BENIGN, PATHOGENIC AND COPY NUMBER VARIATIONS OF UNKNOWN CLINICAL SIGNIFICANCE IN PATIENTS WITH CONGENITAL MALFORMATIONS AND DEVELOPMENTAL DELAY
Mihaylova M1,*, Staneva R1,2, Toncheva D1, Pancheva M1,2, Hadjidekova S1,2
*Corresponding Author: Dr. Marta Mihaylova, Department of Medical Genetics, Medical Faculty, Medical University of Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria. Tel: +3592-9172-735. E-mail: marta.mih@gmail.com
page: 5

DISCUSSION

In 31 patients, 41 pathogenic variations were found. In six of these patients, eight pathogenic aberrations associated with the corresponding phenotype were defined. The interpretation of other variations was made on the basis of the frequency in the studied group, the size of the variations, content of genes in the region and the type of the CNVs (deletion or duplication). The CNVs with a 1.0-3.0% frequency in the population are accepted as benign polymorphisms. This gave us reason to consider as probably benign, those varia tions that occurred at frequencies higher than 1.2% in the studied group. Twenty-four of the CNVs conform with these criteria and were therefore considered to probably be benign. Abnormal variations with a frequency higher than 1.2%, were found in the following chromosomal loci: 2q13 (2.5%), 3q29 (2.5%), 7q11.23 (3.7%), 8p23.1 (8.6%) and Xp22.33 (18.5%). The deletion in the (2)(p16.3) region, found in patient 79, was pathogenic and covered one HGNC gene (NRXN1) and one OMIM gene (NRXN1). It covered the OMIM loci associated with autism. The detected deletion in the (5) (q35.2q35.3) region in the same patient was also pathogenic and covered 40 HGNC and 24 OMIM genes among which was the NSD1, whose loss of function was considered a major cause of Sotos syndrome. The NSD1 protein controls the activity of genes related to normal growth and development, although many of these genes have not been identified [33]. The described pathogenic CNVs in this gene were more than 100. Sotos syndrome is characterized by facial dysmorphism, dolichocephaly, cognitive decline, mild-to-severe intellectual disability and overgrowth. In the second patient (#52), aCGH revealed a pathogenic deletion, del(10)(q26.12q26.3), covering 85 HGNC and 49 OMIM genes. This type of chromosomal aberration leads to phenotypic manifestations such as facial dysmorphism, postnatal growth retardation, developmental delay, intellectual disability, hypotonia in newborns, feeding disorders, microcephaly, digital anomalies, heart defects and defects of the genitourinary system. The common feature of the patients with these aberrations is that they have behavioral problems. Some sources considered four candidate genes: CTBP2, ADRB1, DPYSL4, DRD1IP, associated with neural development and function [34]. The pathogenic deletion in patient 46, del(4) (q34.3q35.2), included 49 HGNC and 21 OMIM genes and the duplication, also pathogenic, on chromosome 12, dup(12) (p13.33p13.1), covered 226 HGNC and 156 OMIM genes. The presence of terminal aberrations is very often a result of family rearrangements, but due to lack of samples from the parents, the origin of the detected aberrations was not set. The clinical features included facial dysmorphism, obesity, increased appetite and other symptoms. Patient 41 was revealed to carry pathogenic deletion 17, del(17)(q12q12), covering 24 HGNC and 24 OMIM genes, which are associated with renal cysts, diabetic syndrome, developmental delay, autism and schizophrenia, seizures and less common phenotypes with dysmorphic features, transitory neonatal hypercalcemia, Müller aplasia and congenital diaphragmatic hernia. An important candidate gene was HNF1B associated with the development of the kidneys and pancreas. The detected deletion on chromosome 22, del(22) (q11.21q11.22), in patient 35, was also pathogenic covering 68 HGNC and 12 OMIM genes and affecting many organs and systems. It was assumed that the majority of the symptoms (heart defects, cleft palate, facial dysmorphism, hearing loss, hypocalcaemia), were caused by deletion of the TBX1 gene. The last detected pathogenic aberration was a duplication in chromosome 15, dup(15)(q11.2q13.1), which included 111 HGNC and 16 OMIM genes. This syndrome is represented by autism, intellectual disability, muscular hypotonia, ataxia, seizures, developmental delay and behavioral problems [35]. According to Tan et al. [36], at least three genes (NIPA1, NIPA2, CYFIP1), located in this region were associated with the development of CNS (central nervous system). A duplication of the copy of the SNRPN gene obtained from the mother is associated with autism. Other important genes associated with the development and neurological disorders are GABRA5, GABRA3, GABRG3, MAGEL2, MKRN3, NDN, SNRPN and UBE3A. The first three encode subunits of the GABA-receptors that mediate the main inhibitory neurotransmitter in the brain (GABA) [36]. The total number of established benign CNVs and CNVs of unknown clinical significance, amounted to 239, 141 of which were deletions and 98 were duplications. The total number of variations (with pathogenic ones) was 280, an average of 3.5 variations per patient. Two large studies in 2004 revealed that the genome of each person contains approximately 12 CNVs [27,28]. Later, in 2009, Itsara et al. [19] analyzed 2500 controls and found that the average number of CNVs for one person is between three and seven variations. Our data is very similar to that of Itsara et al. [19]. In more than one patient, benign CNVs were identified in the following cytogenetic loci: 8p11.22, 