Genome sequencing as a first-line diagnostic test for hospitalized infants

Abstract

Purpose: SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research.

Methods: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing.

Results: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups.

Conclusion: We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.

Keywords: Diagnostic yield; Genetic diagnosis; Genome sequencing; Infants; Utility.

Figure 1.

Utility of genome sequencing as a first-line genetic test for infants (n=367 babies). (A) Diagnostic yield of SouthSeq study population. Thirty percent (n=109) of study participants received a definitive diagnostic (DD) or likely diagnostic (LD) finding; 14% (n=51) received an uncertain finding, and no genetic findings of interest were identified in the remaining 56% (n=207). (B) Percentage of findings that fall within each mode of inheritance category, including de novo, compound heterozygous or homozygous, X-linked, inherited, or unknown. Unknown represents heterozygous variants (SNV or CNV) where one or both parents were unavailable for testing, or inheritance could not be determined (e.g. non-paternity). (C) Types of variation represented by DD/LD findings, including missense, nonsense, frameshift, splice, and CNV; one case of uniparental disomy (UPD) not shown.