B9D2 – Meckel syndrome

B9D2 encodes a B9 domain–containing protein localized to the ciliary transition zone and is essential for ciliogenesis. Biallelic loss-of-function variants in B9D2 have been implicated in autosomal recessive Meckel syndrome (MKS), a perinatally lethal ciliopathy characterized by occipital encephalocele, polydactyly and cystic kidney disease.

Exome sequencing in MKS cohorts identified two unrelated probands with homozygous B9D2 variants: c.301A>C (p.Ser101Arg) segregates with disease in one family ([PMID:21763481]) and c.15C>A (p.His5Gln) in a second family ([PMID:31411728]). Both variants are absent from population databases and affect conserved residues within the B9 domain, consistent with pathogenic loss of function.

Functional studies demonstrate that murine B9d2 knockout recapitulates key MKS features, including polydactyly, kidney cysts and neural tube defects, concomitant with impaired ciliogenesis ([PMID:21763481]). Zebrafish b9d2 suppression is not rescued by mutant B9D2 mRNA, confirming loss of function in vivo ([PMID:21763481]).

Protein interaction assays reveal that the p.Ser101Arg substitution abrogates B9D2 binding to MKS1, disrupting the B9 protein complex and downstream Hedgehog signaling, a known MKS pathogenic mechanism ([PMID:21763481]). No discordant or refuting clinical evidence has been reported.

Collectively, genetic and experimental data support a Moderate level of clinical validity for B9D2 in Meckel syndrome. Key Take-home: include B9D2 in autosomal recessive ciliopathy gene panels for accurate MKS diagnosis.

References

• American journal of human genetics • 2011 • Disruption of a ciliary B9 protein complex causes Meckel syndrome. PMID:21763481
• Clinical genetics • 2019 • Meckel syndrome: Clinical and mutation profile in six fetuses. PMID:31411728

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