Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies

Abstract

Background: Array comparative genomic hybridization (CGH) has been repeatedly shown to be a successful tool for the identification of genomic variations in a clinical population. During the last decade, the implementation of array CGH has resulted in the identification of new causative submicroscopic chromosome imbalances and copy number variations (CNVs) in neuropsychiatric (neurobehavioral) diseases. Currently, array-CGH-based technologies have become an integral part of molecular diagnosis and research in individuals with neuropsychiatric disorders and children with intellectual disability (mental retardation) and congenital anomalies. Here, we introduce the Russian cohort of children with intellectual disability, autism, epilepsy and congenital anomalies analyzed by BAC array CGH and a novel bioinformatic strategy.

Results: Among 54 individuals highly selected according to clinical criteria and molecular and cytogenetic data (from 2426 patients evaluated cytogenetically and molecularly between November 2007 and May 2012), chromosomal imbalances were detected in 26 individuals (48%). In two patients (4%), a previously undescribed condition was observed. The latter has been designated as meiotic (constitutional) genomic instability resulted in multiple submicroscopic rearrangements (including CNVs). Using bioinformatic strategy, we were able to identify clinically relevant CNVs in 15 individuals (28%). Selected cases were confirmed by molecular cytogenetic and molecular genetic methods. Eight out of 26 chromosomal imbalances (31%) have not been previously reported. Among them, three cases were co-occurrence of subtle chromosome 9 and 21 deletions.

Conclusions: We conducted an array CGH study of Russian patients suffering from intellectual disability, autism, epilepsy and congenital anomalies. In total, phenotypic manifestations of clinically relevant genomic variations were found to result from genomic rearrangements affecting 1247 disease-causing and pathway-involved genes. Obviously, a significantly lesser part of them are true candidates for intellectual disability, autism or epilepsy. The success of our preliminary array CGH and bioinformatic study allows us to expand the cohort. According to the available literature, this is the first comprehensive array CGH evaluation of a Russian cohort of children with neuropsychiatric disorders and congenital anomalies.

Figure 1

Examples of array CGH graphical overviews. A. Case #8: a deletion of chromosome X short arm and a duplication of chromosome 3 short arm — arr Xp22.33p22.2(2,333,897-9,726,574)x1,3p26.3p22.3(200,000-36,550,871)x3 — due to an unbalanced maternal translocation t(X;3) (conventional karyotyping was performed after array CGH analysis). B. Case #27: a deletion of chromosome 7 long arm (subtelomeric 7q deletion) — arr 7q36.2q36.3(152,768,630-158,261,821)x1. C. Case #18: a duplication of chromosome 19 short arm — arr 19p13.3(260,000-4,953,188)x3. D. Case #20: a deletion of chromosome 10 long arm (subtelomeric 10q deletion) — arr 10q26.2q26.3(128,192,760-134,070,099)x1. E. Case #40: a duplication of chromosome 5 long arm — arr 5q13.2(68,931,140-72,690,180)x3.

Figure 2

The incidence of chromosome imbalances (subdivided to cytogenetically detectable and undetectable abnormalities), CNVs and meiotic genome instability in the Russian cohort of children with intellectual disability with or without autism and congenital anomalies. Cytogenetically detectable cases were patients, who were cytogenetically re-evaluated. This has yielded the correct diagnosis (see also Table 1).