The present study evaluated the role of SNP microarray in 101 cases of clinically suspected FISH negative (noninformative/normal) 22q11.2 microdeletion syndrome. SNP microarray was carried out using 300 K HumanCytoSNP-12 BeadChip array or CytoScan 750 K array. SNP microarray identified 8 cases of 22q11.2 microdeletions and/or microduplications in addition to cases of chromosomal abnormalities and other pathogenic/likely pathogenic CNVs. Clinically suspected specific deletions (22q11.2) were detectable in approximately 8% of cases by SNP microarray, mostly from FISH noninformative cases. This study also identified several LOH/AOH loci with known and well-defined UPD (uniparental disomy) disorders. In conclusion, this study suggests more strict clinical criteria for FISH analysis. However, if clinical criteria are few or doubtful, in particular newborn/neonate in intensive care, SNP microarray should be the first screening test to be ordered. FISH is ideal test for detecting mosaicism, screening family members, and prenatal diagnosis in proven families.
The 22q11.2 microdeletion syndrome is the most common microdeletion syndrome and seen at a prevalence of 1 in 4000 to 6000 live births [
This study was conducted in the Department of Reproduction Biology, All India Institute of Medical Sciences, New Delhi, India, from September 2011 to August 2014. A total of 101 FISH negative/noninformative (FISH was normal in 85 cases, was not attempted in 12 cases due to frozen/clotted samples, and failed in 4 cases due to few/lysed/clumped cells) clinically suspected 22q11.2 microdeletion syndrome cases were prospectively enrolled for the study using SNP microarray. FISH was carried out using noncommercial FISH probe (22q11.2; RP5-882J5; genomic coordinate/exact position of probe is unavailable; obtained from Uniba Biologia, University of Bari, Italy, by curtsy of Professor Mariano Rocchi,
A total of 101 DNA samples from FISH negative/noninformative clinically suspected 22q11.2 microdeletion syndrome were analyzed by SNP microarray successfully. Details of SNP microarray findings of all 101 FISH negative/noninformative samples are available as master table (Supplementary file 2). Out of 101 FISH negative for 22q11.2 microdeletion cases, SNP microarray detected several cases of chromosomal abnormalities (Table
Details of chromosomal abnormalities in FISH negative
DBN | Locus/loci | CNV | Start | End | Size (mb) | Genes | Disease |
---|---|---|---|---|---|---|---|
93 | 18p11.32-p11.21 | 3 | 2842 | 15365878 | 15.3 | 89 | Trisomy 18 |
18q11.1-q23 | 3 | 16786754 | 76115554 | 59.3 | 241 | ||
98 | All chromosomes | 3 | Triploidy (mosaicism confirmed by FISH) | ||||
103 | 18q21.31-q23 | 1 | 54144903 | 78014582 | 23.8 | Partial 18q monosomy | |
115 | 11q23.2-q25 | 3 | 113077541 | 134944006 | 21.8 | Partial 11q trisomy (Jacobsen, Bartter 2, 11q) | |
116 | All chromosomes | 3 | Triploidy (mosaicism confirmed by FISH) | ||||
205 | 21q11.2 q21.1 | 3 | 13609442 | 46923252 | 33.3 | 256 | Trisomy 21 |
q21.2 q21.3 | |||||||
q22.11 q22.12 | |||||||
q22.13 q22.2 | |||||||
q22.3 |
FISH negative
DBN: database number (CNV 1 = deletion; CNV 3 = duplication).
