Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging

Abstract

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 wholegenome 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.genomics | advanced imaging | precision medicine | deep phenotyping | metabolomics

Whole-body magnetic resonance imaging (WB-MRI) for cancer screening in asymptomatic subjects of the general population: review and recommendations

“…To address this short coming, we identified using PubMed searches and cross-checking of citations, 14 studies published between 2005 and 2020 describing the use of WB-MRI for cancer screening in asymptomatic subjects in the general population. For 12 of the 14 studies (6423 subjects) the intended purpose was or included cancer screening [37][38][39][40][41][42][43][44][45][46][47][48]. In the remaining two studies, the main purpose was the mapping of body fat (148 subjects) [49], or cardiovascular disease screening (138 subjects) [50], with any lesion suspicious for cancer described as incidental findings.…”

“…These two studies were not considered for this review. We note that the 209 subjects included in the pilot study by Perkins et al [39] were included also in the larger study by Hou et al [40]. Therefore, this was considered in the overall count of screened subjects, as reported in Table 1.…”

“…In nine [39-41, 43-45, 47, 48], both T1 and T2 weighted images were acquired across the whole body, while in the remaining three studies, just one morphological sequence was acquired (Table 1 and supplementary Table 1). Whole body DWI sequences were utilized in just five studies [39,40,42,45,47]. All studies provided detailed information regarding the WB-MRI protocol used for cancer screening.…”

“…Whole-body T2-weighted images were acquired in eight studies using TSE sequences: with fat-suppression via Inversion Recovery techniques in five, with both fatsuppressed and unsuppressed acquisitions in one, and without fat suppression in two. Whole body DWI was performed in five studies [39,40,42,45,47], always in addition to the morphological T1 and/or T2-weighted imaging.…”

Precision Medicine for Lysosomal Disorders

“…Currently, molecular analyses using these three approaches have several roles in LD diagnosis: (1) to confirm the final diagnosis, mainly in milder and atypical cases [29]; (2) to clarify borderline biochemical results in screening and enzymatic assays, as obtained in carriers and pseudodeficiency cases (when enzyme activity is decreased but with no clinical consequences) [30]; (3) to characterize a novel gene associated with a new type of LD, such as the cases of VPS33A in MPSPS [21] and DESG1 in leukodystrophy [31]; (4) for prenatal diagnosis [32,33]; (5) to predict disease severity [34,35]; (6) for the identification of patients with variants amenable to targeted therapy [36,37].…”