Nuclear and mitochondrial results of whole genome sequencing analyses
| Type | No. of variants, mean ± SD | No. of variants, median (range) | No. of participants | Sum (1–56) | Size range (kb) |
|---|---|---|---|---|---|
| Sequence-level variants (SNVs, indels) | |||||
| All | 3 708 264 ± 366 708 | 3 851 444 (2 491 596–4 102 372) | 56 | 207 662 805 | |
| Rare* coding | 1198 ± 115 | 1188 (939–1457) | 56 | 67 101 | |
| Rare potentially disease-associated† | |||||
| All | 28.41 ± 8.45 | 29.5 (11–43) | 56 | 1591 | |
| Autosomal dominant | 6.77 ± 3.24 | 6 (1–15) | 56 | 379 | |
| Semidominant | 6.79 ± 3.35 | 7 (0–14) | 55 | 380 | |
| Autosomal recessive | 13.68 ± 4.71 | 14 (4–25) | 56 | 766 | |
| X-linked | 0.79 ± 1.06 | 1 (0–6) | 30 | 44 | |
| Mitochondrial‡ | 0.39 ± 0.68 | 0 (0–3) | 17 | 22 | |
| Rare (likely) pathogenic§ or risk factor | |||||
| All | 3.04 ± 1.68 | 3 (0–8) | 53 | 175 | |
| Autosomal dominant | 0.05 ± 0.30 | 0 (0–2) | 2 | 3 | |
| Semidominant | 0.20 ± 0.48 | 0 (0–2) | 9 | 11 | |
| Autosomal recessive | 2.77 ± 1.63 | 2.5 (0–8) | 52 | 155§§ | |
| X-linked | 0 ± 0 | 0 (0) | 0 | 0 | |
| Mitochondrial | 0.02 ± 0.13 | 0 (0–1) | 1 | 1 | |
| Risk | 0.11 ± 0.31 | 0 (0–1) | 6 | 6§§ | |
| Copy number variants and other structural variants | |||||
| All CNVs | |||||
| Deletion | 431 ± 45.90 | 438 (275–521) | 56 | 24 140 | 1–1919 (+ mosaic X loss) |
| Duplication | 60 ± 4.80 | 60 (40–73) | 56 | 3354 | 3–863 |
| Rare¶ coding** CNV | |||||
| Deletion | 1.23 ± 0.96 | 1 (0–4) | 41 | 69 | 2–1919 (+ mosaic X loss) |
| Duplication | 1.09 ± 0.93 | 1 (0–4) | 42 | 61 | 7–863 |
| Rare coding CNV, covering CGD genes | |||||
| Deletion | 0.25 ± 0.51 | 0 (0–2) | 13 | 14 | 2–1919 (+ mosaic X loss) |
| Duplication | 0.29 ± 0.45 | 0 (0–1) | 16 | 16 | 15–863 |
| Rare (likely) pathogenic§ or risk factor CNV | |||||
| Deletion | 0.16 ± 0.42 | 0 (0–2) | 8 | 9¶¶ | 4–1919 (+ mosaic X loss) |
| Duplication | 0 ± 0 | 0 (0) | 0 | 0 | 0 |
| Rare inversion | 0.02 ± 0.13 | 0 (0–1) | 1 | 1 | 8630 |
| Clinically relevant pharmacogenomics diplotype†† | |||||
| All | 3.86 ± 1.09 | 4 (1–6) | 56 | 216 | |
| Serious adverse drug reaction‡‡ | 0.23 ± 0.43 | 0 (0–1) | 13 | 13 | |
Note: ACMG = American College of Medical Genetics and Genomics, CGD = Clinical Genomic Database, CNV = copy number variant, HGMD = Human Gene Mutation Database, kb = kilobase pairs, SD = standard deviation, SNV = single nucleotide variant, WGS = whole genome sequencing.
↵* Rare sequence level variants are defined as those with allele frequencies < 5% in control databases (Supplementary methods in Appendix 1).
↵† Variants in CGD genes, either predicted null alleles or disease-associated in HGMD or ClinVar (Supplementary methods in Appendix 1).
↵‡ All mitochondrial variants detected at > 5% heteroplasmy.
↵§ Interpretation according to the ACMG guideline.16
↵¶ Rare CNVs are defined as those with < 50% overlap with all gold standard variants in the Database of Genomic Variants (http://dgv.tcag.ca/) and occurring at a frequency of < 1% among all WGS-CNVs in the unrelated parents in the Autism Speaks MSSNG cohort (http://www.mss.ng/).
↵** Coding CNVs are defined as those overlapping coding exons.
↵†† Haplotype pairs on homologous chromosomes that are associated with risk for altered drug efficacy or adverse drug reactions.
↵‡‡ HLA-A*3101 and HLA-B*5701 associated hypersensitivity reactions; TPMT- poor/intermediate metabolizers with myelotoxicity risk.
↵§§ MUTYH variant was interpreted both as likely pathogenic (autosomal recessive) and a risk factor for colorectal cancer.
↵¶¶ One likely pathogenic deletion (25 kb) was identified by microarray only; 3 likely pathogenic deletions (4–7 kb) were identified by WGS only.19