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Diagnostic yield of chromosomal microarray and trio whole exome sequencing in congenital brain anomalies
- E. A. Fonova, A. A. Kashevarova, M. E. Lopatkina, A. A. Sivtsev, A. A. Zarubin, V. V. Demeneva, G. N. Seitova, L. I. Minaycheva, O. A. Salyukova, S. V. Fadyushina, V. V. Petrova, E. O. Belyaeva, L. P. Nazarenko, I. N. Lebedev
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S887
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Introduction
The deductive method: from karyotyping to aCGH and WES is an important aspect in the diagnosis and search for the causes of intellectual disability due to congenital brain anomalies. There is recommendation to exclude the presence of CNV or monogenic variants for patients with a normal karyotype, but with a clinical picture of syndromic disease.
ObjectivesImprovement of diagnosis of intellectual disability.
MethodsaCGH with 60K Agilent microarrays, WES with SureSelect Human All Exon V8
ResultsPathogenic or potentially pathogenic CNVs were excluded previously by aCGH for 10 families (total 32 people, 2 families had 2 children) with intellectual disability and congenital brain anomalies (for example, polymicrogyria, pachygyria, lissencephaly). The WES identified candidate variants for all families that can lead to impaired neurodevelopment, including 3 pathogenic variants in 3 families, 3 likely pathogenic in three other families, and 10 variants with uncertain clinical significance for 4 families. Almost all of these variants were identified de novo, except for one family, where the proband has been a compound heterozygous for two variants in the RELN gene. The first case of pathogenic mutation de novo was detected in a girl with agenesis of the corpus callosum. It was a missense mutation DYNC1H1 (NM_001376.5): c.4868G>A (p.Arg1623Gln), which leads to impaired intellectual development in autosomal dominant type 13 (OMIM 614563). The second variant was detected in a boy with corpus callosum agenesis, pontine hypogenesis, pachygyria in the frontal lobes. It was a missense variant MACF1 (ENST00000567887.5): c.21989A>G(p.Asp7330Gly), which leads to lissencephaly 9 with complex brainstem malformation (OMIM 614563). The third variant was found in a girl with epilepsy and impaired myelination of the white matter of the parietal-occipital areas of the cerebral hemispheres. It was a missense variant CDKL5 (NM_001323289.2):c.404-1G>A that leads to developmental and epileptic encephalopathy 2 (OMIM 300672).
ConclusionsSixteen candidate variants potentially responsible for mental health were reported in this study. Most of these variants were missense changes in genes. All except one anomalies arisen de novo. Trio-based WES has been shown to be an important step in making a genetic diagnosis if other chromosomal and subchromosomal abnormalities had been excluded. The clinical description of the patient is the most important step for the correct interpretation of WES results, which allows to establish the exact genetic cause of the disease if several variants with unclear clinical significance were previously identified.
This study was supported by the Russian Science Foundation, grant 21-65-00017, https://rscf.ru/project/21-65-00017/
Disclosure of InterestNone Declared
Combined whole exome sequencing and chromosomal microarray analysis improve clinical interpretation of genomic variants in patients with intellectual disability
- A. A. Kashevarova, E. O. Belyaeva, E. A. Fonova, M. E. Lopatkina, O. Y. Vasilyeva, D. A. Fedotov, A. A. Zarubin, A. A. Sivtsev, V. V. Demeneva, O. A. Salyukova, V. V. Petrova, S. V. Fadiushina, L. I. Minaycheva, G. N. Seitova, L. P. Nazarenko, I. N. Lebedev
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S887
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Introduction
aCGH determines pathogenic copy number variations (CNVs) in about 10% of patients with intellectual disability (ID). In another 20% of patients, probably pathogenic CNVs or variants with uncertain clinical significance are detected. It may be variants that do not fully explain the patient’s symptoms, aberrations with reduced penetrance or inherited from healthy parents. The use of a sequencing method for such cases is advisable.
ObjectivesImprovement of diagnosis of intellectual disability.
MethodsaCGH with 60K Agilent microarrays, qPCR, targeted sequencing, whole exome sequencing (WES).
ResultsSix patients with ID and inherited deletions/duplications detected by aCGH and their parents if available were further examined by sequencing. Four patients had maternal CNVs: (1) del1q41 (SPATA17, LINC00210, RRP15), (2) del7q35 (TCAF2, exon 8), (3) dup8p22p21.3 (PSD3, exons 1-11), and (4) del12p11.1 (SYT10, exons 1-2). Two patients had paternal CNVs: (5) dup1q44 (SMYD3, exons 2-5) and (6) del15q11.2 (TUBGCP5, CYFIP1, NIPA1, NIPA2, LOC283683). The severe phenotype of patient (5) with dup1q44 could not be explained by the paternally inherited disruption of the single SMYD3 gene. WES determined probably pathogenic SNV in the MID1 gene associated with Opitz GBBB syndrome (OMIM 300000), which corresponds better to the patient’s phenotype and is likely to be the cause of the disease. Although del1q41 is included in the region of chromosome 1q41-q42 deletion syndrome (OMIM 612530) the phenotype of the patient (1) is much milder; WES in the patient detected two pathogenic (MPO, MAN2C1) and one probably pathogenic (ARID1B) SNVs. In patient (6) with del15q11.2 pat WES detected additional pathogenic SNV in exon 7 of the ARSE gene. In patient (3) with dup8p22p21.3 WES determined two SNVs with uncertain significance in the KIDINS220, FOXG1 genes. No SNVs were detected by WES in patient (2) with del7q35. For patient (4) with del12p11.1 targeted SYT10 sequencing revealed no pathogenic SNVs as well.
