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

Abstract

BackgroundArray 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.ResultsAmong 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.ConclusionsWe 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.

Complex Mosaic Ring Chromosome 11 Associated with Hemizygous Loss of 8.6 Mb of 11q24.2qter in Atypical Jacobsen Syndrome

“…In 3 of them, the ring chromosome 11 was present as a mosaic, and Paris-Trousseau syndrome was associated with JBS in only 2 patients [Valente et al, 1977;Niikawa et al, 1981;Cousineau et al, 1983;Romain et al, 1983;Daniele et al, 1986;Palka et al, 1986;Fagan et al, 1988;Adewale et al, 1991;Park et al, 2007;Carella et al, 2010;Hansson et al, 2012;Iourov et al, 2012;Zhang et al, 2012;Lange et al, 2015;Peng et al, 2015]. The present study is the first analysis by array CGH of a mosaic ring chromosome 11 linked to JBS of a boy without evidence of neonatal thrombocytopenia.…”

“…Eight patients with ring chromosome 11 were studied by array CGH previously. Three of them were related to JBS, and all were female [Hansson et al, 2012;Iourov et al, 2012;Peng et al, 2015].…”

Chromosomal Abnormalities in Patients with Intellectual Disability: A 21-Year Retrospective Study

“…This was connected to the co-occurrence of a chromosome 21 long arm deletion at 21q22.3 and a chromosome 9 long arm deletion at 9q34.2q34.3 in 3 cases of NS-ID. One can suggest that an approximately 179-kbp interval on 9q34.2 and an approximately 187-kbp interval on 21q22.3 are both specifically organized at the sequence level to produce a complex genomic rearrangement causing ID with autistic features, speech delay, and facial dysmorphisms [32]. …”

Mental health disorders in the first years of life: autism spectrum disorders, constitutional and residual-organic abnormalities

“…В частности, выде-лен ряд генетических синдромальных форм: синдром ломкой Х-хромосомы (синдром Мартина-Белл), син-дром Ретта, РАС при синдроме Ангельмана, туберозном склерозе, фенилкетонурии и некоторых формах синдрома Дауна. Большой прогресс в понимании генетики недиф-ференцированных форм РАС достигается внедрением вы-сокоразрешающих геномных технологий, в частности мо-лекулярного кариотипирования [33,34]. Так, при иссле-довании когорты детей с недифференцированной формой аутизма, ассоциированной с умственной отсталостью, в 88% случаев были выявлены различные аномалии и вари-ации генома [35].…”