Details of 22q11.2 microdeletion and/or microduplication in FISH negative
DBN | FISH | Locus | CNV | Start | End | Size (mb) | Genes (no) | Gene details |
---|---|---|---|---|---|---|---|---|
42 | Not done due to frozen blood sample | 22q11.21 | 1 | 18877787 | 21914652 | 3 | 58 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2; DGCR2; DGCR14; TSSK2; GSC2; SLC25A1; CLTCL1; HIRA; MRPL40; C22orf39; C22orf39; UFD1L; CDC45L; CLDN5; LOC150185; SEPT5; GP1BB; TBX1; GNB1L; C22orf29; TXNRD2; COMT; COMT; COMT; COMT; ARVCF; C22orf25; MIR185; DGCR8; MIR1306; TRMT2A; RANBP1; ZDHHC8; Em:AC006547.7; RTN4R; MIR1286; DGCR6L; LOC375133; RIMBP3; ZNF74; SCARF2; KLHL22; MED15; POM121-like 1; DKFZp434N035; PI4KA; SERPIND1; SNAP29; CRKL; AIFM3; AIFM3; LZTR1; THAP7; FLJ39582; MGC16703; P2RX6; P2RX6; SLC7A4; P2RX6P; LOC400891 |
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47 | Not done due to frozen blood sample | 22q11.21 | 1 | 17257787 | 19792353 | 2.53 | 68 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2; DGCR11; DGCR14; TSSK2; GSC2; SLC25A1; CLTCL1; HIRA; MRPL40; C22orf39; C22orf39; UFD1L; CDC45L; CLDN5; LOC150185; SEPT5; GP1BB; TBX1; GNB1L; C22orf29; TXNRD2; COMT; COMT; COMT; COMT; ARVCF; C22orf25; MIR185; DGCR8; MIR1306; TRMT2A; RANBP1; ZDHHC8; LOC150197; RTN4R; MIR1286; DGCR6L; LOC375133; RIMBP3; ZNF74; SCARF2; KLHL22; MED15; POM121L4P; TMEM191A; PI4KA; SERPIND1; SNAP29; CRKL; AIFM3; AIFM3; LZTR1; THAP7; FLJ39582; MGC16703; P2RX6; P2RX6; SLC7A4; P2RX6P; LOC400891 |
|
||||||||
48 | Not done due to frozen blood sample | 22q11.21 | 1 | 19405537 | 19792353 | 0.38 | 16 | PI4KA; SERPIND1; SNAP29; CRKL; AIFM3; AIFM3; LZTR1; THAP7; FLJ39582; MGC16703; P2RX6; P2RX6; SLC7A4; P2RX6P; LOC400891; TBX1 |
|
||||||||
87 | Not done due to sample clotting | 22q11.21 | 1 | 18877787 | 21050552 | 2.1 | 47 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2; DGCR2; DGCR14; TSSK2; GSC2; SLC25A1; CLTCL1; HIRA; MRPL40; C22orf39; C22orf39; UFD1L; CDC45L; CLDN5; LOC150185; SEPT5; GP1BB; TBX1; GNB1L; C22orf29; TXNRD2; COMT; COMT; COMT; COMT; ARVCF; C22orf25; MIR185; DGCR8; MIR1306; TRMT2A; RANBP1; ZDHHC8; Em:AC006547.7; RTN4R; MIR1286; DGCR6L; LOC375133; RIMBP3; ZNF74; SCARF2; KLHL22; MED15; POM121-like 1 |
|
||||||||
182 | Not done due to sample clotting | 22q11.21 | 1 | 18877787 | 21811991 | 2.9 | 69 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2; DGCR2; DGCR14; TSSK2; GSC2; SLC25A1; CLTCL1; HIRA; MRPL40; C22orf39; C22orf39; UFD1L; CDC45L; CLDN5; LOC150185; SEPT5; GP1BB; TBX1; GNB1L; C22orf29; TXNRD2; COMT; COMT; COMT; COMT; ARVCF; C22orf25; MIR185; DGCR8; MIR1306; TRMT2A; RANBP1; ZDHHC8; Em:AC006547.7; RTN4R; MIR1286; DGCR6L; LOC375133; RIMBP3; ZNF74; SCARF2; KLHL22; MED15; POM121-like 1; DKFZp434N035; PI4KA; SERPIND1; SNAP29; CRKL; AIFM3; AIFM3; LZTR1; THAP7; FLJ39582; MGC16703; P2RX6; P2RX6; SLC7A4; P2RX6P; LOC400891; POM121L8P; RIMBP3C; RIMBP3B; HIC2 |
|
||||||||
188 | Not done due to sample clotting | 22q11.21 | 1 | 18877787 | 21798907 | 2.9 | 69 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2; DGCR2; DGCR14; TSSK2; GSC2; SLC25A1; CLTCL1; HIRA; MRPL40; C22orf39; C22orf39; UFD1L; CDC45L; CLDN5; LOC150185; SEPT5; GP1BB; TBX1; GNB1L; C22orf29; TXNRD2; COMT; COMT; COMT; COMT; ARVCF; C22orf25; MIR185; DGCR8; MIR1306; TRMT2A; RANBP1; ZDHHC8; Em:AC006547.7; RTN4R; MIR1286; DGCR6L; LOC375133; RIMBP3; ZNF74; SCARF2; KLHL22; MED15; POM121-like 1; DKFZp434N035; PI4KA; SERPIND1; SNAP29; CRKL; AIFM3; AIFM3; LZTR1; THAP7; FLJ39582; MGC16703; P2RX6; P2RX6; SLC7A4; P2RX6P; LOC400891; POM121L8P; RIMBP3C; RIMBP3B; HIC2 |
|
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191 | Normal | 22q11.21 | 3 | 18844632 | 19033532 | 0.18 | 6 | DGCR6; PRODH; KIAA1647; DGCR9; DGCR10; DGCR2 |
|
||||||||
244 | Not done due to sample clotting | 22q11.21 | 1 | 19004730 | 21800471 | 2.79 | 68 | DGCR9, DGCR10, DGCR2, DGCR11, DGCR14, TSSK2, GSC2, SLC25A1, CLTCL1, HIRA, MRPL40, C22orf39, UFD1L, CDC45, CLDN5, LINC00895, SEPT5, SEPT5-GP1BB, GP1BB, TBX1, GNB1L, C22orf29, TXNRD2, COMT, MIR4761, ARVCF, TANGO2, MIR185, DGCR8, MIR3618, MIR1306, TRMT2A, RANBP1, ZDHHC8, LOC388849, LOC284865, LINC00896, RTN4R, MIR1286, DGCR6L, LOC729444, TMEM191B, PI4KAP1, RIMBP3, ZNF74, SCARF2, KLHL22, MED15, POM121L4P, TMEM191A, PI4KA, SERPIND1, SNAP29, CRKL, AIFM3, LZTR1, THAP7, THAP7-AS1, TUBA3FP, P2RX6, SLC7A4, P2RX6P, LOC400891, BCRP2, POM121L8P, RIMBP3C, RIMBP3B, HIC2 |
FISH negative
DBN: database number (CNV 1 = deletion; CNV 3 = duplication).
