Molin Arnaud, Lopez-Cazaux Serena, Pichon Olivier, Vincent Marie, Isidor Bertrand, Le Caignec Cédric
Service de Génétique, Laboratoire de cytogénétique, CHU de Caen, Caen, France.
Departement d'odontologie pédiatrique, faculté de chirurgie dentaire, Nantes, France.
Am J Med Genet A. 2015 Jun;167(6):1386-90. doi: 10.1002/ajmg.a.37052. Epub 2015 Apr 21.
Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dominant disorder characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicles, moderate short stature and supernumerary teeth. By contrast, an increased gene dosage is expected for duplication of the entire RUNX2 sequence and thus, a phenotype different from cleidocranial dysplasia. To date, two cousins with a duplication including the entire RUNX2 sequence in addition to MIR586, CLIC5 and the 5' half of SUPT3H have been reported. These patients presented with metopic synostosis and hypodontia. Here, we report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. Interestingly, the mother and one child had isolated hypodontia without craniosynostosis, broadening the phenotype observed in patients with such duplications.
RUNX2功能丧失性突变可导致锁骨颅骨发育不全，这是一种常染色体显性疾病，其特征为颅缝闭合延迟、锁骨发育不全或发育不良、身材中度矮小以及多生牙。相比之下，预计整个RUNX2序列重复会导致基因剂量增加，从而产生与锁骨颅骨发育不全不同的表型。迄今为止，已有报道称两名表亲除了MIR586、CLIC5和SUPT3H的5' 半部分外，还存在包含整个RUNX2序列的重复。这些患者表现为额缝早闭和缺牙症。在此，我们报告一个家庭，母亲和三个孩子均受影响。这四名患者通过阵列比较基因组杂交鉴定出存在285 kb的重复。该重复包括RUNX2的完整序列和SUPT3H的5' 半部分。我们通过实时定量PCR在这四名患者中证实了该重复。两名儿童出现了先前描述的额缝早闭和少牙/缺牙症的关联，证实了RUNX2重复导致的表型。有趣的是，母亲和一名儿童仅有缺牙症，无颅缝早闭，这拓宽了此类重复患者中观察到的表型范围。
