Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency

Abstract

Rapid whole-genome sequencing (rWGS) has shown that genetic diseases are a common cause of infant mortality in neonatal intensive care units. Dried blood spots collected for newborn screening allow investigation of causes of infant mortality that were not diagnosed during life. Here, we present a neonate who developed seizures and encephalopathy on the third day of life that was refractory to antiepileptic medications. The patient died on day of life 16 after progressive respiratory failure and sepsis. The parents had lost two prior children after similar presentations, neither of whom had a definitive diagnosis. Postmortem rWGS of a dried blood spot identified a pathogenic homozygous frameshift variant in the SUOX gene associated with isolated sulfite oxidase deficiency (c.1390_1391del, p.Leu464GlyfsTer10). This case highlights that early, accurate molecular diagnosis has the potential to influence prenatal counseling and guide management in rare, genetic disorders and has added importance in cases of a strong family history and risk factors such as consanguinity.

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

“…There is evidence that rapid WGS in infants in ICUs with diseases of unknown etiology is effective for genetic disease diagnosis, which has JAMA Network Open | Pediatrics been followed by a practice guideline from the American College of Medical Genetics and Genomics and Medicaid coverage policies in 6 US states. 15,18,[27][28][29][30][31][32][33]54 SCN1A-DEE6 and PCDH19-DEE9, respectively). A limitation of this study was the uncertainty associated with reconstruction of the counterfactual clinical courses in these 5 infants.…”

“…Rapid diagnostic WGS was used in 501 of 125 605 infants (0.4%) treated at this hospital system during this period. [26][27][28][29][30][31][32][33] The obverse of this is that it is likely that there is even greater underrecognition of genetic etiologies of infant mortality in regions where rapid diagnostic WGS is not available. A future, alternative, and comprehensive approach to avoid underdiagnosis of the approximately 600 genetic diseases with current, effective treatments may be newborn screening (NBS) by automated WGS.…”

“…Whole-genome sequencing was performed from blood samples or dried blood spots, as described. [26][27][28][29][30][31][32][33]36 Premortem WGS was performed with parent-child duos or trios for whom parental samples were available, and parents gave permission for their genomes to be sequenced.…”

“…To further understand genetic determinants of infant deaths, we compared all 112 infants who died with all 434 surviving infants who underwent diagnostic WGS as inpatients at the same health system during the same period [26][27][28][29][30][31][32][33]36 (Figure). There were no differences in sex, race, or ethnicity between infant deaths and survivors with or without underlying genetic diseases (eTables 1 and 2 in Supplement 1).…”

“…Furthermore, at least 30% of death certificates have inaccuracies . The effect of such imprecision could be large since many genetic diseases have treatments that can improve outcomes, and undiagnosed genetic diseases often recur within families, causing preventable deaths . Early implementation of genomic sequencing could improve understanding about causes and suggest novel strategies to reduce infant mortality.…”