Details of other microdeletions and/or duplications in FISH negative
DBN | Locus/loci | CNV | Start | End | Size | Genes | Gene details/disease |
---|---|---|---|---|---|---|---|
88 | 15q11.2 | 3 | 22754322 | 23222284 | 0.46 | 6 | Prader-Willi/Angelman syndrome and chromosome 15q11-q13 duplication syndrome (TUBGCP5; CYFIP1; CYFIP1; NIPA2; NIPA1; WHAMML1) |
|
|||||||
102 | 16p11.2 | 1 | 29661217 | 30347731 | 0.68 | 46 | C16orf54; MAZ; PRRT2; C16orf53; MVP; MVP; CDIPT; LOC440356; LOC440356; SEZ6L2; ASPHD1; KCTD13; TMEM219; TAOK2; HIRIP3; INO80E; DOC2A; FLJ25404; FAM57B; ALDOA; ALDOA; ALDOA; ALDOA; PPP4C; TBX6; YPEL3; YPEL3; GDPD3; MAPK3; LOC100271831; CORO1A; LOC606724; BOLA2; GIYD1; SULT1A4; SULT1A4; LOC388242; LOC613037; IMAA; CD2BP2; TBC1D10B; MYLPF; SEPT1; ZNF48; ZNF771; DCTPP1 |
|
|||||||
197 | 1q21.1 | 3 | 144943150 | 146916824 | 1.9 | 24 | PDZK1; GPR89A; GPR89C; PDZK1; LOC200030; NBPF11; LOC728989; PRKAB2; PDIA3P; FMO5; FMO5; CHD1L; BCL9; ACP6; GJA5; GJA8; GPR89B; GPR89C; PDZK1; LOC200030; NBPF11; FLJ39739; PPIAL4B; PPIAL4A; NBPF14; PPIAL4F; NBPF15; NBPF15; NBPF16; PPIAL4E; NBPF16; PPIAL4F; LOC645166; LOC645166 |
|
|||||||
229 | 15q11.1 | 3 | 20192086 | 22508324 | 2.3 | 13 | GOLGA6L6; GOLGA8C; BCL8; POTEB; NF1P1; LOC646214; CXADR; POTEB; NF1P1; LOC727924; OR4M2; OR4N4; OR4N3P |
q11.2 |
FISH negative
DBN: database number (CNV 1 = deletion; CNV 3 = duplication).
Details of likely pathogenic CNVs in FISH negative
DBN | Locus/loci | CNV | Start | End | Size | Genes | Gene details/disease |
---|---|---|---|---|---|---|---|
18 | 22q11.22 | 3 | 22901370 | 23307965 | 0.4 | 7 | PRAME, LOC648691, POM121L1P, GGTLC2, MIR650, IGLL5; hsa-mir-650 |
7q11.21 | 1 | 64651296 | 65148399 | 0.49 | 3 | INTS4L1, ZNF92, INTS4L2 (cutis marmorata, epicanthus, everted lower lip vermilion, intellectual disability, microcephaly, retinoblastoma, short nasal septum, and thick lower lip vermilion) | |
|
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20 | 1q21.2 | 3 | 147828939 | 149723885 | 1.9 | 18 | 2-3-toe syndactyly, abnormality of the helix, aplasia cutis congenita over the scalp vertex, attention deficit hyperactivity disorder, clinodactyly of the 5th finger, facial asymmetry, flat occiput, gait ataxia, global developmental delay, hyperpigmentation of the skin, hypoplastic areola, long eyelashes, microcephaly, muscular hypotonia, pointed chin, short 3rd toe, short neck, short stature, skull asymmetry, and walking on tiptoes |
|
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46 | 19p13.11 |
3 | 19863014 | 24556461 | 4.6 | 35 | LOC284440; ZNF506; ZNF253; ZNF93; ZNF682; ZNF90; ZNF486; LOC284441; ZNF826; ZNF737; ZNF626; ZNF626; ZNF85; ZNF430; ZNF714; ZNF431; ZNF708; ZNF738; ZNF493; ZNF429; ZNF100; LOC641367; ZNF43; ZNF208; ZNF257; ZNF676; ZNF98; ZNF492; ZNF99; ZNF91; ZNF675; ZNF681; RPSAP58; ZNF254; LOC100101266 |
