Table 1 Comparison of ABCD1 mosaicism in five male individuals identified through newborn screening
mXALD-1 | mXALD-2 | mXALD-3 | mXALD-4 | mXALD-5 | ||
|---|---|---|---|---|---|---|
Initial VLCFA testing | NBS Tier 1: C26:0-LPC (µmol/L) | 0.52 (cutoff ≧ 0.22) | 0.48 [Ref Range < 0.2] | 0.48 [RR 0.25–0.38; cutoff ≧ 0.42] | 0.48 (cutoff > 0.42; RR 0.16–0.38) | 0.306 (cutoff < 0.18) |
NBS Tier 2: C26:0-LPC (µmol/L) | 0.36 (cutoff ≧ 0.12) | 0.37 [Ref Range < 0.2] | 0.2 [RR 0.04–0.09; cutoff ≧ 0.15] | 0.17 (cutoff > 0.15; RR 0.04–0.09) | ||
Confirmatory C26:0 (µmol/L) | 0.7 (RR 0.05–0.41) | 2.09 [RR ≦ 1.3 nmol/mL] | 1.19 [RR ≦ 1.3 nmol/mL] | 0.800 (0.23 ± 0.09) | ||
Confirmatory C26:0/C22:0 ratio | 1.4 (RR 0.6–1.1) | 0.039 [RR ≦ 0.023] | 0.02 (RR not provided) | 0.04 (0.01 ± 0.004) | ||
Confirmatory C24:0/C22:0 ratio | 0.05 (RR < 0.02) | 1.23 [RR ≦ 1.39 ratio] | 0.93 (RR not provided) | 1.256 (0.84 ± 0.10) | ||
Variant analysis | Tissue tested | blood | buccal | blood | blood | blood |
Mosaic Variant Identified | c.1988 T > C, p.Leu663Pro | c.1817 C > T, p.Ser606Leu | c.1826 A > G, p.Glu609Gly | c.1025 C > T, p.Ser342Leu | c.1850 G > A, p.Arg617His | |
% VAF—Lab #A (NGS coverage) | 82% (77×) | 60% (285×) | unknown (not reported by lab) | unknown |
| |
% VAF—Lab #B (NGS coverage) | 80% (117×) | n/a | unknown (not reported by lab) | n/a | 60% (35×) | |
Next-generation sequencing (±Sanger) | NGS (+Sanger) | NGS (+Sanger) | NGS (+Sanger) | NGS (+Sanger) | NGS (+Sanger) | |
Variant Classification | Likely pathogenic | Pathogenic | Likely Pathogenic | Variant of Uncertain Significance | Pathogenic | |
Age at time of testing | 11.5 weeks old | unknown | 4 months | unknown | 1 day old | |
Verification | Confirmed XY? (i.e. karyotype or SNP) | YES | YES | YES | NO | YES |
Maternal ABCD1 testing negative? | YES | YES | YES | YES | YES | |
Negative family history? | YES | YES | YES | unknown | YES | |
Sibling testing? | YES | n/a | n/a | unknown | n/a | |
Confirm 1 ABCD1 copy (i.e. MLPA) | YES | YES | unknown | YES | YES | |
Clinical Information | Current age (2023) | 4.0 years | 2.5 years | 5 years | 6 years | 1 year |
Clinical symptoms | pre/asymptomatic | pre/asymptomatic | pre/asymptomatic | pre/asymptomatic | pre/asymptomatic**** | |
Age of most recent MRI results | 4.0 years | 2.5 years | 5 years | 6 years | 11 months | |
Most recent MRI results (LOES score) | normal (LOES 0) | normal (LOES 0*) | normal (LOES 2**) | normal (LOES 1***) | normal (LOES 0) |
- Note: NBS newborn screening C26:0-LPC, C26:0, C24:0, C22:0 = very long-chain fatty acids. RR reference range, NGS next-generation sequencing, “Sanger” Sanger sequencing. Clinical “cutoff” for abnormal values and/or RR provided, as reported by clinical sequencing laboratories. Labs 1 and 2 indicate samples were sent for verification at a second lab, but are not necessarily obtained from identical labs or the labs listed in Table 2. *Areas of non-enhancing T2 hyperintensity, T1 hypointensity in the periventricular white matter along the frontal horns. **mild hyperintensity involving the bilateral parietal occipital periventricular white matter on axial FLAIR images, score 1. Tiny foci of FLAIR hyperintensities noted involving the central part of the bilateral parietal occipital white matter, score 1. ***Suspected minor T2/FLAIR hyperintensities.
Did not initially identify mosaic ABCD1 variant, whole genome sequencing was sent at 1-day old for non-ALD indications, and resulted prior to knowledge of abnormal NBS. The lab was later able to identify the presence of a variant, but only after Sanger sequencing of ABCD1 was performed through a second lab. **** Non-ALD related clinical features include arthrogryposis.
Did not initially identify mosaic ABCD1 variant, whole genome sequencing was sent at 1-day old for non-ALD indications, and resulted prior to knowledge of abnormal NBS. The lab was later able to identify the presence of a variant, but only after Sanger sequencing of ABCD1 was performed through a second lab. **** Non-ALD related clinical features include arthrogryposis.