Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Speech and Language Pathology Section, Department of Rehabilitation Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Genet Med. 2018 Jan;20(1):14-23. doi: 10.1038/gim.2017.68. Epub 2017 Jun 22.
PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.
目的
随着医疗水平的提高，一些患有前脑无裂畸形（HPE）的患者能够存活到成年期。我们研究了 HPE 青少年和成年人的临床表现，并探讨了潜在的分子病因。
方法
参与者包括 20 名年龄在 15 岁及以上的患者。临床评估包括畸形学检查、认知测试、吞咽研究、眼科检查和脑磁共振成像。基因检测包括染色体微阵列、SHH、ZIC2、SIX3 和 TGIF 的 Sanger 测序，以及 10 个三联体的外显子组测序（WES）。
结果
半侧 HPE 是最常见的 HPE 亚型，占参与者的 50%。神经发育障碍与 HPE 亚型相关。与长期存活相关的因素包括 HPE 亚型非全前脑、女性和非典型面部特征。四名参与者在 ZIC2 中有新生致病性变异。对 11 名参与者的 WES 分析未发现可能的候选基因，提示这些病例存在复杂的遗传。事实上，在两个先证者中，存在未经控制的母亲 1 型糖尿病病史。
结论
各种 HPE 亚型的患者可以存活到成年期，神经发育结局各不相同。根据面部特征和分子评估，我们认为经典的 HPE 遗传原因在该队列中可能作用较小。
