Interpretation of pathogenic copy number variations

Сhromosomal microarray (CMA) testing is a first-tier test for patients with developmental delay, autism spectrum disorder, or congenital anomalies. CMA has high diagnostic yield for those patients and can detect chromosomal aberrations of less than 5 Mb. However, copy number variations (CNVs) detected by CMA in the form of deletion and duplication (triplication) cannot always be visualized in the context of metaphase chromosomes and hence, the mechanism causing the chromosomal imbalance cannot be identified. In some cases further techniques are needed for detailed characterization of chromosomal abnormalities to understand the structure of the abnormalities. The only way to do this is by karyotyping of methaphase chromosomes, combined, if necessary with FISH. Identification of the underlying mechanism is required for genetic counseling purposes, for example for presenting an estimate of the recurrence risk to the patient’s parents. Follow-up studies after CMA in patients with developmental delay and/or congenital anomalies, suspected chromosome abnormalities leading to the formation of pathogenic CNVs and the mechanisms causing the chromosome imbalance are discussed.

клинически значимые CNVs, хромосомный микроматричный анализ, кариотипирование, FISH, двухсегментный хромосомный дисбаланс, односегментный хромосомный дисбаланс, хромосомные аномалии, патологическая мейотическая сегрегация, pathogenic CNVs, chromosomal microarray, karyotyping, FISH, double-segment chromosome imbalance, single-segment chromosome imbalance, chromosome abnormalities, meiotic malsegregation

1. Miller D, Adam M, Aradhya S. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 2010;86:749-764.

2. Ahn J, Bint S, Bergbaum A. et al. Array CGH as a first line diagnostic test in place of karyotyping for postnatal referrals results from four years’ clinical application for over 8,700 patients. Molecular Cytogenetics. 2013;6:16.

3. Lay-Son G, Espinoza K, Vial C. et al. Chromosomal microarrays testing in children with developmental disabilities and congenital anomalies. J. Pediatr (Rio J). 2015;91:189-195.

4. Ho KS, Wassman ER, Baxter AL. et al. Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders using an ultra-high resolution chromosomal microarray optimized for neurodevelopmental disorders. 2016;17(12): 2070.

5. Fan Y, Wu Y, Wang L. et al. Chromosomal microarray analysis in developmental delay and intellectual disability with comorbid conditions. BMC Medical Genomics. 2018;11:49.

6. Kang, S-H, Shaw C, Ou G.et al. Insertional translocation detected using FISH confirmation of array-comparative genomic hybridization (aCGH) results.Am. J. Med. Genet. 2010;152A:1111 - 1126.

7. Bui T, Vetro A, Zuffardi O. et al. Current controversies in prenatal diagnosis 3: is conventional chromosomal analysis necessary in the post-array CGH era? Prenat. Diagn. 2011;31:235-243.

8. Chromosome abnormalities and genetic counseling. Oxford monographs of medical genetics no. 6, Gardner RJ, Sutherland GR, Shaffer LG (eds); Int. Oxford press 2012.

9. Золотухина ТВ., Канивец ИВ., Коростелев СА. и др. Опыт использования комплекса современных методов исследования в конституциональной цитогенетике. Медицинская генетика. 2014;(12):22-28.

10. Hermetz KE, Newman S, Connely KN. et al. Large inverted duplications in the human genome form via a fold-back mechanism. PLOS Genetics. 2014;10(1):e1004139.

11. Weckselblatt B, Rudd MK. Human structural variation: mechanisms of chromosomal rearrangements. Trends in Genetics. 2015;31(10):587-599.

12. Миньженкова МЕ, Маркова ЖГ, Дадали ЕЛ, Шилова НВ. Интерхромосомная и интрахромосомная инсерции с участием хромосомы 2. Медицинская генетика. 2018;17(2):12-17.

13. Shaffer LG, Rosenfeld JA. Microarray-based prenatal diagnosis for the identification of fetal chromosome abnormalities. Expert Rev. Mol. Diagn. 2013;13(6):601-611.

14. Liehr T. «Classical genetics» is not equal to «banding cytogenetics». Molecular Cytogenetics. 2017;10:3.