Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

中文翻译：

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整合了全基因组测序，综合代谢组学和先进成像技术的精密医学。

基因组测序已建立了罕见疾病诊断的临床应用。尽管越来越多的人接受了选择性基因组测序，但尚未报道一项全面的研究，该研究调查了具有深表型的成年人的全基因组疾病相关基因。在这里，我们报告了一项3年精确医学研究的结果，其目标是将全基因组测序与深表型整合在一起。共有1,190名成年参与者（402名女性[33.8％]；平均年龄54岁[范围从20至89岁]； 70.6％的欧洲人）进行了全基因组测序，并使用代谢组学，先进的影像学和临床实验室进行了深表型分析除了家族/病史的测试。在1,190名成年人中，有206名（17.3％）至少有1个具有病原（P）或可能的病原（LP）评估的遗传变异，提示有遗传风险的倾向。一个多学科临床团队审查了所有可报告的发现，以评估基因型和表型的关联，其中137个（11.5％）具有基因型和表型的关联。在血脂异常（n = 24），心肌病，心律不齐和其他心脏病（n = 42）以及糖尿病和内分泌疾病（n = 17）中，观察到高比例的基因型和表型关联（> 75％）。在有P / LP变异的69名（5.8％）个体中观察到缺乏基因型和表型关联，这是患者护理的潜在负担。基因组学和代谢组学协会确定了61个（5.1％）杂合子，其表型表现影响氨基酸，脂质和辅因子以及维生素途径中的血清代谢物水平。