Adult genomic medicine: lessons from a multisite study of 2700 patients

Abstract

Background: Clinical exome and genome sequencing has transformed the diagnostic workup of patients with genetic disorders. The extensive body of evidence supporting the application of this clinical genomics approach in pediatric patients stands in stark contrast to the relative paucity of evidence for its use in the adult population. Here, we describe the largest cohort to date of adult patients who underwent clinical exome and genome sequencing for suspected genetic diagnoses.

Methods: A total of 2763 adult patients (2529 families) from all regions of Saudi Arabia are included in this cohort (2202 exomes, and 561 genomes).

Results: The diagnostic rate is 38.9% spanning 535 Mendelian genes and revealing clinical diagnostic errors in 38% of patients with positive reports. Structured feedback using C-GUIDE demonstrates clinical utility in 90% of positive cases. Consistent with the highly consanguineous nature of the local population, the majority (61%) of diagnosed phenotypes are recessive (94.6% homozygous) and founder variants account for 85% (414/487) of these variants. The same population characteristic has also led to the encounter of extremely rare, even novel recessive disorders including a highly penetrant novel RNF43-related hemochromatosis, NFXL1-related syndrome of hyperlaxity, short stature, and kidney disease, as well as autosomal recessive forms of typically dominant disorders. Multilocus phenotypes are observed in 5% of cases although only 26.7% of these are caused by two recessive variants. That 70% of molecular diagnoses encountered in our cohort are typically described in pediatric patients allowed us to observe highly unusual clinical presentations in the adult population. This delayed diagnosis also represents a missed opportunity for effective treatment in many instances and we note the availability of treatment for 26% of diagnosed conditions. Of particular interest are patients with monogenic disorders that could be overlooked as common multifactorial adult diseases (e.g., diabetes, dyslipidemia, stroke, chronic kidney disease, and dementia). Finally, we note the opportunities of deploying adult clinical genomics in an underrepresented population where 45.5% (373/819) of encountered variants are completely absent in gnomAD.

Conclusions: Our results illustrate numerous benefits of a clinical genomics approach in adult medicine and argue for a broader implementation than currently practiced.

Keywords: Clinical utility; Exome; Founder variants; Mendelian phenocopies; Novel allelic disorders; Novel disease genes; Rare diseases; Reflex genome; Underrepresented population.

Fig. 1

Schematic representation of the study design and outcome. Adult patients from Saudi Arabia (aged 18 and older) underwent clinical exome and genome sequencing because of phenotypic presentation (all organ systems are represented). Diagnostic yield was ~ 40%. Due to the high prevalence of consanguinity, there is enrichment of autosomal recessive disorders (the majority of which are homozygous). There was ~ 90% reported positive clinical utility from the 155 surveys collected from 23 physicians. The majority of the phenotypes are pediatric onset and 26% of them have treatment available. Fhx: family history, AR: autosomal recessive, Hom: homozygous. The figure was created with https://BioRender.com

Fig. 2

Distribution of phenotypic categories. This figure shows all 27 categories and highlights notable disparities in their diagnostic yield

Fig. 3

Examples of clinical and radiographic features of adult patients with confirmed genetic diagnoses. A Facial photographs of a patient with splice variant c.169 + 1G > A in MGP gene show the typical presentation of Keutel syndrome with midface hypoplasia. B Facial photograph of a patient with Koolen-De Vries syndrome, who has a frameshift variant c.2642_2654del p.Gln881Profs*14 in KANSL1 gene. C Facial photograph of a patient with Marfan syndrome with a missense variant c.5866 T > C p.Cys1956Arg in FBN1 gene shows malar hypoplasia and myopia. D Scalp image of a patient with alopecia caused by a pathogenic nonsense variant NM_001793.5:c.747C > A p.(Tyr249*) in CDH3 gene, which is associated with autosomal recessive congenital hypotrichosis with juvenile macular dystrophy. E Lower extremity photograph of a patient with congenital ichthyosis, displaying severe scaling and hyperkeratosis; the genetic analysis revealed compound heterozygous pathogenic variants NM_173483.3:c.1303C > T (p.(His435Tyr) and c.177C > G (p.(Phe59Leu) in the CYP4F22 gene. F Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) showing global thinning in both eyes with reduced RNFL thickness, particularly in the temporal and inferior quadrants, consistent with optic atrophy in a patient with homozygous missense variant c.1586C > T p.(Ala529Val) in AFG3L2 gene. G Mouth photograph of a patient with autosomal recessive dentin dysplasia, type I, harboring a homozygous deletion of approximately 589 Kb encompassing the entire SMOC2 gene. The photograph shows missing teeth, microdontia, and misshapen dentition. H The corresponding panoramic dental X-ray for the same patient in G, which further illustrates the dental anomalies consistent with the clinical findings. I Brain MRI (sagittal (Ii) and axial (Iii)) showing cerebellar atrophy in a patient with missense variant c.562 T > C p.(Phe188Leu) in CLN5 gene, which represents a novel allelic disorder. J Axial MRI image showing cavernous malformations with multiple cerebral lesions. A recent hemorrhage is evident in the right parietal cavernous malformation. Genetic analysis identified a pathogenic 475 kb deletion in the 3q26.1 region encompassing the PDCD10 gene, confirming the diagnosis of autosomal dominant cerebral cavernous malformations type 3. K Chest X-rays showing Pre-OP (left) and Post-OP (right) cardiomyopathy in a patient with homozygous likely pathogenic missense variant c.574G > A p.(Glu192Lys) in TPM1 gene. L Pedigree shows the pseudodominant inheritance pattern of autosomal recessive retinitis pigmentosa type 14. The index patient (ID: 141LO0350) was found to be homozygous for the nonsense pathogenic variant (NM_003322.4:c.901C > T p.(Gln301*)) in the TULP1 gene

Fig. 4

Breakdown of diagnostic molecular variant classes. This figure summarizes the molecular findings in our cohort and further delineates them into various classes

Fig. 5

Clinical utility of positive genetic testing results as assessed by C-GUIDE. This figure displays the breakdown of C-GUIDE scores across various domains, including diagnosis/prognosis understanding, medical management, reproductive, and health risk awareness. The panel corresponds to the answers provided for each category in the same order in which they appear in the standard questionnaire (see Supplemental C-GUIDE Material)