FORENSIC SCIENCE
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Croat Med J. 2017;58:231-8 https://doi.org/10.3325/cmj.2017.58.231
Chromosomal microarray in clinical diagnosis: a study of 337 patients with congenital anomalies and developmental delays or intellectual disability
Ivona Sansović1, Ana-Maria Ivankov1, Adriana Bobinec1, Mijana Kero1, Ingeborg Barišić1 Department of Medical Genetics and Reproductive Health, Children’s Hospital Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
1
Aim To determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA). Method CMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods. Results In 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was 1 Mb. VOUS were discovered in 35 patients: 25 had one VOUS, seven had two VOUS, and three subjects had one pathogenic CNV and one VOUS (subjects No. 49, 22, and 70). There were 17 microdeletions and 25 microduplications (Table 3). Only seven of these 42 microdeletions and microduplications were >1Mb.
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Genomic regions that were the most commonly affected by pathogenic CNVs were 8p23 (6 patients), 15q11.2 (6 patients), and 22q11.21 (5 patients). In the group with complex rearrangement, the most affected, relatively large region was 18q22.1q23 (5 patients). Parents of 44 probands with pathogenic CNV or VOUS were available for DNA testing. Four VOUS were de novo and 16 were inherited. In eight cases, pathogenic CNVs were inherited from parents with balanced translocations, in seven cases one of the parent had same patho-
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Sansović et al: Chromosomal microarray in clinical diagnosis
genic CNV as his offspring, and 19 pathogenic CNVs were de novo. Discussion Pathogenic CNV were found in 43 of total 307 patients previously not tested by other cytogenetic or molecular methods or in whom these tests were negative for genomic imbalances, representing an overall diagnostic yield of 14%. Our results are in accordance with other studies on genome-wide oligonucleotide arrays (1,4,5). The diagnostic yield is known to correlate with the array resolution and the genomic coverage of the array used. Currently, we are using 8x60K array with 60 kb overall median probe spacing (higher in ISCA regions), and the results of this study showed that this platform is suitable for genetic testing of children with developmental disorders. The microdeletion syndromes that were identified in more than one individual were: 15q11.2 deletion syn-
drome (MIM#615656)-3 patients, 22q11.21 deletion syndrome (MIM#188400; DiGeorge syndrome)-3 patients, 4p16.3 deletion syndrome (MIM#194190; Wolf-Hirschhorn syndrome)-2 patients, 7q11.23 deletion syndrome (MIM#194050; Williams-Beuren syndrome)-2 patients, 8q24.1 deletion syndrome (MIM#150230; Trichorhinophalangeal syndrome, type II)- 2 patients, 15q11.2q13.1 deletion (MIM#105830; Angelman syndrome/MIM#176270; Prader-Willi syndrome)-2 patients, and 15q26-qter deletion syndrome (MIM#612626))-2 patients. Also, the same 61 kb deletion in 2p16.3 region disrupting NRXN1 gene was detected in two patients. One third of pathogenic CNVs ranged 1-5 Mb in size. Even though CNVs of
231
Croat Med J. 2017;58:231-8 https://doi.org/10.3325/cmj.2017.58.231
Chromosomal microarray in clinical diagnosis: a study of 337 patients with congenital anomalies and developmental delays or intellectual disability
Ivona Sansović1, Ana-Maria Ivankov1, Adriana Bobinec1, Mijana Kero1, Ingeborg Barišić1 Department of Medical Genetics and Reproductive Health, Children’s Hospital Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
1
Aim To determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA). Method CMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods. Results In 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was 1 Mb. VOUS were discovered in 35 patients: 25 had one VOUS, seven had two VOUS, and three subjects had one pathogenic CNV and one VOUS (subjects No. 49, 22, and 70). There were 17 microdeletions and 25 microduplications (Table 3). Only seven of these 42 microdeletions and microduplications were >1Mb.
www.cmj.hr
Genomic regions that were the most commonly affected by pathogenic CNVs were 8p23 (6 patients), 15q11.2 (6 patients), and 22q11.21 (5 patients). In the group with complex rearrangement, the most affected, relatively large region was 18q22.1q23 (5 patients). Parents of 44 probands with pathogenic CNV or VOUS were available for DNA testing. Four VOUS were de novo and 16 were inherited. In eight cases, pathogenic CNVs were inherited from parents with balanced translocations, in seven cases one of the parent had same patho-
235
Sansović et al: Chromosomal microarray in clinical diagnosis
genic CNV as his offspring, and 19 pathogenic CNVs were de novo. Discussion Pathogenic CNV were found in 43 of total 307 patients previously not tested by other cytogenetic or molecular methods or in whom these tests were negative for genomic imbalances, representing an overall diagnostic yield of 14%. Our results are in accordance with other studies on genome-wide oligonucleotide arrays (1,4,5). The diagnostic yield is known to correlate with the array resolution and the genomic coverage of the array used. Currently, we are using 8x60K array with 60 kb overall median probe spacing (higher in ISCA regions), and the results of this study showed that this platform is suitable for genetic testing of children with developmental disorders. The microdeletion syndromes that were identified in more than one individual were: 15q11.2 deletion syn-
drome (MIM#615656)-3 patients, 22q11.21 deletion syndrome (MIM#188400; DiGeorge syndrome)-3 patients, 4p16.3 deletion syndrome (MIM#194190; Wolf-Hirschhorn syndrome)-2 patients, 7q11.23 deletion syndrome (MIM#194050; Williams-Beuren syndrome)-2 patients, 8q24.1 deletion syndrome (MIM#150230; Trichorhinophalangeal syndrome, type II)- 2 patients, 15q11.2q13.1 deletion (MIM#105830; Angelman syndrome/MIM#176270; Prader-Willi syndrome)-2 patients, and 15q26-qter deletion syndrome (MIM#612626))-2 patients. Also, the same 61 kb deletion in 2p16.3 region disrupting NRXN1 gene was detected in two patients. One third of pathogenic CNVs ranged 1-5 Mb in size. Even though CNVs of