11p11.2 |
3 | 48359268 | 51530241 | 3.1 | 10 | OR4C45; OR4A47; FOLH1; LOC440040; OR4C13; OR4C12; LOC441601; LOC646813; OR4A5; OR4C46 | |
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49 | 1q31.3 | 4 | 193973521 | 197781198 | 3.8 | 13 | KCNT2; CFH; CFHR3; CFHR1; CFHR4; CFHR2; CFHR5; F13B; ASPM; ZBTB41; CRB1; DENND1B; DENND1B |
Xq21.1-q22.1 | 2 | 80368850 | 99441815 | 19 | 27 | HMGN5; SH3BGRL; POU3F4; CYLC1; RPS6KA6; HDX; UBE2DNL; APOOL; SATL1; ZNF711; POF1B; CHM; CHM; DACH2; DACH2; KLHL4; CPXCR1; TGIF2LX; PABPC5; PCDH11X; PCDH11X; PCDH11X; NAP1L3; FAM133A; LOC643486; DIAPH2; RPA4; LOC442459 | |
Xq23 q24 | 2 | 112244679 | 117105172 | 4.8 | 18 | HTR2C; SNORA35; MIR764; MIR1912; MIR1264; MIR1298; MIR1911; MIR448; IL13RA2; LRCH2; RBMXL3; LUZP4; PLS3; PLS3; AGTR2; SLC6A14; CXorf61; KLHL13 | |
Xq27.2-q28 | 2 | 141247401 | 148041505 | 6.7 | 36 | MAGEC2; SPANXN4; SPANXN3; SLITRK4; SPANXN2; UBE2NL; SPANXN1; SLITRK2; SLITRK2; CXorf1; MIR890; MIR888; MIR892A; MIR892B; MIR891B; MIR891A; CXorf51; CXorf51; MIR506; MIR507; MIR508; MIR509-2; MIR509-3; MIR509-3; MIR509-1; MIR509-2; MIR509-3; MIR510; MIR514-1; MIR514-3; MIR514-3; ASFMR1; FMR1; FMR1NB; AFF2; AFF2 | |
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51 | 1q21.1 | 3 | 144007842 | 145384225 | 1.3 | 12 | LOC728855; LOC728875; PPIAL4B; PPIAL4A; LOC728875; COAS3; NBPF20; PDE4DIP; PDE4DIP; PDE4DIP; SEC22B; NOTCH2NL; NBPF10 |
Xp22.33 | 2 | 449065 | 1705775 | 1.2 | 10 | SHOX; CRLF2; CRLF2; CSF2RA; CSF2RA; IL3RA; SLC25A6; PP1164; ASMTL; P2RY8 | |
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71 | 15q11.2 | 1 | 20482360 | 22754322 | 2.2 | 19 | CYFIP1; CYFIP1; p; WHAMML1; GOLGA9P; HERC2P2; GOLGA8E; MKRN3; MAGEL2; NDN; PWRN2; PWRN1; C15orf2; SNRPN; SNRPN; SNURF; SNURF |
10q11.22 | 3 | 46167847 | 48338944 | 2.1 | 23 | BMS1P1; FAM35B; SYT15; SYT15; GPRIN2; PPYR1; LOC728643; ANXA8; ANXA8L1; FAM25C; LOC642826; FAM35B2; ANTXRL; ANXA8L2; FAM21B; LOC642826; FAM25G; ANXA8; ANXA8L1; ZNF488; RBP3; GDF2; GDF10 | |
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197 | 1q21.1 | 3 | 144943150 | 146916824 | 1.9 | 24 | PDZK1; GPR89A; GPR89C; PDZK1; LOC200030; NBPF11; LOC728989; PRKAB2; PDIA3P; FMO5; FMO5; CHD1L; BCL9; ACP6; GJA5; GJA8; GPR89B; GPR89C; PDZK1; LOC200030; NBPF11; FLJ39739; PPIAL4B; PPIAL4A; NBPF14; PPIAL4F; NBPF15; NBPF15; NBPF16; PPIAL4E; NBPF16; PPIAL4F; LOC645166; LOC645166 |
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204 | 22q11.23 | 3 | 23980648 | 24240879 | 0.26 | 2 | IGLL3; LRP5L (downslanted palpebral fissures, long palpebral fissure, moderate global developmental delay, short upturned nose, and wide nasal bridge) |
FISH negative
DBN: database number (CNV 1 = deletion; CNV 3 = duplication).
Details of LOH/AOH detected with known UPD (uniparental disomy) disorder in suspected 22q11.2 microdeletion.
