National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland.
J Med Genet. 2012 Apr;49(4):242-5. doi: 10.1136/jmedgenet-2012-100803.
A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event.
Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives.
A locus for the syndrome was identified at 8p11.21-q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients.
Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.
本研究报道了 10 名来自爱尔兰旅行者群体的近亲生育的儿童，他们患有一种新的综合征。该综合征的特征是自然杀伤 (NK) 细胞缺陷、非典型范可尼贫血型 DNA 断裂障碍的证据以及家族性糖皮质激素缺乏症 (FGD) 的特征。NK 细胞缺陷可能导致患者反复发生病毒感染。分子检测支持 mosaic Fanconi's anaemia 的诊断，但患者没有表现出该疾病的任何预期临床特征。FGD 的症状表现延迟出现，可能是继发性表型。由于所有三种表型都一起遗传，作者推测 NK 细胞缺陷、DNA 修复障碍和 FGD 是由单个隐性遗传事件引起的。
对 10 名患者和 16 名未受影响的亲属进行单核苷酸多态性纯合性作图和靶向下一代测序。
在 8p11.21-q11.22 确定了该综合征的一个基因座。对候选区域的靶向重测序发现，所有 10 名受影响的个体均存在 MCM4/PRKDC 的纯合突变。与观察到的 DNA 断裂障碍一致，MCM4 和 PRKDC 均参与 ATM/ATR（ataxia-telangiectasia-mutated/ATM-Rad 3-related）DNA 修复途径，该途径在范可尼贫血患者中存在缺陷。小鼠中 PRKDC 的缺陷已被证明会导致 NK 细胞生理异常，类似于这些患者的观察结果。
MCM4/PRKDC 的突变代表了 DNA 断裂和 NK 细胞缺陷的一个新原因。这些发现表明，临床医生应考虑在出现生长不良、色素沉着或反复感染的患者中考虑这种疾病。
