Faculty of Medicine, University of Oslo, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Eur J Hum Genet. 2021 Jun;29(6):920-929. doi: 10.1038/s41431-020-00788-4. Epub 2020 Dec 7.
An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.
准确诊断综合征型颅缝早闭（CS）对于个性化治疗、监测和遗传咨询至关重要。我们描述了综合征型 CS 的详细临床标准以及队列中遗传诊断的分布。使用挪威颅面外科国家单位的前瞻性登记来检索 2002 年 1 月 1 日至 2019 年 6 月 30 日期间出生的综合征型 CS 患者。所有患者均由临床遗传学家进行评估，并使用定义的临床标准进行分类。采用逐步方法，包括单基因分析、比较基因组杂交（aCGH）和基于外显子组的高通量测序，首先筛选与综合征型 CS 相关的 72 个基因，然后对所有综合征型 CS 病例进行 1570 个基因的扩展三核苷酸组面板分析。共登记了 381 名 CS 患者，其中 104 名（27%）被临床诊断为综合征型 CS。通过单基因分析、aCGH 和定制设计的面板，在 94 名（73%）患者中确认了遗传诊断。在添加扩展三核苷酸组面板的结果后，诊断率增加到 84%。在 53 名（56%）患者中发现了常见的综合征型 CS 病因，而 26 名（28%）患者有其他遗传综合征，包括 17 名与 CS 不常见相关的综合征。只有 15 名患者（16%）的基因分析呈阴性。通过使用定义的临床标准组合，我们检测到了报告的综合征型 CS 病例数量最多，遗传诊断率高达 84%。观察到的遗传异质性鼓励广泛采用遗传方法诊断综合征型 CS。