DBN | Cytoband | Size (mb) | Gene number | UPD disorder | Genes | Remarks (associated CNVs and LOH/AOH) |
---|---|---|---|---|---|---|
17 | 11q13.4-q14.1 | 12.3 | 96 | Dysmorphism and mental retardation | Unknown | One benign ( |
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45 | 14q32.2 | 3.0 | 11 | Kagami-Ogata syndrome/Temple syndrome | DLK1, GTL2, RTL1, and so forth | No CNV |
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75 | 6p22.3-p22.1 | 7.4 | 112 | Diabetes mellitus, transient neonatal, 1 | ZFP57 | No CNV |
p21.33 p21.32 | ||||||
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83 | 7p12.2-p11.2 | 7.3 | 29 | Silver-Russell syndrome (7p11.2-p13) | GRB10 | One benign ( |
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97 | 6q24.2-q25.1 | 8.2 | 49 | Transient neonatal diabetes mellitus and isolated cleft lip and palate | PLAGL1 | Two uncertain ( |
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110 | 7q31.32-q35 | 20 | 167 | Silver-Russell syndrome (7q31-qter) | MEST | One likely benign ( |
|
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128 | 11p15.4 | 4.1 | 552 | Beckwith-Wiedemann syndrome | No CNV | |
|
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220 | 11p15.5-p15.4 | 3.5 | Beckwith-Wiedemann syndrome | CDKN1C | One benign ( |
|
|
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227a | 15q11.2 q12 | 4.8 | 701 | Prader-Willi/Angelman syndrome | SNRPN, SNORD116, UBE3A | No associated CNVs |
|
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227b | 11q24.2 q24.3 | 5.9 | 901 | Dysmorphism and mental retardation | Unknown | No associated CNVs |
q25 |
DBN: database number.
Large (>5 mb) UPD/LOH/AOH locus/loci detected in suspected 22q11.2 microdeletion
DBN | Cytoband | Size (mb) | Gene number | Remarks (associated CNVs and LOH/AOH) |
---|---|---|---|---|
20 | 6p21.1 p12.3 | 5.7 | 38 | One uncertain (3) CNV of chromosome 1 (q21.2) |
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43 | 4q21.23-q22.1 | 8.7 | 38 | One benign (1) CNV of chromosome 9 (p24.3) |
|
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49 | Xq21.1 q21.2 q21.31 | 19 | 28 | Partial tetrasomy of chromosomes 1–8, 11–14, and 18 and partial disomy of chromosome X |
q21.32 q21.33 q22.1 | ||||
Xq27.2 q27.3 q28 | 6.7 | 25 | Multiple LOH/AOH of chromosome X and one LOH/AOH of chromosome 1 | |
|
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73 | 2p25.2 p25.1 | 5.7 | 33 | One likely benign (3) CNV of chromosome 4 (q22.3) |
2q21.1-q23.3 | 18 | 44 | ||
3p21.31-p14.2 | 13 | 161 | ||
3q21.1-3 q23 | 16 | 135 | ||
4q31.3-q35.1 | 32 | 112 | ||
6p21.1 p12.3 | 5.7 | 86 | ||
9p24.2-p23 | 8.3 | 29 | ||
10q25.1-q26.11 | 11.8 | 60 | ||
10q26.11-q26.3 | 12.8 | 68 | ||
11p15.4-p15.1 | 11.7 | 102 | ||
14q11.2 q12 | 8.8 | 63 | ||
14q12-q22.3 | 23.9 | 112 | ||
15q22.33-q25.2 | 14.4 | 155 | ||
18p11.31-p11.21 | 11.9 | 55 | ||
18q11.1-q12.3 | 22.8 | 85 | ||
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76 | 17q12-q21.1 | 5.3 | 102 | One benign (1) CNV of chromosome 14 (q11.2) |
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84 | 3p21.31-p21.1 | 7 | 34 | No CNVs; multiple LOH/AOH of many chromosomes |
|
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85 | 8q23.1 q23.2 q23.3 | 6 | 14 | No CNVs |
|
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87 | 6q21 q22.1 q22.2 q22.31 | 12 | 60 | No CNVs |
|
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101 | 6q14.1-q15 | 10.5 | 51 | One benign CNV |
|
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105 | 1q23.1-q31.1 | 29.5 | 232 | Multiple benign/likely benign CNVs |
3q27.1-q29 | 13.6 | 108 | ||
5q33.3-q35.3 | 24.7 | 195 | ||
7p14.2 p14.1 | 5.3 | 22 | ||
10p15.1 p14 | 5.4 | 34 | ||
16q22.3-q23.3 | 10 | 44 | ||
