Table 1.
Newborn screen, biochemical, and molecular features of 44 Pennsylvanian infants who screened positive for X-ALD between 1 April 2017 and 26 May 2021 and harbored ABCD1 variants. Screening was considered positive for second-tier LC-MS/MS quantitation of C26:0-LPC > 0.15 µmol/L on initial and repeat dried blood spot specimens. First-tier results from FIA-MS/MS are not shown. Confirmatory biochemical testing with C26:0 quantitation was performed on a clinical basis (reference range: 0.17–0.73 µmol/L). “-” denotes that the clinical information was unavailable. All units are in µmol/L. ABCD1 variants and their laboratory interpretation using ACMG criteria are listed. Variants identified in the ALD Variant Database are indicated as previously reported. Inheritance pattern is provided for families in whom parental testing was performed and available. Finally, known family history is denoted for patients in whom there were family members with confirmed, symptomatic X-ALD phenotype. “*” indicates individuals with family members identified via NBS who are known to carry the same variant but are asymptomatic. “^” indicates family individuals whose medical histories were suspicious for symptomatic individuals but for whom an X-ALD diagnosis had not been made (for example: an adult male uncle with progressive gait disturbance).
| # | Sex | NBS C26:0-LPC Initial/Repeat |
VLCFA C26:0 | ABCD1 Variant | Classification | Previously Reported? | Inheritance | Family History | ||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Female | 0.32 | 0.52 | 3.40 | c.887A>C | p.Tyr296Ser | Likely pathogenic | Yes | Maternal | No |
| 2 | Female | 0.38 | 0.3 | 2.12 | c.1166G>A | p.Arg389His | Pathogenic | Yes | Paternal | No |
| 3 | Female | 0.31 | 0.23 | 1.03 | c.1415_1416delAG | p.Gln472Profs*84 | Pathogenic | Yes | Maternal | Yes |
| 4 | Female | 0.62 | 0.32 | - | c.1447dupA | - | Pathogenic | No | - | - |
| 5 | Female | 0.29 | 0.34 | 1.97 | c.1516dupA | - | Pathogenic | No | De novo | No |
| 6 | Female | 0.43 | 0.26 | - | c.1628del | p.Pro543Argfs*15 | Pathogenic | Yes | - | No |
| 7 | Female | 0.31 | 0.28 | 2.34 | c.1690delG | - | Pathogenic | No | De novo | No |
| 8 | Female | 0.73 | 0.47 | 2.67 | c.1978C>T | p.Arg660Trp | Pathogenic | Yes | Maternal | No ^ |
| 9 | Female | 0.54 | 0.4 | 1.84 | c.2135G>A | p.Arg712His | Pathogenic | Yes | Paternal or De novo | No |
| 10 | Female | 0.81 | 0.39 | - | c.264C>A | p.Cys88* | Pathogenic | Yes | De novo | No |
| 11 | Female | 0.58 | 0.37 | 0.93 | c.346G>A | p.Gly116Arg | Pathogenic | Yes | Maternal | Yes |
| 12 | Female | 0.39 | 0.35 | 2.52 | c.390dupT | - | Pathogenic | No | Paternal or De novo | No |
| 13 | Female | 0.51 | 0.29 | 2.50 | c.521A>G | p.Tyr174Cys | Pathogenic | Yes | - | No |
