Table 2.
NGS-NBS and Diagnostic Findings in the NC NEXUS Inborn Errors of Metabolism Cohort
| NC NEXUS Participant | NGS-NBS Result | Diagnostic (Dx) Result | Gene(s) | Disease Association with Gene (Inheritance) | Variant and (Predicted Protein Change) | Zygosity in NC NEXUS Participant |
|---|---|---|---|---|---|---|
| M001 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.799G>A (p.Gly267Arg); c.985A>G (p.Lys329Glu) | heterozygous for both variants |
| M002 | abnormal | positive | PAH | PKU (AR) | c.1315+1G>A (p.?); c.782G>A (p.Arg261Gln) | heterozygous for both variants |
| M003 | abnormal | positive | PAH,OTC | PKU (AR), OTC deficiency (XL) | PAH c.1222C>T (p.Arg408Trp) and c.896T>G (p.Phe299Cys); OTC c.1061T>G (p.Phe354Cys) | heterozygous for PAH and OTC variants |
| M004 | abnormal | positive | PAH | PKU (AR) | c.1315+1G>A (p.?); c.284_286del (p.Ile95del) | heterozygous for both variants |
| M005 | abnormal | positive | PAH | PKU (AR) | c.194T>C (p.Ile65Thr); c.814G>T (p.Gly272∗) | heterozygous for both variants |
| M006 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu) | homozygous |
| M007 | abnormal | positive | PAH | PKU (AR) | c.1315+1G>A (p.?); c.842C>T (p.Pro281Leu) | heterozygous for both variants |
| M008 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu) | homozygous |
| M009 | normal | inconclusive (VUS) | MLYCD | malonyl-coA decarboxylase deficiency (AR) | c.1013T>C (p.Leu338Pro) | homozygous |
| M010 | abnormal | positive | PAH | PKU (AR) | c.117C>G (p.Phe39Leu); c.842C>T (p.Pro281Leu) | heterozygous for both variants |
| M011 | abnormal | positive | PAH | PKU (AR) | c.194T>C (p.Ile65Thr) | homozygous |
| M012 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu) | homozygous |
| M013 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu) | homozygous |
| M014 | abnormal | positive | SLC22A5 | renal carnitine transport deficiency (AR) | c.506G>A (p.Arg169Gln) | homozygous |
| M015 | normal | inconclusive (heterozygous variant) | BCKDHA | MSUD type 1A (AR) | c.1312T>A (p.Tyr438Asn) | heterozygous |
| M016 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu) | homozygous |
| M017 | abnormal | positive | ACADM | MCAD deficiency (AR) | c.985A>G (p.Lys329Glu); c.199T>C (p.Tyr67His) | heterozygous for both variants |
The NC NEXUS participant column includes “M” (indicating inborn errors of metabolism cohort) followed by the participant number. Each row in the table represents one NC NEXUS participant. An abnormal NGS-NBS result was indicated by a likely pathogenic or pathogenic variant found in the newborn screen gene list. A positive diagnostic result was indicated by a likely pathogenic or pathogenic variant found in a gene on the inborn errors of metabolism diagnostic list. An inconclusive diagnostic result was indicated by any variant of uncertain significance (VUS) finding or a single heterozygous variant found in a gene associated with autosomal-recessive inborn errors of metabolism. A negative diagnostic result indicated we did not detect any pathogenic or likely pathogenic variants or any VUS on the inborn errors of metabolism gene list. Gene symbols are italicized. NGS-NBS, next-generation sequencing newborn screen; AR, autosomal-recessive pattern of inheritance; XL, X-linked pattern of inheritance; PKU, phenylketonuria; MCAD deficiency, medium-chain acyl-coA dehydrogenase deficiency; MSUD, maple syrup urine disease.