17p13.1-p11.2 | 11.7 | 124 | ||
18q12.1-q12.3 | 13 | 46 | ||
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112 | 5p15.2 p15.1 | 7 | 18 | One benign CNV |
9q31.1-q32 | 8.3 | 71 | ||
|
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169 | 1p13.3-p12 | 9.9 | 101 | 2 likely benign CNVs of chromosomes 8 and X |
5q35.1-q35.3 | 8 | 107 | ||
10q11.21 q11.22 | 5.4 | 49 | ||
10q21.1-q22.1 | 19 | 81 | ||
10q24.1-q25.2 | 14 | 133 | ||
12q22-q24.32 | 34.3 | 281 | ||
14q23.3-q32.2 | 30.3 | 231 | ||
19q13.32-q13.42 | 7.2 | 272 | ||
20q13.13-q13.32 | 8 | 43 | ||
22q11.1-q12.1 | 11.4 | 173 | ||
Xp22.32-p21.1 | 27 | 123 | ||
Xq23 q24 | 9.8 | 51 | ||
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178 | 5p13.3 p13.2 | 5.8 | 37 | No CNV |
17p11.2-q11.2 | 9.9 | 125 | No other LOH/AOH | |
|
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182 | 13q14.2-q21.32 | 18.6 | 75 | No CNV |
6p22.3-p21.33 | 10.3 | 269 | ||
2q32.3 q33.1 | 5.2 | 717 | ||
2q34-q36.1 | 9.6 | 765 | ||
2q36.1-q37.1 | 7.4 | 622 | ||
7p22.2-p21.3 | 5.7 | 49 | ||
|
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189 | 17q21.32-q23.2 | 13.3 | 175 | No CNV |
|
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200 | 4q32.3-q34.3 | 9.7 | 616 | No CNV |
2q11.1-q12.1 | 8.8 | 996 | ||
2p12-p11.2 | 8.2 | 844 | ||
2p22.3 p22.2 p22.1 | 6.1 | 719 | ||
3p26.1 p25.3 p25.2 p25.1 | 7.8 | 830 | ||
15q23-q24.3 | 8 | 1205 | ||
|
||||
204 | 3q11.2 q12.1 q12.2 q12.3 | 6 | 49 | One likely benign CNV |
16p12.1 p11.2 p11.1 | 8 | 107 | ||
16q11.2 q12.1 q12.2 | 7 | 40 | ||
|
||||
211 | 5q21.3-q22.3 | 7.3 | 30 | No CNV |
14q22.1-q23.1 | 7.3 | 51 | One LOH/AOH of chromosome 7 | |
|
||||
214 | 18q11.2-q12.1 | 5.6 | 29 | One likely benign CNV |
6p25.2-p24.3 | 5.5 | 42 | Two LOH/AOH of chromosomes 12 and 19 | |
|
||||
228 | 8q24.21 q24.22 | 5.5 | 20 | No CNV or no other LOH/AOH |
DBN: database number.
This SNP microarray study identified 6 cases of chromosomal abnormalities (Table
Clinical details of chromosomal abnormalities detected by SNP microarray.
Locus/loci (CNV) | Microarray diagnosis | Clinical details | Referral reason |
---|---|---|---|
18p11.32-p11.21 |
Trisomy 18 | Seven-month-old male with acyanotic congenital heart defect (CHD) | CHD |
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All chromosomes ( |
Triploidy (mosaicism confirmed by FISH; 33% triploid cells) | Five-year-old female (at first visit) and now 13 years old without any secondary sex character (Figure |
CHD |
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18q21.31-q23 ( |
Partial 18q monosomy | One-month-old male in intensive care unit (ICU), acyanotic CHD with congestive cardiac failure (CCF), and Noonan syndrome like face, plagiocephaly, low set ears, upslanted eyes, sandal gap, and so forth | ?Noonan syndrome |
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11q23.2-q25 ( |
Partial 11q trisomy (Jacobsen, Bartter 2, 11q) | Seven-day-old female neonate in ICU, asymmetric IUGR (intrauterine growth restriction), preterm, multiple malformations, respiratory infection, VSD (ventricular septal defect), hypoplastic nail and alae nasi, blepharophimosis, hypotonia, and so forth | CHD |
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All chromosomes ( |
Triploidy (mosaicism confirmed by FISH; 24% triploid cells) | Eight-year-old female with dysmorphism (broad nose, cleft palate, thin lip, and long philtrum), long slender fingers, GDD, recurrent respiratory infection, behavioral problem, and so forth | Broad nose, behavioral problem |
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21q11.2 q22.3 ( |
Trisomy 21 | Three-month-old male in Pediatric ICU with CCF, very sick | ?CHD |
Clinical details of 22q11.2 CNVs detected by SNP microarray.