| 14 | Female | 0.4 | 0.29 | 2.22 | c.838C>T | p.Arg280Cys | Pathogenic | Yes | - | No |
| 15 | Female | 0.63 | 0.36 | - | c.978G>A | p.Trp326* | Pathogenic | No | - | - |
| 16 | Female | 0.48 | 0.37 | 3.48 | Deletion of exons 3 and 4 | - | Pathogenic | No | - | No |
| 17 | Female | 0.49 | 0.26 | 2.99 | c.1533C>G | p.Cys511Trp | VUS | Yes | Maternal | No ^ |
| 18 | Female | 0.55 | 0.22 | 1.39 | c.262T>C | p.Cys88Arg | VUS | No | Maternal | No |
| 19 | Female | 0.33 | 0.34 | 1.79 | c.467G>A | p.Gly156Asp | VUS | No | Maternal | No |
| 20 | Female | 0.28 | 0.28 | 1.46 | c.700C>T | p.Arg234Cys | VUS | Yes | Maternal | No ^ |
| 21 | Female | 0.24 | 0.17 | - | c.739G>A | p.Ala247Thr | VUS | Yes | Maternal | No * |
| 22 | Female | 0.24 | 0.21 | 2.14 | c.880G>A | p.Ala294Thr | VUS | Yes | Maternal | No |
| 23 | Female | 0.23 | 0.19 | 0.76 | c.970C>T | p.Arg324Cys | VUS | Yes | Maternal | No ^ |
| 24 | Male | 0.7 | 0.2 | 2.32 | c.565C>T | p.Arg189Trp | Likely pathogenic | Yes | Maternal | Yes |
| 25 | Male | 0.52 | 0.56 | - | c.1390C>T | p.Arg464* | Pathogenic | Yes | Maternal | Yes |
| 26 | Male | 0.84 | 0.9 | - | c.1415_1416delAG | p.Gln472Profs*84 | Pathogenic | Yes | Maternal | No |
| 27 | Male | 1.08 | 0.52 | 2.90 | c.1661G>A | p.Arg554His | Pathogenic | Yes | Maternal | Yes |
| 28 | Male | 0.62 | 0.36 | - | c.1772G>A | p.Arg591Gln | Pathogenic | Yes | Maternal | No * |
| 29 | Male | 0.62 | 0.33 | - | c.1772G>A | p.Arg591Gln | Pathogenic | Yes | Maternal | No * |
| 30 | Male | 0.76 | 0.61 | 4.06 | c.796G>A | p.Gly266Arg | Pathogenic | Yes | Maternal | No |
| 31 | Male | 0.28 | 0.2 | 1.51 | c.1184C>T | p.Ala395Val | VUS | No | Maternal | No * |
| 32 | Male | 0.35 | 0.29 | 2.50 | c.1253G>A | p.Arg418Gln | VUS | Yes | Maternal | No ^ |
| 33 | Male | 0.55 | 0.3 | 3.13 | c.1448C>T | p.Thr483Met | VUS | No | Maternal | No ^ |
| 34 | Male | 0.64 | 0.75 | - | c.1832A>G | p.Gln611Arg | VUS | Yes | - | - |
| 35 | Male | 0.48 | 0.2 | - | c.229_237delTGGCTCCTG | p.Trp77_Leu79del | VUS | Yes | - | - |
| 36 | Male | 0.37 | 0.25 | 3.35 | c.229_237delTGGCTCCTG | p.Trp77_Leu79del | VUS | Yes | Maternal | No ^ |
| 37 | Male | 0.3 | 0.27 | 2.60 | c.452T>C | p.Ile151Thr | VUS | No | Maternal | Yes |
| 38 | Male | 0.67 | 0.33 | - | c.487C>T | p.Arg163Cys | VUS | No | - | - |
| 39 | Male | 0.82 | 0.39 | 2.67 | c.700C>T | p.Arg234Cys | VUS | Yes | Maternal | No * |
| 40 | Male | 0.69 | 0.3 | 3.18 | c.700C>T | p.Arg234Cys | VUS | Yes | Maternal | Yes |
| 41 | Male | 0.29 | 0.27 | - | c.739G>A | p.Ala247Thr | VUS | Yes | - | - |
| 42 | Male | 0.86 | 0.97 | 3.05 | c.824G>C | p.Arg275Pro | VUS | Yes | Maternal | No ^ |
| 43 | Male | 0.41 | 0.33 | 1.34 | c.851C>T | p.Ser284Leu | VUS | No | Maternal | No |
| 44 | Male | 0.31 | 0.27 | - | c.851C>T | p.Ser284Leu | VUS | Yes | Maternal | No * |