Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis
Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis
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DOI：
10.3324/haematol.2016.147769
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发表时间：
2016-10-01
期刊：
影响因子：
10.1
通讯作者：
Dokal, Inderjeet
中科院分区：
文献类型：
--
作者：
Walne, Amanda J.;Collopy, Laura;Dokal, Inderjeet
先天性角化不良是一种高度多效性的遗传性疾病。这种异质性可能导致难以作出准确的诊断和延误适当的管理。本研究的目的是确定潜在的遗传基础，在典型的先天性角化不良基因突变呈阴性的先天性角化不良的特点的患者。通过全外显子组和靶向测序，我们在来自12个家族的17个个体中鉴定了与先天性角化不良无关的基因的双等位基因变体。具体而言，这些是USB 1中的纯合变体（8个家族）、GRHL 2中的纯合错义变体（2个家族）和LIG 4中的相同复合杂合变体（2个家族）。所有患者都有先天性角化不良的多种躯体特征，但没有特征性的短端粒。我们的病例系列显示，USB 1、LIG 4和GRHL 2中的双等位基因变体，即在伴有中性粒细胞减少症的多发性骨髓瘤、LIG 4/Dubowitz综合征和最近认识到的外胚层发育不良/身材矮小综合征中突变的基因，分别引起与先天性角化不良重叠的特征。引人注目的是，这些基因的生物学功能也与已知的先天性角化不良基因重叠，这些基因涉及端粒维持和DNA修复途径。总的来说，这些观察结果表明先天性角化不良与其他四种遗传综合征有明显的重叠，混淆了准确的诊断和随后的治疗。这对于当新患者出现在诊所时建立基因诊断具有重要意义。具有先天性角化不良临床特征的患者除了经典的先天性角化不良基因和端粒长度测量外，还需要进行USB 1、LIG 4和GRHL 2的遗传分析。
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.