Solomon B D, Pineda-Alvarez D E, Hadley D W, Hansen N F, Kamat A, Donovan F X, Chandrasekharappa S C, Hong S-K, Roessler E, Mullikin J C
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md., USA.
Mol Syndromol. 2013 Feb;4(1-2):27-31. doi: 10.1159/000345406.
Exome sequencing offers an efficient and affordable method to interrogate genetic factors involved in human disease. Performing exome sequencing of monozygotic twins discordant for VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association-type congenital malformations was hypothesized to potentially reveal discordant variants that could demonstrate disease cause(s). After demonstrating monozygosity, we applied high-density microarrays and exome sequencing to 2 twin pairs in which 1 twin had features of VACTERL association while the other was phenotypically normal (demonstrated through comprehensive clinical and radiological evaluation). No obvious discordant genotypic results were found that would explain phenotypic discordance. We conclude that VACTERL association is a complex disease, and while performing microarray analysis and exome sequencing on phenotypically discordant monozygotic twins may hypothetically reveal genetic causes of disorders, challenges remain in applying these methods in this circumstance.
外显子组测序提供了一种高效且经济的方法来探究参与人类疾病的遗传因素。对患有VACTERL（脊柱异常、肛门闭锁、心脏畸形、气管食管瘘、肾脏异常和肢体异常）关联型先天性畸形的单卵双胞胎进行外显子组测序，据推测可能会揭示出不一致的变异，这些变异可能会证明疾病的病因。在证实为单卵双生后，我们对2对双胞胎应用了高密度微阵列和外显子组测序，其中1对双胞胎具有VACTERL关联的特征，而另一个在表型上正常（通过全面的临床和放射学评估证实）。未发现明显的不一致基因型结果能够解释表型不一致。我们得出结论，VACTERL关联是一种复杂疾病，虽然对表型不一致的单卵双胞胎进行微阵列分析和外显子组测序理论上可能会揭示疾病的遗传原因，但在这种情况下应用这些方法仍存在挑战。
