Vetro Annalisa, Iascone Maria, Limongelli Ivan, Ameziane Najim, Gana Simone, Della Mina Erika, Giussani Ursula, Ciccone Roberto, Forlino Antonella, Pezzoli Laura, Rooimans Martin A, van Essen Antoni J, Messa Jole, Rizzuti Tommaso, Bianchi Paolo, Dorsman Josephine, de Winter Johan P, Lalatta Faustina, Zuffardi Orsetta
Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Hum Mutat. 2015 May;36(5):562-8. doi: 10.1002/humu.22784. Epub 2015 Apr 7.
The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death.
VACTERL综合征的诊断可能具有挑战性，尤其是在产前阶段，因为其存在的畸形与其他遗传疾病（包括范可尼贫血（FA））中的畸形有重叠。我们报告了两个家族中的三例VACTERL综合征病例，其中两名出生的患儿因严重器官畸形在出生后不久死亡。VACTERL综合征的疑似诊断基于产前超声评估和产后特征。随后的染色体断裂分析提示了FA的诊断。最后，通过对一个家族的外显子组和另一个家族的一组范可尼基因进行下一代测序，我们在两个家族中均鉴定出了新的FANCL截短突变。我们使用野生型FANCL的异位表达对两种突变在功能上校正了细胞FA表型。我们的研究强调，当怀疑存在VACTERL综合征时应考虑FA的诊断。此外，我们表明FANCL的功能丧失突变会导致以出生后早期死亡为特征的严重临床表型。
