Abstract：
BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.
METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.
RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.
CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.
RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.
CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
摘要：
背景：导致罕见疾病的遗传变异可能仍然难以捉摸，即使经过广泛的测试，例如外显子组测序。基因组测序的诊断产量，特别是在负面评价之后，仍然定义不清。
方法：我们对具有不同表型的家族的基因组进行了测序和分析，这些家族被怀疑患有罕见的单基因疾病，并且基因检测未发现诊断结果。以及独立临床中心的复制队列的基因组。
结果：我们对822个家族（初始队列中744个，复制队列中78个）的基因组进行了测序，并对744个家族中的218个（29.3％）进行了分子诊断。218个家庭中,61（28.0％）-初始队列中8.2％的家庭-具有需要基因组测序才能鉴定的变异，包括编码变体，内含子变体，小型结构变体，非复制反转，复杂的重新安排,和串联重复扩展。在先前的非诊断性外显子组测序后进行分子诊断的大多数家族（63.5％）具有可以通过重新分析外显子组序列数据（53.4％）或通过其他分析方法检测到的变异。例如拷贝数变体调用，外显子组序列数据（10.8%）。我们在复制队列中获得了类似的结果：在进行分子诊断的33％的家族中，或8%的队列，需要基因组测序，这表明这些发现适用于研究和临床环境。
结论：基因组测序的诊断产量不同的研究队列,在一个由以前接受过基因检测的患者组成的小型临床队列中,约占8%,其中包括几种以前未通过外显子组测序或其他技术检测到的致病变异.（由国家人类基因组研究所等资助。).
方法：我们对具有不同表型的家族的基因组进行了测序和分析，这些家族被怀疑患有罕见的单基因疾病，并且基因检测未发现诊断结果。以及独立临床中心的复制队列的基因组。
结果：我们对822个家族（初始队列中744个，复制队列中78个）的基因组进行了测序，并对744个家族中的218个（29.3％）进行了分子诊断。218个家庭中,61（28.0％）-初始队列中8.2％的家庭-具有需要基因组测序才能鉴定的变异，包括编码变体，内含子变体，小型结构变体，非复制反转，复杂的重新安排,和串联重复扩展。在先前的非诊断性外显子组测序后进行分子诊断的大多数家族（63.5％）具有可以通过重新分析外显子组序列数据（53.4％）或通过其他分析方法检测到的变异。例如拷贝数变体调用，外显子组序列数据（10.8%）。我们在复制队列中获得了类似的结果：在进行分子诊断的33％的家族中，或8%的队列，需要基因组测序，这表明这些发现适用于研究和临床环境。
结论：基因组测序的诊断产量不同的研究队列,在一个由以前接受过基因检测的患者组成的小型临床队列中,约占8%,其中包括几种以前未通过外显子组测序或其他技术检测到的致病变异.（由国家人类基因组研究所等资助。).