ConclusionsSometimes aCGH-analysis is sufficient to identify the causes of ID, however, in the case of detection of CNVs with uncertain clinical significance and/or inherited from healthy parents, it may be necessary to further examine the patient using sequencing methods. So, the accurate diagnosis was made by WES for one patient of eight. For another two patients the combination of CNVs and SNPs should be considered. For the last three patients the described aberrations could not explain the phenotype and whole genome sequencing may be the solution.This study was supported by the Russian Science Foundation, grant 21-65-00017, https://rscf.ru/project/21-65-00017/
Disclosure of InterestNone Declared
EPA-0644 - 3p26.3 - Candidate Loci of Intellectual Disability
- A. Kashevarova, N. Skryabin, L. Nazarenko, N. Chechetkina, O. Salyukova, E. Tolmacheva, E. Sazhenova, P. Magini, C. Graziano, G. Romeo, I. Lebedev
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- Journal:
- European Psychiatry / Volume 29 / Issue S1 / 2014
- Published online by Cambridge University Press:
- 15 April 2020, p. 1
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Introduction:
To date 56 reciprocal microdeletion/microduplication syndromes have been described. Due to intensive application of microarray technologies new submicroscopic rearrangements are being published. The reciprocal rearrangements are particularly valuable, since they allow to determine the dosage-sensitive pathogenic genes.
Objectives:To improve ID diagnostics.
Aims:To identify novel candidate loci of ID.
Methods:We performed the genome-wide analysis for 79 patients with idiopathic ID using CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA). Pathogenically significant cases were confirmed by qPCR.
Results:We present two patients with microdeletion (369 kb) and microduplication (766 kb) at 3p26.3 containing the only gene - CNTN6. The microduplication was inherited from apparently healthy father. The child with microdeletion was an orphan. Recently, the microduplication in 3p26.3 (containing CNTN6) has been shown to be associated with autism spectrum disorders (ASDs). Contactin 6 is also suggested to play a neuroprotective role in ischemic injury and contribute to granule cell maturation and/or synaptic formation in the developing cerebellum.
Considering the experiments with mice we found myotonic syndrome, late development of sit and walk ability in the anamnesis, current fine motor skills impairment and dysarthria in patient with dup3p26.3. His IQ is 47. Dysarthria was also observed in the patient with del3p26.3 (IQ 55).
Conclusions:Obviously, CNTN6 can be a novel pathogenic gene associated with ASDs, ID, and motor functions impairment. This study was supported by EU Seventh Framework Program, CHERISH project no. 223692 and by Federal Program of Ministry of Education and Science of Russian Federation no. 8727.
1866 – Novel Candidate Genomic Loci For Mental Retardation
- A. Kashevarova, O. Salyukova, P. Magini, C. Graziano, G. Romeo, I. Lebedev
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- Journal:
- European Psychiatry / Volume 28 / Issue S1 / 2013
- Published online by Cambridge University Press:
- 15 April 2020, 28-E1114
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Introduction
Genetic disorders underlie a significant number of cases of mental retardation (MR). However, the traditionally used routine karyotyping is not able to detect small but often clinically relevant aberrations. High-resolution genome-wide microarray technologies may help to increase the detectability of MR etiology.
ObjectivesTo improve MR diagnostics.
AimsTo identify the novel CNV regions and susceptibility genes in MR patients.
MethodsLarge chromosomal rearrangements, biochemical defects, and known monogenic syndromes accompanied by MR were ruled out for 71 patients. Further the genome-wide analysis using CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA) was performed.
ResultsEight novel CNVs in 9 patients not described in healthy individuals and not associated with any disease were indentified implicating regions at 11q22.3, 5q33.1, 3p26.3, 15q11.1-q11.2, 15q22.2, 1q25.1-q25.2, 7q21.3, 2q12.3. They include candidate genes DDX10 (putative RNA helicase), IL17B (cytokine, primarily localized to neuronal cell bodies), CNTN6 (may play a role in the formation of axon connections), TLN2 (plays a role in cell adhesion and recycling of synaptic vesicles), TNR (an extracellular matrix protein, expressed primarily in the central nervous system), ASTN1 (a neuronal adhesion molecule), PON1 (detoxifies organophosphate neurotoxicants), and SLC5A7 (choline transporter in the brain and periphery).
ConclusionsPreviously unknown CNVs, containing genes responsible for proper central nervous system functioning, were detected in 13% of patients. The novel CNVs and genes identified by aCGH may help discovering new etiological mechanisms of MR. This study was supported by European Community's Seventh Framework Programme, CHERISH (project 223692) and by Federal Program (grant 8727).