Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.
Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.
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DOI：
10.1016/j.ymgme.2014.09.007
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发表时间：
2014-12
影响因子：
3.8
通讯作者：
Del Gaudio D
中科院分区：
文献类型：
--
作者：
Alkorta-Aranburu G;Carmody D;Cheng YW;Nelakuditi V;Ma L;Dickens JT;Das S;Greeley SAW;Del Gaudio D
主要影响胰腺β细胞功能的单基因突变约占所有糖尿病病例的1-2%。与常见形式的糖尿病重叠的临床特征使得单基因糖尿病的诊断具有挑战性。基因诊断通常会导致治疗的重大改变，可以更好地预测疾病的预后和进展，并对家庭成员产生影响。目前，单基因糖尿病的基因检测依赖于选择适当的个体基因进行分析，这是基于通常有限的表型信息的可用性，从而降低了进行基因诊断的可能性。因此，我们开发了一种靶向的下一代测序（NGS）检测方法，用于检测已知引起单基因型糖尿病的36种基因中的突变，包括短暂性或永久性新生儿糖尿病（TNDM或PNDM），年轻人的成熟型糖尿病（MODY）和罕见的综合征型糖尿病。共分析了95例患者样本：19例具有已知的因果突变，76例具有临床提示表型但缺乏遗传诊断。检测到了所有之前鉴定的突变，验证了我们的检测方法。76例患者中有19例（25%）发现致病序列改变：32例NDM病例中有7例（22%），44例MODY病例中有12例（27%）。在2例NDM患者中，由于未报告血缘关系，并且除糖尿病外无临床特征，因此预期不会发生因果突变。1例3月龄时诊断为NDM的3岁患者，既往INS、KCNJ 11和ABCC 8突变检测阴性，发现EIF 2AK 3携带一种新的纯合突变（与Wolcott-Rallison综合征相关），该基因以前未被怀疑，因为没有报告血缘关系、生长迟缓、骨发育异常和肝脏并发症。同样，另一名没有血缘关系的婴儿在出生时被发现患有纯合GCK突变，导致PNDM。本研究证明了多基因面板分析在发现单基因型糖尿病患者的分子诊断中的有效性。
Single gene mutations that primarily affect pancreatic β-cell function account for approximately 1–2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott–Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homo-zygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel anal ysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.