Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Institute of Pathology, Medical Faculty, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Pediatr Nephrol. 2017 Oct;32(10):1989-1992. doi: 10.1007/s00467-017-3710-8. Epub 2017 Jun 15.
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.
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.
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.
Meckel-Gruber 综合征（MKS，OMIM#607361）是一种罕见的产前或围产期致死性常染色体隐性纤毛病，由至少 12 个已知基因的突变引起。它与其他可行纤毛病（尤其是 Joubert 综合征和 Joubert 综合征相关疾病）在临床和遗传上存在重叠。MKS 的特征是多囊肾发育不良、中枢神经系统畸形（通常为枕骨脑膨出）、肝内胆管板畸形和后轴多指（趾）。
我们在受 MKS 影响的胎儿中鉴定出 TMEM67（MKS3）的纯合突变；然而，只有母亲是该突变的携带者。用多态性微卫星标记和单核苷酸多态性（SNP）阵列进行基因分型显示，整个 8 号染色体（携带 TMEM67 的 upd(8)mat）存在母源性单亲二体性（UPD）。
这是首例 UPD 作为 MKS 病因的报道。对单亲二体性（UPD）的潜在机制进行了综述。即使罕见，在隐性突变出现意外纯合的情况下，对 UPD 的认识和全面检查对于准确的遗传咨询和复发风险评估至关重要。
