A retrospective review of multiple findings in diagnostic exome sequencing: half are distinct and half are overlapping diagnoses

Abstract

Purpose: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF).

Methods: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated.

Results: Among patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic.

Conclusion: Patients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

Keywords: comorbidity; diagnostic exome sequencing; distinct vs. overlapping phenotypes; multilocus genomic variation; multiple genetic diseases.

Fig. 1

Diagnostic rates of first 7698 cases submitted for diagnostic exome sequencing. Cases that simultaneously had two potentially relevant findings were included in the multiple potentially relevant findings (MPRF) group.

Fig. 2

Clinical features of cases that had multiple relevant findings. (a) The proportion of solved cases that had multiple potentially relevant findings was not significantly different between trios and nontrios. Both trios and nontrios had about 2% rate of multiple positive or likely positive results. Nontrios had a trend toward more uncertain second results, but this difference was not significant. (b) The origin of autosomal dominant (AD) findings in trios. Cases with multiple potentially relevant findings had a higher proportion of inherited variants than did cases with single findings. (c) Inheritance patterns of genetic diagnoses. (d) Males had a slightly higher proportion of multiple relevant findings than single findings, compared with females. (e) Cases from consanguineous families had significantly more multiple potentially relevant findings (MPRF) than those from nonconsanguineous families. AR autosomal recessive, LP likely pathogenic, MGD multiple genetic diagnoses, P pathogenic, XL X-linked.

Fig. 3

Relationship of clinical complexity to number of genetic diagnoses. (a) Patients with more organ systems affected received more genetic diagnoses. Shown is mean +/- s.e.m. (b) Histogram shows the diagnostic rate for patients with the number of organ systems indicated. Cases with 6–10 organ systems affected had the highest rate of single findings (22.5%) and of multiple potentially relevant findings (2.7%).