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Abstract：
BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes.
METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery.
RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP.
CONCLUSIONS: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.
METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery.
RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP.
CONCLUSIONS: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.
摘要：
背景：最近的重大努力促进了许多中心对患有罕见疾病的儿童进行临床遗传学评估和基因组测序的获取，但是成年人的服务仍然存在差距。奥斯汀健康成人未诊断疾病计划（AHA-UDP）旨在补充现有的UDP计划，这些计划专注于儿科罕见疾病，并解决维多利亚州未诊断罕见疾病的成年人未满足的诊断需求。澳大利亚。它是在维多利亚州的一家大型医院进行的，目的是证明将目前主要用于研究环境的基因组技术带入医院临床实践的好处。并确定将患有未诊断的罕见疾病的成年人纳入UDP计划的好处。主要目标是确定所登记的个人和家庭的各种疾病的因果突变，并发现新的疾病基因。
方法：未解决的患者，其中标准的基因组诊断技术，如靶向基因面板，全外显子组下一代测序，和/或染色体微阵列，已经进行了招募。来自研究环境的基因组测序和增强的基因组分析被用于帮助新基因发现。
结果：总计，16/50（32％）家庭/病例得到解决。在18/50（36％）家族中检测到一种或多种具有不确定意义的候选变体。在16/50(32%)家族中未鉴定出候选变体。两个新的疾病基因（TOP3B，PRKACB)和两个新的基因型-表型相关性(NARS，和KMT2C基因)被鉴定。八分之三的疑似镶嵌结节性硬化症患者的诊断得到证实，这为两名患者提供了生殖选择。在项目开始时，没有特别设想对患有马赛克疾病的患者进行诊断（使用高读取深度测序和ddPCR）的效用。但是根据需要提供招募和分析的灵活性被证明是AHA-UDP的优势。
结论：AHA-UDP证明了UDP方法的实用性，该方法应用基因组测序方法诊断患有罕见疾病的成人，这些成人具有无信息的常规遗传分析，告知临床管理，复发风险,给亲戚的建议。
方法：未解决的患者，其中标准的基因组诊断技术，如靶向基因面板，全外显子组下一代测序，和/或染色体微阵列，已经进行了招募。来自研究环境的基因组测序和增强的基因组分析被用于帮助新基因发现。
结果：总计，16/50（32％）家庭/病例得到解决。在18/50（36％）家族中检测到一种或多种具有不确定意义的候选变体。在16/50(32%)家族中未鉴定出候选变体。两个新的疾病基因（TOP3B，PRKACB)和两个新的基因型-表型相关性(NARS，和KMT2C基因)被鉴定。八分之三的疑似镶嵌结节性硬化症患者的诊断得到证实，这为两名患者提供了生殖选择。在项目开始时，没有特别设想对患有马赛克疾病的患者进行诊断（使用高读取深度测序和ddPCR）的效用。但是根据需要提供招募和分析的灵活性被证明是AHA-UDP的优势。
结论：AHA-UDP证明了UDP方法的实用性，该方法应用基因组测序方法诊断患有罕见疾病的成人，这些成人具有无信息的常规遗传分析，告知临床管理，复发风险,给亲戚的建议。
