Meckel-Gruber syndrome

Meckel-Gruber syndrome is a lethal autosomal recessive ciliopathy defined by a cardinal triad of occipital encephalocele, polycystic renal dysplasia, and postaxial polydactyly. Onset is prenatal, and the condition is incompatible with life, with death occurring in utero or shortly after birth. Central nervous system involvement frequently extends beyond encephalocele to include hydrocephalus, Dandy-Walker malformation, and agenesis of the corpus callosum. Renal abnormalities are universal in affected fetuses, most commonly hyperechogenic parenchyma (~72%), cystic dysplasia (~67%), and bilateral renal enlargement (~61%), accompanied by oligohydramnios. Additional features may involve hepatobiliary ductal-plate malformation, skeletal anomalies beyond polydactyly, and cardiac malformations, reflecting the multisystem nature of primary cilium dysfunction during embryogenesis. Inter- and intrafamilial variability in regard to the extent and severity of organ involvement is well documented.

The global birth prevalence varies significantly due to pronounced regional and ethnic differences, with literature figures ranging between 1:13,500 and 1:140,000 live births. Data from the European EUROCAT registry indicates an average birth prevalence of approximately 1:38,500. Significantly higher frequencies are observed in genetically isolated populations or regions with high rates of consanguinity, such as Finland (approx. 1:9,000) or the Gujarati population of western India (up to 1:1,300).

Meckel-Gruber syndrome is caused by germline biallelic pathogenic variants in any of at least 14 genes encoding components of the primary cilium and the transition zone. The most frequently implicated genes include MKS1, TMEM67, CC2D2A, CEP290, and RPGRIP1L; additional contributors include B9D1, B9D2, and TCTN2. The encoded proteins localize to the ciliary transition zone, and loss of function disrupts ciliogenesis and cilium-dependent signaling during embryonic development. The disease-burden distribution across these genes is not reliably quantified in the available literature.

Meckel-Gruber syndrome is inherited in an autosomal recessive manner. The recurrence risk for siblings of an affected individual is 25% when both parents are heterozygous carriers of a pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Meckel-Gruber syndrome is diagnosed primarily by molecular genetic testing. Prenatal ultrasound findings, including hyperechogenic and enlarged cystic kidneys, occipital encephalocele, postaxial polydactyly, and oligohydramnios, raise the clinical suspicion. Molecular confirmation is established by exome sequencing or a targeted ciliopathy gene panel that captures the heterogeneous causal spectrum.

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for accurate genetic counselling of the family.
• Identification of the causal variants enables clinical management decisions, taken by the treating physicians in consultation with the affected individual or the family.
• Once the familial pathogenic variants are known, predictive and reproductive genetic testing of at-risk family members becomes possible.

• Campobasso G, Mercuri L, De Razza F, Cosentino A, Mele M, Monittola A, et al. Investigating the role of B9D1 in Meckel-Gruber syndrome: a case report and comprehensive literature review. Genes (Basel). 2025;16(6):643. PMID: .
• Junior JHMF, Junior SP, Pustilnik HN, de Almeida Leão L, da Paz MGDS, Araujo TB, et al. Neurosurgical intervention for the Meckel-Gruber syndrome: a systematic review. Childs Nerv Syst. 2024;40(7):2161-2168. PMID: .
• Simonini C, Floeck A, Strizek B, Mueller A, Gembruch U, Geipel A. Fetal ciliopathies: a retrospective observational single-center study. Arch Gynecol Obstet. 2022;306(1):71-83. PMID: .