Table 1 WGS diagnoses, WES reanalysis diagnoses, and reasons why WES diagnoses missed.
From: Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis
F | Pt. | Phenotype | WGS diagnosis | Genomic testing | ES analysis/reanalysis | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
System | Description | Gene / Inheri-tance | Disease-causing variant | ACMG variant classification | Disorder | Original WES approach | WGS approach | Why missed on original WES | Retrospective contemporary WES reanalysis | WES coverage NovaSeq 6000 | ||
1 | 1,2 | Haemat-ological | Oculocutanous albinism, absent platelet dense granules, ddx: Hermansky-Pudlak syndrome; parental consanguinity for both probands | HPS6 AR, hom | NC_000010.11:g.102066504 G > T (GRCh38); NM_024747.5:c.1030 G > T; NP_079023.2:p.(Glu344Ter) SCV:001809937 | Pathogenic: PVS1, PM2, PM3_supporting | Hermansky-Pudlak syndrome | Affected grandmother & grandson | Affected grandmother & grandson | Bioinformatics pipeline | Diagnosed. Updated bioinformatics pipeline. | |
2 | 3,4,5 | Haemat-ological | Macrothrombocytopaenia, platelet count 30-40 ×109/L; abnormal platelet function & bleeding disorder. N/C | ANKRD26 AD | NC_000010.11:g.27100442 G > A (GRCh38); NM_014915.2:c.-116C > T; exon 1 of 34 (5ʹUTR) position 57 of 414 SCV:001809938 | Likely Pathogenic: RCV000851960.1 | Thrombocytopenia 2 (MIM 188000) | 3 affected individuals (cousins & uncle) | 3 affected (cousins & uncle) & 1 unaffected (sibling) | 5ʹUTR not covered | Undiagnosed. No coverage of 5ʹUTR | Genomic location covered |
3 | 6,7,8 | NS-ID | ID, epilepsy; consanguinity | ALG11 AR, hom | NC_000013.11:g.52024914 T > C (GRCh38); NM_001004127.2:c.1184 T > C NP_001004127.2:p.(Met395Thr) SCV:001809939 | Likely Pathogenic: PM1, PM2, PM3_supporting, PP3 | Congenital disorder of glycosylation type 1p (MIM 613661) | Sibling pair | Affected sibling pair, aunt & unaffected parents | Reduced coverage | Undiagnosed. Reduced coverage. | Genomic location covered |
4 | 9,10 | NS-ID | ID; additional phenotype Dec 2017:Parkinson’s diagnosis, increased tremors, epilepsy, peripheral neuralgia, scoliosis?cerebral brain iron accumulation. N/C | RAB39B XLR | NC_000023.11:g.155264167_155265545del (GRCh38); Partial exon 1 deletion SCV:001809940 | Pathogenic | X-linked mental retardation; Waisman syndrome (MIM: 300271; 311510) | Sibling pair | Sibling pair | CNV caller may have missed due to issues with exon 1 calling | Undiagnosed. Not identified through CNV analysis. | |
5 | 11,12 | NS-ID | Severe ID, absent speech, hypotonia microcephaly. N/C | AP1S2 XLR | NC_000023.11:g.15854687 C > T (GRCh38); NM_001272071.2:c.-1 + 1 G > A p.(?) | Likely Pathogenic: PVS1, PM2 | Mental retardation, X-linked syndromic 5 (MIM 304340) | Sibling pair | Sibling pair | Reduced coverage | Undiagnosed. Reduced coverage. | Reduced coverage of genomic location |
6 | 13 | S-ID | Severe ID, no speech, dysmorphic features: thick hair, epicanthic folds, mildly dysplastic helices, keratosis pilaris, dermatographia, pes planus, slender fingers & toes, flat nail beds, mild contractures of elbows & knees, mild obesity. N/C | MSL3 AD de novo | NC_000023.11:g.11765731 T > A (GRCh38); chrX:g.11783850 T > A; NM_078629.3:c.1171 + 2 T > A SCV:001809941 | Pathogenic: PVS1, PS2, PS3, PM2 | X-linked neurodevelopmental delay, dysmorphism, and progressive neurological disorder | Trio | Trio | Bioinformatics pipeline | Diagnosed. Updated bioinformatics pipeline. | |
7 | 14 | S-ID | Moderate ID, adducted thumbs, hypotonia, abnormal aortic valve & prominent aortic root. N/C | OGT XLR | NC_000023.11:g.71537917 G > A (GRCh38); NM_181672.2:c.307 G > A; NP_858058.1:p.(Gly103Arg); In region with 2 prior pathogenic variants reported in N-terminal TPR domain SCV:001809942 | Likely Pathogenic: PM1, PM2, PP2, PP3, PS4_supporting (RCV000624465.1) | X-linked mental retardation (MIM 300997) | Trio | Trio | Unknown disease gene association | Diagnosed. Interim disease gene publication. | |
