Nadia Ortiz Bruechle1,2, Peter Steuernagel3, Klaus Zerres1, Ingo Kurth1, Thomas Eggermann1, Cordula Knopp4. 1. Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. 2. Institute of Pathology, Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. 3. Institute of Human Genetics, Hospital Oldenburg, Rahel-Straus-Straße 10, 26133, Oldenburg, Germany. 4. Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany. cknopp@ukaachen.de.
Abstract
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.
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.
Entities:
Keywords:
Ciliopathy; Meckel–Gruber syndrome; SNP array; TMEM67; Upd(8)mat
Authors: Z E Karanjawala; H Kääriäinen; S Ghosh; J Tannenbaum; C Martin; D Ally; J Tuomilehto; T Valle; F S Collins Journal: Am J Med Genet Date: 2000-07-31
Authors: C Knopp; S Rudnik-Schöneborn; T Eggermann; C Bergmann; M Begemann; K Schoner; K Zerres; N Ortiz Brüchle Journal: Mol Cell Probes Date: 2015-05-21 Impact factor: 2.365
Authors: J E Spence; R G Perciaccante; G M Greig; H F Willard; D H Ledbetter; J F Hejtmancik; M S Pollack; W E O'Brien; A L Beaudet Journal: Am J Hum Genet Date: 1988-02 Impact factor: 11.025