Microarray details | Genes | TBX1/DGCR2/DGCR6/DGCR14/DGCR8 | Clinical details | Other CNVs |
---|---|---|---|---|
3 mb deletion | 58 | Y/Y/Y/Y/Y | Male of 3+ years with tetralogy of Fallot (TOF; operated) and facial dysmorphism, broad nose, feeding difficulty, and so forth | Nil |
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2.5 mb deletion | 65 | Y/Y/Y/Y/Y | 7-year-old female with TOF and dysmorphism | 7q11.21 ( |
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0.38 mb deletion | 15 | Y/N/N/N/N | 1.5-year-old male with TOF | Nil |
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2.17 mb deletion | 49 | Y/Y/Y/Y/Y | 34-year-old male referred from anesthesia ICU for hypoparathyroidism, hypocalcemia, recurrent fungal infection, seizure, and respiratory failure (since last 45 days) | Nil |
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2.9 mb deletion | 69 | Y/Y/Y/Y/Y | 1.5-year-old male with TOF, facial dysmorphism, GDD, and speech delay | Nil |
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2.9 mb deletion | 69 | Y/Y/Y/Y/Y | 45-day-old female with TOF, recurrent intractable seizure, recurrent infection, suckling difficulties, low calcium, absent thymic shadow on X-ray, and history of polyhydramnios during pregnancy | Nil |
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0.18 mb duplication | 6 | N/Y/Y/N/N | 10-month-old female with CHD, frontal bossing, prominent metopic suture, hypertelorism, V shaped lip, dysplastic ear, wide spaced nipple, pectus carinatum, mid gut volvulus, and so forth | 2p22.3 ( |
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2.79 mb deletion | 68 | Y/Y/Y/Y/Y | 3-year-old male with seizure, GDD, dysmorphism, high arched palate, long slender fingers, low parathyroid hormone (PTH), low calcium, recurrent infection, and so forth | Nil |
Clinical details of other pathogenic CNVs detected by SNP microarray.
Microarray details | Genes | Diagnosis | Clinical details | Other CNVs |
---|---|---|---|---|
15q11.2 |
6 | 15q11-q13 duplication | Three-month-old male with TOF, feeding difficulty, hypocalcemia, dysmorphism, poly/syndactyle, hypoplastic mandible, IUGR, and so forth | 10q11.22 ( |
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16p11.2 |
46 | 16p11.2 deletion | 4-month-male with CHD (DORV, PS/pulmonary stenosis), blepharophimosis, ptosis, and so forth | 15q12 ( |
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1q21.1 |
24 | 1q21.1 duplication | Male of 2+ years with TOF, broad nose, thin upper lip, absent philtrum, small and low set ears, antimongoloid slant, telecanthus, long slender fingers, widow peak, and so forth | 11p11.12 ( |
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15q11.1 q11.2 |
13 | 15q11.1 q11.2 duplication | 1-year-old male with CHD (VSD), dysmorphism, GDD, and so forth | 14q11.2 ( |
Clinical details of likely pathogenic CNVs detected by SNP microarray.
Locus/loci | Microarray details | Genes | Clinical details |
---|---|---|---|
22q11.22 |
0.4 mb duplication |
7 |
2-year-old male with TOF |
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1q21.2 | 1.9 mb duplication | 18 | 9-year-old male with TOF (operated) |
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19p13.11-12 |
4.6 mb duplication |
35 |
17-year-old female with TOF (operated) |
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1q31.3 |
3.8 mb triplication |
13 |
13-year-old male with TOF (operated) |
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1q21.1 |
1.3 mb duplication |
12 |
4-year-old male with TOF (operated) |
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15q11.2 |
2.2 mb deletion |
19 |
One-month-old male with hypocalcaemia (Ca 5.6; PTH-46), convulsion, osteopenia, squint, small toe, deep furrow feet, and so forth (Figure |
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22q11.23 | 0.26 mb duplication | 2 | 6-year-old female with dysmorphism, square nose tip, proportionate short stature, cyanotic CHD (tricuspid atresia, ostium secundum ASD, etc.), clubbing, tracheal shift, right pneumothorax with lung collapse, right anotia, synophrys, pear shaped nose, webbed neck, and so forth |
Clinical details of LOH/AOH detected by SNP microarray with known UPD disorders.