8 | 15,16 | S-ID | ID, dysmorphic, epilepsy, osteoporosis and fractures (one proband). N/C | SMS XLR | NC_000023.11:g.21967298 A > G (GRCh38); NM_004595.4:c.152 A > G; NP_004586.2:p.(Tyr51Cys); Large Grantham 194 SCV:001809943 | Likely pathogenic: PM2, PS4_moderate, PP4_moderate | Snyder-Robinson syndrome (MIM 309583) | Sibling pair | Sibling pair | Variant prioritization pipeline; stringent pathogenicity filter applied (CADD > / = 15) | Diagnosed. Updated variant prioritisation pipeline. | |
9 | 17 | S-ID | Severe ID, hypotonia, hypermobility, constipation, macrocephaly, prominent forehead, long face, slender hands & feet, prominent foetal finger pads, kyphoscoliosis, muscle wasting without significant weakness. N/C | NFIX AD de novo | NC_000019.10:g.13025339 C > T (GRCh38); NM_001271043.2:c.370 C > T; NP_001257972.1:p.(Arg124Trp) SCV:001809944 | Pathogenic: PS2, PM1, PM2, PM5, PS4_moderate, PP2, PP3 | Sotos type 2 (MIM 614753) | Trio | Trio | Bioinformatics pipeline; unlisted parental zygosity at genomic location | Diagnosed. Updated bioinformatics pipeline. | |
10 | 18 | S-ID | Marked polyhydramnios, umbilical cysts 20/40 USS, scalp oedema, severe microcephaly, bilateral coronal synostosis, eye proptosis, midface hypoplasia, cupid bow, cleft gum, lowset ears, bulbous digits, severe ascites, choanal stenosis, congenital pulmonary alveolar malformation type 3. N/C | FGFR2 AD de novo | NC_000010.11:g.121515280 T > C (GRCh38); NM_000141.4:c.1124 A > G; NP_000132.3:p.(Tyr375Cys) SCV:001809945 | Recurrent Pathogenic RCV000762799 | Beare-Stevenson syndrome (extended FGFR2 spectrum; MIM: 123790) | Trio | Trio | Bioinformatics pipeline | Undiagnosed. Variant calling failure in bioinformatics pipeline. | |
11 | 19,20 | Neurological | Neonatal deaths; microcephaly, cerebellar hypoplasia & simplified gyral pattern; oligohydramnios & pulmonary hypoplasia (pt.19); IUGR; Cardiac: globular heart & VSD (pt.19), cardiac hypertrophy (pt.20); CK 2,642 (pt.20); Eyes: posterior globe flattening, microphthalmia, optic atrophy, abnormal retinal vessels & fundi (pt.19), possible cataracts or vitreous anomaly (pt.20). N/C | MIPEP AR, comp het | (1) NC_000013.11:g.23837561 G > C (GRCh38); NM_005932.3:c.1534 C > G; NP_005923.2:p.(His512Asp); SCV:001809946 (2) NC_000013.11:g.23841336 A > G; NM_0059323:c.1259 T > C; NP_005923.2:p.(Leu420Pro) SCV:001809947 | (1) Likely Pathogenic; PS4, PM1, PM3, PP3 (2) Likely pathogenic; PM1, PM2, PM3, PP3 | Combined oxidative phosphorylation deficiency 31 (MIM 602241) | Sibling pair | Sibling pair | Unknown disease gene association; first publication within 1 week of analysis completion | Diagnosed. New disease gene publication. | |
12 | 21 | Skeletal | Sagittal craniosynostosis, ADHD. N/C | ERF AD | NC_000019.10:g.42254976 A > C (GRCh38); NM_005932.3:c.1259 T > C; Exon 1 donor canonical site | Pathogenic: PVS1, PM2, PP1_strong | Craniosynostosis (MIM: 600775) | Multiple affected individuals | Singleton | Reduced coverage | Undiagnosed. Reduced coverage. | Genomic location covered |
13 | 22,23 | Skeletal | Hernias, widened scars, fused radius/ulna, keratoconus, high myopia, subluxation of lenses, short stature; Weill-Marchesani syndrome? Parental consanguinity identified for pt. 22 after WGS. | ASPH 22: AR hom; 23: AR comp het | Patient 22: NC_000008.11:g.61548140 G > T (GRCh38); NM_004318.3:c.1695C > A; NP_004309.2:p.(Tyr565Ter); Patient 23: 1st variant and NC_000008.11:g.61526095 C > T (GRCh38); NM_004318.3:c.1782G > A; NP_004309.2:p.(Trp594Ter) SCV:001809948 | (1) Pathogenic; PVS1, PM2, PM3_supporting (2) Pathogenic; PVS1, PM2, PM3 | Traboulsi syndrome (MIM: 601552) | Multiple affected individuals | Multiple affected individuals | Variant prioritization pipeline; inheritance pattern assumption | Diagnosed. Analysis outside standard pipeline. | |
