Prevalence and spectrum of chromosomal microduplications in patients with mental retardation
Abstract
To date, more than 230 microdeletion and 80 microduplication syndromes were revealed in patients with intellectual deficiency and developmental delay. The fact that deletions predominate may be an indirect confirmation of the established opinion that microduplications are less pathogenic in case of a milder clinical manifestation. The aim of the study was to determine the frequency and spectrum of pathogenetically significant chromosomal microduplications among patients with disabilities of mental development, to estimate the ratio of clinically significant microdilutions and microdeletions in this group of patients. The sample consists of 216 patients aged 2 to 18 years: children with mental development disorders, and having dysmorphia and/or congenital anomalies. The search for chromosomal microduplications was carried out using matrix comparative genomic hybridization on microarrays (8х60K, Agilent Technologies). To confirm the segmental trisomy identified in the probands and determine their parental origin, a quantitative real-time PCR method was used. Among the detected pathogenetically significant variations in the number of copies of DNA regions registered in 81 patients with mental development disorders (37%), unbalanced translocations or combinations of different types of CNVs were identified in 9 patients, 2 patients were carriers of ring chromosomes 13 and 22, 70 patients were found with 36 deletions and 34 duplications, the ratio of which was 51% and 49% respectively. In the process of analyze of the origin of partial trisomy it was established that 8 cases (47%) of microduplication appeared de novo and 9 cases (53%) were inherited from phenotypically healthy parents. The frequency of clinical significant chromosomal microduplications in the group of patients with mental development disorders was 15,7%, microdeletions - 16,7%. Perhaps this confirms the underestimation of microduplications as a cause of the development of pathological conditions and points to the importance of their more detailed study.
About the Authors
E. O. Belyaeva
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
A. A. Kashevarova
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
N. A. Skryabin
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
M. E. Lopatkina
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
O. A. Salyukova
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences; Siberian State Medical University
Russian Federation
Russian Federation
M. N. Filimonova
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
O. V. Lezhnina
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences
Russian Federation
Russian Federation
A. R. Shorina
Novosibirsk City Clinical Hospital № 1
Russian Federation
Russian Federation
A. B. Maslennikov
Novosibirsk Regional Children’s Clinical Psychoneurologic Dispensary
Russian Federation
Russian Federation
L. P. Nazarenko
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences; Siberian State Medical University
Russian Federation
Russian Federation
I. N. Lebedev
Research Institute of Medical Genetics, Tomsk National Research Medical Center of Russian Academy of Sciences; Siberian State Medical University
Russian Federation
Russian Federation
References
1. Khan MA, Khan S, Windpassinger C et al. The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations. Ann Hum Genet. 2016; 80(6):342-368.
2. Кашеварова А.А., Лебедев И.Н. Геномная архитектура хромосомных болезней человека // Генетика. 2016. 52. № 5. С.511-528.
3. Протокол CGH для микрочипов Agilent Technologies - http://www.chem-agilent.com/pdf/G4410-90020v3_1_CGH_ULS_Protocol.pdf
4. Кашеварова А.А., Лебедев И.Н. Траектории интерпретации фенотипа и кариотипа через призму взаимодействия врача-генетика и лабораторного генетика. Молекулярно-биологические технологии в медицинской практике / Под ред. чл.-корр. РАЕН А.Б. Масленникова. 2017; 26:47-55.
5. Беляева Е.О., Кашеварова А.А., Никонов А.М. и др. Значимость молекулярного кариотипирования для уточнения диагноза при цитогенетически визуализируемой хромосомной патологии. Медицинская генетика. 2016; 7:17-20.
6. Lebedev IN, Nazarenko LP, Skryabin NA et al. A de novo microtriplication at 4q21.21-q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech. Am J Med Genet A. 2016; 170(8):2089-2096.
7. Park, Sang-Jin, et al. Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases. Molecular cytogenetics. 2011; 4(1):12.
8. D’Arrigo S. et al. The diagnostic yield of array comparative genomic hybridization is high regardless of severity of intellectual disability/developmental delay in children. 2016; 31(6):691-699.
9. Cappuccio, Gerarda, et al. New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants. Italian journal of pediatrics. 2016; 42(1):39.
10. Carvalho C, Lupski JR. Mechanisms underlying structural variant formation in genomic disorders. Nat. Rev. Genet. 2016; 17(4):224-238.
Review
For citations:
Belyaeva E.O., Kashevarova A.A., Skryabin N.A., Lopatkina M.E., Salyukova O.A., Filimonova M.N., Lezhnina O.V., Shorina A.R., Maslennikov A.B., Nazarenko L.P., Lebedev I.N. Prevalence and spectrum of chromosomal microduplications in patients with mental retardation. Medical Genetics. 2017;16(12):39-42. (In Russ.)
Views:
470
Email this article 