Locus/loci | Genes | Clinical details | UPD disorders |
---|---|---|---|
11q13.4-q14.1 | 96 | 9-year-old male with TOF (operated) | Dysmorphism and mental retardation |
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14q32.2 | 11 | 5-year-old male with TOF (operated) | Kagami-Ogata syndrome/Temple syndrome |
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6p22.3-p21.32 | 112 | 4-year-old male with TOF (operated), cleft lip and palate (repaired), broad and bifid nose, small left cornea and eye, GDD, hearing problem, being still unable to suck/drink, long fingers, small philtrum, mental retardation, and so forth (Figure |
Diabetes mellitus, transient neonatal, 1 |
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7p12.2-p11.2 | 29 | 3.5-year-old male with TOF (operated), GDD, and previous 2 siblings with CHD | Silver-Russell syndrome (7p11.2-p13) |
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6q24.2-q25.1 | 49 | 10-month-old male with cyanotic CHD, GDD, obesity, hypospadias, no cryptorchidism, dysmorphism, and one elder sister who has CHD | Transient neonatal diabetes mellitus and isolated cleft lip and palate |
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7q31.32-q35 | 167 | 14-month-old female with TOF, small nose, wide philtrum, narrow forehead, low frontal hairline, GDD, broad nose, short stature, bilateral cataract, and previous 3 siblings with malformations (including CHD in one) | Silver-Russell syndrome (7q31-qter) |
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11p15.4 | 552 | 1.5-year-old male with cyanotic CHD, dysmorphism, clubbing, dysplastic small low set ears, weight of 8 kg (overweight), and so forth | Beckwith-Wiedemann syndrome |
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11p15.5-p15.4 | 6-day-old very sick (in ICU) male with dysmorphism, CCF, and so forth | Beckwith-Wiedemann | |
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15q11.2-q12 | 701 | 9-year-old male with TOF (operated) | Prader-Willi/Angelman |
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11q24.2-q25 | 901 | 5-year-old male with TOF (operated) | Dysmorphism and mental retardation |
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11q13.4-q14.1 | 96 | 4-year-old male with TOF (operated), cleft lip and palate (repaired), broad and bifid nose, small left cornea and eye, GDD, hearing problem, being still unable to suck/drink, long fingers, small philtrum, mental retardation, and so forth | Dysmorphism and mental retardation |
Mosaic triploidy case showing facial profile (a), flat rocker bottom foot ((b) clinical and (c) X-ray), and triploid metaphase cell (d).
Male child with 15q11.2 deletion and 10q11.22 duplication showing squint, small toe and deep furrow feet.
Male child with LOH/AOH of 6p22.3-p21.32 showing repaired cleft lip, broad and bifid nose, small left cornea and eye, long fingers, and rough creased skin over hands.
We have been investigating microdeletion syndrome using FISH since 2005. Our experience with FISH in microdeletion syndrome including 22q11.2 microdeletion syndrome (most common microdeletion syndrome) is unsatisfactory as FISH detects approximately 8% of cases of 22q11.2 microdeletions [
In this prospective study, SNP microarray was carried out in 101 FISH negative/noninformative clinically suspected 22q11.2 microdeletion syndrome cases to assess the role of SNP microarray in the evaluation of clinically suspected 22q11.2 microdeletion syndrome. There were 12 samples that were not processed for FISH due to freezing or clotting. Microarray was successfully carried out in all 101 cases. Chen et al. [
One of the major referral criteria for our patients was congenital heart disease, mainly conotruncal heart defect [
This study detected several cases of LOH/AOH of known UPD disorders (Table
Our study indicates that microarray should be first tier of test when samples are scant, lysed, or clumped/clotted/frozen as FISH or conventional cytogenetics are bound to fail/noninformative. This study suggests that microarray is a superior technique in clinically doubtful cases as well as ICU admissions on life support and 22q11.2 microdeletion is suspected on the basis of convulsion and/or cardiac defect/failure. Furthermore, in early weeks of life dysmorphology and malformation detection is difficult, in particular sick neonate on life support. We have observed in this study that clinically suspected microdeletion syndrome cases are frequently associated with second/more hits (deletion or duplication) elsewhere in the genome (tables/associated CNVs). Microarray also detected several cases of chromosomal aneuploidy, partial aneuploidy, triploidy, and so forth. This approach of DNA microarray will provide the highest chance of making a diagnosis and sparing the patient unnecessary diagnostic testing from many places, in addition to saving crucial times. Our conclusion is in agreement with the consensus statement [
We conclude that more strict clinical criteria should be followed for FISH test. If clinical diagnosis is uncertain or doubtful then microarray should be the first screening test. This is most important with newborn/neonate in intensive care unit as clinical criteria are few and difficult to elicit. Microarray is applicable in all samples irrespective of frozen, lysed, clotted, clumped, and other samples. Furthermore, SNP microarray provides information on aneuploidy, triploidy, partial aneuploidy, and associated small CNVs (often many) besides information on LOH/AOH (indicating UPD disorders/in case of consanguinity homozygosity of recessive disorders). FISH may be used for detecting mosaicism, screening family members, prenatal diagnosis, and preimplantation diagnosis of specific deletions in proven family.
The authors declare that there are no competing interests regarding the publication of this paper.
The study was supported by grant from Indian Council of Medical Research, New Delhi, India. Authors thank Departments of Pediatrics, Pediatric Surgery, Cardiovascular Surgery, and Cardiology of All India Institute of Medical Sciences and various hospitals of Delhi, India, for referring the cases for the research/service, and also they thank the family members of patients for their cooperation during the study. Authors acknowledge Professor Mariano Rocchi (University of Bari, Italy) for providing molecular probes (PAC/BAC clones) for FISH study.