6p25.3, 1q21.2, 2q37.3, 10q11.22, 14q11.2, 5q13.2, 10q26.3, 15q11.2, 19q13.31, and two different CNVs were detected in region 8p23.1. In six patients, six single variations in the loci were found: 14q32.33, 10q11.22, 5p15.33, 16p13.11, 15q14, 14q21.2 (Figure 1). The most common benign CNVs were found in over 10.0% of the tested patients and were at the following locations: 8p11.22 and 1q21.2, and two different variations in the 8p23.1 locus. Deletions were identified in some of the cases, while in others, duplications, which indicated that these areas contained a significant number of variations. To establish the actual frequency of the detected unique benign CNVs, it was better to perform a genomic screening of a larger group of patients. According to Kooy [37], polymorphic CNVs are part of the natural genetic differences in humans, while rare variants can be related to certain disorders. A large study found that polymorphic CNVs are probably not closely related to the genetic etiology of multifactorial diseases, and it is possible that they are part of the benign genetic variations between individuals [38]. The number of variants of unknown clinical significance was 121. They were distributed by size as follows: 89 (73.6%) 100-500 kb; 31 (25.6%) 500 kb-1 Mb; one (0.8%) larger than 1 Mb. There were 50 deletions and 71 duplications. From the identified 121 variations of unknown clinical significance, in the following cytogenetic loci: 8p11.22, 8p23.1, 14q32.33, Xp22.33, 17q21.31, 16p11.2,2q37.3, 14q11.2, 22q11.23, 11q25, 12p13.31, Xq22.3, 2p11.1, CNVs were found in more than one patient. There were 33 single CNVs detected in 27 patients. Our results revealed a high rate of CNVs of unknown clinical significance. It is very likely that some of these variations are benign for the Bulgarian population. It is well known that the Bulgarian nation has a great genetic heterogeneity. Thirteen types of CNVs of unknown clinical significance were defined. They were located as follows: 8p11.22, 8p23.1, 14q32.33, Xp22.33, 17q21.31, 16p11.2, 2q37.3, 14q11.2, 22q11.23, 11q25, 12p13.31, Xq22.3, 2p11.1 (88 of the total number), and occurred in over 1.2% of the patients. That gave us reason to assume that they had no pathogenic nature. The most common, probably benign CNVs in our study, were in loci 14q32.33, 17q21.31 and 16p11.12, occurring in over 15.0% of the patients. Thirteen of the CNVs detected in loci 14q32.33, 16p11.2, 16p12.3, 17q21.31, 1q21.2, 20p12.1, 22q11.22, 2q37.3, 4q35.2, 8p23.1 were found in patients with already defined pathogenic aberrations of major size, and associated with the corresponding phenotype. According to some sources, in the presence of large chromosomal aberrations associated with a particular phenotype, it is unlikely for the identified smaller rearrangement to be essential for the development of the disease [23]. Therefore we assumed that it was possible for these 13 variants to have no relation with the clinical phenotype. In patient 30 a duplication of unknown clinical significance was identified in the 1q21.2 region, which contained 15 HGNC and 1 OMIM genes. Among them was the NBPF23 gene, which belongs to a gene family, characterized by tandem repeats of the DUF1220 protein domains. Several developmental problems and neurogenetic disorders such as microcephaly, macrocephaly, autism, schizophrenia, learning disorders, congenital heart disease, neuroblastoma, congenital anomalies of the kidney and urinary tract [39], are associated with identified CNVs located in the region with more DUF1220 domains. Based on this information, we could not exclude the potential pathogenic effect of the CNVs in this region. Nineteen of the rest of the CNVs of unknown clinical significance could not be interpreted as probably benign. We need more complementary studies to clarify the phenotypic effect. Five types of the pathogenic CNVs, located in chromosomal loci 2q13, 3q29, 8p23.1, 7q11.23, Xp22.33 (24 variations) were found in a high percentage (over 1.2%) of the patients. Their high frequencies gave us reason to suppose that despite their pathogenic nature, these variations might be considered to be CNVs of unknown clinical significance or probably benign. In four patients, we identified four pathogenic variations with no clinical significance, in the following chromosomal loci: 22q11.22, 8p23.2, 2q13, 4q12. To determine participation in the variation genes, we made a reference to the Database of Genomic Variants (DGV). The OMIM genes responsible for the clinical phenotype were found in none of the four CNVs. In the selected group of patients with congenital anomalies, 280 CNVs have been proven, respectively 41 pathogenic, 118 benign and 121 of unknown clinical significance. We found 13.6% incidence of pathogenic CNVs by aCGH. Eight pathogenic variations corresponding to the clinical phenotype of the patients, were identified. We revealed genotype-phenotype correlations between many genes and the manifested clinical features. During the interpretation of the CNVs of unknown clinical significance and the pathogenic ones, an additional category was defined, “probably benign variations.” It was concluded that there is a need to apply new genomic technologies with greater resolution, as a significant proportion of the patients were left with an unclear diagnosis. This would facilitate the detection and interpretation of the genomic aberrations in order to make an accurate diagnosis and to optimize therapeutic approaches.



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