Uniparental disomy as an unexpected cause of Meckel-Gruber syndrome: report of a case

Pediatr Nephrol. 2017 Oct;32(10):1989-1992. doi: 10.1007/s00467-017-3710-8. Epub 2017 Jun 15.


Background: Meckel-Gruber syndrome (MKS, OMIM #607361) is a rare pre- or perinatal lethal autosomal recessive ciliopathy caused by mutations in at least 12 known genes. It has a clinical and genetic overlap with other viable ciliopathies, especially Joubert syndrome and Joubert syndrome-related disorders. MKS is characterized by multicystic kidney dysplasia, central nervous system malformations (usually occipital encephalocele), ductal plate malformation of the liver, and postaxial polydactyly.

Case diagnosis: We identified a homozygous mutation in TMEM67 (MKS3) in a fetus affected by MKS; however, only the mother was a carrier of the respective mutation. Genotyping with polymorphic microsatellite markers and single nucleotide polymorphism (SNP) array revealed a maternal uniparental disomy (UPD) of the entire chromosome 8 (upd(8)mat), harboring TMEM67.

Conclusions: This is the first reported case of UPD as a cause of MKS. The possible underlying mechanisms for uniparental disomy (UPD) are reviewed. Even if rare, awareness of UPD and comprehensive work-up in the case of unexpected homozygosity for a recessive mutation is essential for accurate genetic counseling and assessment of the risk of recurrence.

Keywords: Ciliopathy; Meckel–Gruber syndrome; SNP array; TMEM67; Upd(8)mat.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Abortion, Induced
  • Adult
  • Chromosomes, Human, Pair 8 / genetics*
  • Ciliary Motility Disorders / diagnosis
  • Ciliary Motility Disorders / genetics*
  • DNA Mutational Analysis / methods
  • Encephalocele / diagnosis
  • Encephalocele / genetics*
  • Female
  • Fetal Diseases / diagnosis
  • Fetal Diseases / genetics*
  • Genetic Testing / methods
  • Homozygote
  • Humans
  • Karyotyping / methods
  • Male
  • Membrane Proteins / genetics*
  • Mutation
  • Polycystic Kidney Diseases / diagnosis
  • Polycystic Kidney Diseases / genetics*
  • Pregnancy
  • Prenatal Diagnosis
  • Retinitis Pigmentosa / diagnosis
  • Retinitis Pigmentosa / genetics*
  • Ultrasonography, Prenatal
  • Uniparental Disomy*


  • Membrane Proteins
  • TMEM67 protein, human

Supplementary concepts

  • Meckel syndrome type 1