Dubowitz Syndrome Is a Complex Comprised of Multiple, Genetically Distinct and Phenotypically Overlapping Disorders

Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463–65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.杜布维茨综合征（Dubowitz syndrome）是一种罕见病症，以多发先天性畸形、认知发育迟缓、生长障碍、免疫缺陷，以及血液系统异常和恶性肿瘤风险升高为特征。该病存在显著的表型异质性，提示遗传异质性。我们对3例杜布维茨综合征患者进行了临床表型分析，并实施了外显子组测序及高密度SNP芯片基因分型，其中包括一对已报道的兄妹（患者1与患者2）及1例未公开报道的患者（患者3）。鉴于该兄妹存在骨髓异常病史，我们同时评估了端粒长度并开展了放射敏感性试验。 在兄妹二人中，外显子组测序发现其存在核连接酶基因LIG4的复合杂合突变：1种为已知的罕见无义置换（rs104894419, NM_002312.3:c.2440C>T），可导致p.Arg814X（次要等位基因频率MAF:0.0002）；另1种为NM_002312.3:c.613delT变异，可导致p.Ser205Leufs*29移码突变。该移码突变在千人基因组计划、外显子组测序项目（ESP）及ClinSeq数据库中均未见报道。此前已有报道该LIG4突变存在于该兄妹中的妹妹体内，其兄长此前未接受检测。蛋白质免疫印迹（Western blotting）结果显示，该兄妹体内均未检测到连接酶IV条带。 在第3例患者中，高密度SNP芯片基因分型显示其17号染色体q24.2区域存在1段约3.89 Mb的新发中间缺失（chr 17:62,068,463–65,963,102, hg18），该缺失区域涵盖已知的卡尼复合征（Carney complex）致病基因PRKAR1A。 3例患者的淋巴细胞端粒长度中位数均≤第1百分位数，且放射敏感性试验显示其对电离辐射的敏感性升高。 本研究提示，除先天性角化不良（dyskeratosis congenita）外，LIG4综合征及17q24.2综合征也存在端粒缩短表型；为验证这一结论，应对上述两种疾病考虑开展端粒长度检测。 综合本研究及目前已报道的杜布维茨综合征相关文献，当前所定义的杜布维茨综合征并非单一统一的疾病实体，而是一组表型相似的疾病集合。随着其致病表型的明确，作为临床疾病实体的杜布维茨综合征也需要持续的重新评估与重新界定。