CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients Cohort
2.2. Exome and Targeted-Exome Sequencing
2.3. Conventional CNV-Detection Methods—Microarray-Based Chromosome Analyses
2.4. Conventional Locus CNV-Detection Method—MLPA
2.5. NGS-Based CNV Calling, Annotation, and Filtering
2.6. Pathogenic CNVs
2.7. Samples Selection
3. Results
3.1. Disease Categories
3.2. Diagnostic Yield
3.3. Pathogenic CNVs per Disease Categories
3.4. Comparison of arrayCGH and NGS CNV Results
3.5. Pathogenic CNVs Undetected by the NGS Pipeline
3.6. Variants of Unknown Significance in arrayCGH Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Case (Phase) | Disease Category | Clinical Description | NGS Library | NGS CNV Coordinates (Grch37) + Size + Gene If Small CNV | CNV Validation | Acgh/MLPA CNV Results (Grch37) | Known Syndrome (+ Additional Comment) |
---|---|---|---|---|---|---|---|
Case 1 (2) | NDD | DD, mild ID | ES | chr22:44489809-51220722 x1 >6.7 Mb | aCGH 180k | 22q13.31q13.33(44481506_51186249)x1 | Phelan-McDermid syndrome (qTer) |
Case 2 (2) | NDD | DD, language delay, hypotonia | ES | chr15:23609491-28632839 x3 >5 Mb | aCGH 180k | 15q11.2q13.1(22765628_28535051)x3 | 15q11.2-q13.2 microduplication syndrome |
Case 3 (2) | BID | immunodeficiency and ID | ES | chr13:103298645-103301836 x0 >4.4 Kb–TPP2 (exons 20–22) | WGS | Not enough aCGH targets No MLPA available | (patient presented in [24]) |
Case 4 (2) | NDD | DD, renale acidosis, SS, optic atrophy | ES | chr14:99640489-106236323 x3 >7 Mb | aCGH 180k | 14q32.2q32.33(99634561_107278770)x3 | 14q distal duplications (qTer) |
Case 5 (2) | Renal | Renal kystes and DD | ES | chrX: 107224311-107979574 x0 >755 kb | aCGH 180k | Xq22.3(107182490_108105721)x0 | |
Case 6 (2) | NDD | DD with pyramidal signs & facial dysmorphism | ES | chr2:237028837-242815426 x1 >5 Mb | aCGH 180k | 2q37.2q37.3(236980552_243041364)x1 | 2q37 deletion syndrome (qTer) |
Case 7 (2) | NG | Ataxia | ES | chr10:125769666-128860040 x3 chr10:133747956-135379033 x1 >7 Mb | aCGH 180k | 10q26.13q26.2(125757754_128852954)x3 10q26.3(130764002_131513932)x3, 10q26.3(131528966_135434178)x1 | 10q26 deletion syndrome |
Case 8 (2) | NDD | Progressive cognitive decline, epilepsy | ES | chr22:18834446-21414817 x1 >2.5 Mb | aCGH 180k | 22q11.21(18894835_21464119)x1 | 22q11.2 microdeletion syndrome |
Case 9 (2) | NG | Myoclonic dystonia | ES | chr7:92818581-94540820 x1 >1.7 Mb–including SGCE | aCGH 180k | 7q21.2q21.3(92776146_94641008)x1 | |
Case 10 (2) | NDD | Global DD, mild dysmorphic features | ES | chr17:1082962-1657828 x3 >574 Kb | aCGH 180k | 17p13.3(1071072_1658551)x3 | 17p13.3 microduplication syndrome |
Case 11 (2) | NDD | DD, ASD | ES | chr1:146461120-147416212 x3 >955 Kb | aCGH 180k | 1q21.1q21.2(146542843-149243967)x3 | |
Case 12 (3) | Hearing loss | Deafness | TsoE | chr15:43892159-43901532 x1 >9.4 Kb–STRC (exons 16–28) | MLPA | STRC (exon 19-3′UTR) Not enough aCGH targets | + STRC c.4552G>A (p.Gly1518Ser) |
Case 13 (3) | NG | Neuroacanthocytosis | ES | chr9:79827886-79828230 x1 >344 bp–VPS13A (exons 8–9) chr9:80018153-80018237x1 >84 bp–VPS13A (exon 69) | Sanger | Not enough aCGH targets No MLPA available | |
Case 14 (3) | Hearing loss | Deafness, neutropenia | TsoE | chr3:69928286-69988332 x1 >60 Kb–MITF (exons 1–3) | aCGH 1M | 3p13(69917276_69989173)x1 (MITF) | |
Case 15 (3) | Metabolic disease | Hypophosphatemic rickets | TsoE | chrX:21958944-22151741 x1 >192 Kb–PHEX | aCGH 180k | Xp22.11(21950459_22180647)x1 (PHEX) | |
Case 16 (3) | NDD | Early onset epilepsy | TsoE | chrX:99551276_99663595 x1 >112 Kb–PCDH19 | MLPA | PCDH19 fully deleted x1 | |
Case 17 (3) | NG | Familial spastic paraparesia | TsoE | chr2:32352018_32353548 x1 >1.53 Kb–SPAST (exons 8–9) | MLPA | SPAST (exons 8–9) Not enough aCGH targets | |
Case 18 (3) | NDD | DD, epilepsy, hypotonia, hair anomalies | ES | chr15:22742397-28772634 x4 >6 Mb | aCGH 180k | 15q11.1q13.1(20102541_28535051)x4 | maternal 15q duplication syndrome, (supernumerary chromosome) |
Case (Phase) | Disease Category | Clinical Description | NGS Library | CNV Coordinates from NGS (Grch37) | CNV Validation | Acgh CNV Results (Grch37) Size + Gene of Interest | Reason CNV Missed by the CNV Pipeline |
---|---|---|---|---|---|---|---|
Case 19 (2) | NDD | Lissencephaly | ES | Not detected | aCGH 180k | 17p13.3(2433963_2548152)x1 >114 kb–PAFAH1B1 (exons 1–2) | PAFAH1B1: exon1 is not targeted by the ES library, exon 2 is targeted with low coverage (Figure S2). |
Case 20 (2) | NDD | DD, Epilepsy | ES | chr13:35615071-35697711 x1 | aCGH 180k | 13q13.3(35522735_35696113)x1 >173 kb–NBEA (exons 2–17) | Gene not present in the gene panel analysed originally. |
Case 21 (2) | NDD | DD, Epilepsy | ES | chr14:105814831-106370569 x1 | aCGH 180k | 14q32.33(105807673_107278770)x1 >1.4 Mb–including PACS2 | Gene not present in the gene panel analysed originally |
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Royer-Bertrand, B.; Cisarova, K.; Niel-Butschi, F.; Mittaz-Crettol, L.; Fodstad, H.; Superti-Furga, A. CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations. Genes 2021, 12, 1427. https://doi.org/10.3390/genes12091427
Royer-Bertrand B, Cisarova K, Niel-Butschi F, Mittaz-Crettol L, Fodstad H, Superti-Furga A. CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations. Genes. 2021; 12(9):1427. https://doi.org/10.3390/genes12091427
Chicago/Turabian StyleRoyer-Bertrand, Beryl, Katarina Cisarova, Florence Niel-Butschi, Laureane Mittaz-Crettol, Heidi Fodstad, and Andrea Superti-Furga. 2021. "CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations" Genes 12, no. 9: 1427. https://doi.org/10.3390/genes12091427