genes in 12 MKS pedigrees. In a fetus with posterior encephalocele, multicystic dysplastic kidneys, ambiguous genitalia, and bilateral clubfeet, they identified a heterozygous splice donor site change in the B9D1 gene (505+2T-C; 614144.0001), which was inherited from the father. Reverse transcriptase-PCR analysis of B9D1 in fetal RNA revealed a single smaller than normal mRNA product lacking exon 4. Array CGH showed that the second mutation was a 1.71-Mb de novo deletion (614144.0002) at chromosome 17p11.1, eliminating the entire B9D1 gene and 18 other genes. Immunofluorescence analysis revealed a significantly lower level of ciliated patient cells compared to controls, confirming a role for B9D1 in ciliogenesis. From the mother, the fetus inherited an additional, likely pathogenic novel missense change (R2210C) in a second MKS gene, CEP290 (610142), suggesting oligogenic inheritance in this case.
Hopp, K., Heyer, C. M., Hommerding, C. J., Henke, S. A., Sundsbak, J. L., Patel, S., Patel, P., Consugar, M. B., Czarnecki, P. G., Gliem, T. J., Torres, V. E., Rossetti, S., Harris, P. C. B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum. Molec. Genet. 20: 2524-2534, 2011. [PubMed: 21493627] [Full Text: https://doi.org/10.1093/hmg/ddr151]