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Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This research establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening
Disease/Condition | Gene | Allele Count | Carrier Frequency (Lower/Upper CI) | Disease Frequency (Lower/Upper CI) | Known Frequency | References |
---|---|---|---|---|---|---|
Retinal dystrophy, Stargardt disease | ABCA4 | 13 (23) | 0.0350 (0.0206/0.0589) | 3.1 × 10−4 (1.1 × 10−4/8.8 × 10−4) | 1 in 10,000 1 in 8000 |
[7] [8] |
Cystic fibrosis | CFTR | 11 (19) | 0.0296 (0.0167/0.0522) | 2.2 × 10−4 (6.9 × 10−5/6.9 × 10−4) | 1 in 10,000 1 in 3000–16,000 |
Reported carrier frequency of 0.032 [9] [10] |
Phenylketonuria | PAH | 11 (18) | 0.0296 (0.0167/0.0522) | 2.2 × 10−4 (6.9 × 10−5/6.9 × 10−4) | 1 in 10,000 1 in 4500 [Italy]–1 in 125,000 [Japan] |
Reported carrier frequency of 0.029 [11] [12] |
Wilson disease | ATP7B | 4 (6) | 0.0108 (0.0042/0.0274) | 2.9 × 10−5 (4.3 × 10−6/1.9 × 10−4) | 1 in 30,000 1 in 30,000 |
Similar global incidence reported [13][14] |
Galactosemia | GALT | 4 (5) | 0.0108 (0.0042/0.0274) | 2.9 × 10−5 (4.3 × 10−6/1.9 × 10−4) | 1 in 20,000 1 in 48,000 |
Reported carrier frequency of 0.006 [9][15] |
Gene | Patient ID | Exon/Intron | Variant | Allele Frequency in GnomAD | Allele Frequency in [23] | Variant Pathogenicity Classification by ACMG |
---|---|---|---|---|---|---|
LDLR | G31 | 4 | c.316_328delCCCAAGACGTGCT p.(Lis107Argfs*95) | Not found | Not found | P (PVS1 PS1 PM1 PM2 PP3) |
LDLR | G29 | 4 | c.325T>G p.(Cys109Gly) | Not found | Not found | LP (PS1 PM1 PM2 PM5 PP3) |
LDLR | G36 | 4 | c.401G>C (p.Cys134Ser) | Not found | Not found | LP (PS1 PM1 PM2 PM5 PP3) |
LDLR | 1 | 4 | c.433_434insG p(Val145Glyfs*35) | Not found | Not found | P (PVS1 PM2 PP3) |
LDLR | G18 | 4 | c.616A>C (p.Ser206Arg) | Not found | Not found | Uncertain significance (PM2 PP1 PP3) |
LDLR | G21 | IVS6 | c.940+1_c.940+4 delGTGA (g.18154_18157delGTGA) | Not found | Not found | P (PVS1 PM1 PM2 PP3) |
LDLR | 32 | 8 | c.1186G>C p.(Gly396Arg) | Not found | Not found | P (PVS1 PM1 PM2 PM5 PP3) |
LDLR | G26 | IVS8 | c.1186+1G>T (g.22279G>T) | Not found | Not found | P (PVS1 PM2 PP3) |
LDLR | G17 | 11 | c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) | Not found | Not found | P (PVS1 PM1 PM2 PP3) |
Nosology | Efficiency of Diagnostics Prior to NGS, % | Efficiency of Diagnostics after WES, % | Efficiency of Diagnostics with Novel Variants Considered, % | Reference |
---|---|---|---|---|
Cystic fibrosis | 45–55 (1 mutation) 58 (35 mutations) |
67–80 | - | Unpublished |
WD | Up to 75 (4 mutations) Up to 86 (12 mutations) |
Up to 96 | 97 | [30] |
MODY | 15–35 | 40–50 | 55 | [31] |
Genetically heterogeneous condition |
28% | 65% | [32] | |
Neurometabolic disorder | 24% | 35% | [32] | |
Single anomalyy of the fetuses | 6% | [33] | ||
Two and more anomalies of the fetuses | 35% | [33] | ||
Anomalies of the fetuses | 10.3–18.9% | [34] | ||
Anomalies of the fetuses | 8.5–15.4% | [35] | ||
Anomalies of the fetuses | 6.2–80% | [36] |