Genomic imbalance in subjects with idiopathic intellectual disability detected by multiplex ligation-dependent probe amplification

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1 c Indian Academy of Sciences RESEARCH NOTE Genomic imbalance in subjects with idiopathic intellectual disability detected by multiplex ligation-dependent probe amplification SHRUTHI MOHAN, VETTRISELVI VENKATESAN, SOLOMON FD PAUL, TEENA KOSHY and VENKATACHALAM PERUMAL Department of Human Genetics, Sri Ramachandra University, Chennai , India [Mohan S., Venkatesan V., Fd Paul S., Koshy T. and Perumal V Genomic imbalance in subjects with idiopathic intellectual disability detected by multiplex ligation-dependent probe amplification. J. Genet. 95, ] Introduction Materials and methods Intellectual disability (ID) is a complex disorder with heterogeneous aetiology. The prevalence rate is about 2 3% worldwide. The cause of ID in at least half of the affected population is unclear and is reported as idiopathic ID. In addition to chromosomal abnormalities (Rio et al. 2002) and single gene mutations (Curry et al. 1997), segmental aneusomy caused by genomic rearrangements that may occur throughout the genome is implicated as a significant aetiological factor. Of late, the chromosomal subtelomeric regions have gained significance in the evaluation of ID owing to their proximity to telomeric repeat sequences which increases their probability of being involved in a deleterious rearrangement, causing ID (Raynham et al. 1996). These rearrangements are often undetectable by conventional karyotyping and call for sensitive, targeted approaches such as fluorescent in situ hybridization (FISH). In recent times, multiplex ligationdependent probe amplification (MLPA) has emerged as a robust and powerful method for the simultaneous detection of imbalances in multiple regions of the genome (Schouten et al. 2002). In India, ID constitutes 11% of genetic referrals, forming one of the top four genetic disorders in the country (Verma 2000). Considering this, we previously investigated subtelomeric rearrangements by FISH and chromosomal abnormalities by conventional cytogenetics (Mohan et al. 2016) in subjects with ID. In the present study, we extend the evaluation of children with idiopathic ID, with the objective of investigating interstitial genomic rearrangements using MLPA in a subset of the aforementioned study population. In addition, we compare the detection of subtelomeric rearrangements in seven children using MLPA owing to its merits, such as rapidity, cost-effectiveness and scope for simultaneous analysis of multiple samples. For correspondence. venkip@yahoo.com. Study population Children with ID or developmental delay (DD) were recruited from the paediatric outpatient clinics of three hospitals and from three special schools in south India (n = 107). This study was approved by the institutional ethics committee and informed consent was obtained from the parent/caretakers. The age group of the study population ranged between 7 months and 14 years. Study participants were recruited based on the de Vries checklist with modifications (de Vries et al. 2001). Children were evaluated clinically for ID/DD with at least one of the following features: (i) facial (>2) and/or extra-facial (>1) dysmorphism, (ii) prenatal and/or postnatal developmental defects and (iii) a positive family history of unexplained ID or related conditions. Participants with a clinical history suggestive of a known aetiology or with a chromosomal abnormality detected by karyotyping were excluded. About 2 ml of blood was collected from each individual and DNA was isolated using the QiagenQIAamp DNA blood mini kit. MLPA The SALSA MLPA P064 (ver. B3) probe kit with a total of 43 probes was used to detect interstitial chromosomal rearrangements (n = 100). The target regions covered by the probes included 1p36 telomere, 5q35.3 NSD1 gene for Sotos syndrome, 7p21.2 TWIST1 and TWISTNB for Seathre Chotzen syndrome, Williams syndrome region, Prader Willi syndrome region, 17p11.2 Smith Magenis syndrome region, 17p13.3 Miller Dieker syndrome region, 20p12.2 JAG1 gene for Alagile syndrome and 22q11.21 DiGeorge syndrome region. Further, the SALSA MLPA P036 (ver. E2) kit with one probe for each telomere of all the chromosomes except acrocentric p arms Keywords. chromosome rearrangement; multiplex ligation-dependent probe amplification; idiopathic intellectual disability. Journal of Genetics, Vol. 95, No. 2, June

2 Shruthi Mohan et al. was employed to compare the detection of subtelomeric rearrangements previously observed using FISH (n = 7). The test was performed according to the manufacturer s protocol (MRC Holland, Amsterdam, Netherlands) and multiple samples were run in each experiment with unaffected male DNA samples as control. A validation study was performed using 15 control samples. In brief, the isolated DNA was denatured, the probe mix added for hybridization to target and the hybridized probes were ligated and amplified with a universal primer pair. The PCR products were then fragment separated on the ABI 3730 DNA analyser and the data was analysed using the GeneMarker software. Fluorescence intensities were compared between test and control samples and the dosage ratios were calculated after intrasample and intersample normalization by the software. Fluorescence intensity ratios within the range of were interpreted as normal; whereas, ratios below 0.75 were considered deletion and those above 1.3 were considered duplication. Results A cohort of 107 children with ID of south Indian origin was screened for genomic imbalances. The demographic details of the study group are provided in table 1. The SALSA MLPA P064 probe kit was used to detect interstitial rearrangements in 100 children. Normal peak ratios (between 0.75 and 1.3) for all the 43 probes were observed in 98 individuals (98%), while two individuals (M1 and M2) showed deviations of peak ratios (2%). One subject showed microdeletion in the region (figure 1) and the other showed a microduplication in the region. The SALSA MLPA P036 probe kit was used to compare the detection of subtelomeric rearrangements in seven children with known chromosomal alterations, identified earlier by FISH. The rearrangements were microdeletions in two children and unbalanced translocations, resulting in a microdeletion and a microduplication in five children. The results revealed that the MLPA method detected the microdeletions in all seven children (S1 S7), but the microduplications in two (S6 and S7) of five children with unbalanced translocations were not detected. Table 2 shows the various abnormalities and the fluorescence intensity ratios calculated for the study subjects. Figure 2 presents the MLPA analysis of an individual with an unbalanced translocation between chromosomes 3q and 7q, showing microduplication in 3q and microdeletion in 7q. Discussion Genomic rearrangements resulting in altered gene dosages are a significant cause of ID and the frequency of these rearrangements reported vary widely. This could be attributed to a number of factors including study subject selection criteria, sample size and the method of detection. Among the techniques available for the detection of genomic imbalances, MLPA has several merits including ease of automation, and cost and time efficiency. It has also been used to screen for gene copy numbers in many other clinical conditions, such as Duchenne muscular dystrophy (Murugesan et al. 2010), cancers (Janowski et al. 2008; Homig-Holzel and Savola 2012) and neurological disorders (de Luca et al. 2007). Owing to its advantages, MLPA was used for the aetiological evaluation of children with ID from south India the P064 kit was used to screen 43 gene loci and the P036 kit was used to detect subtelomeric rearrangements in the genome which are implicated in the pathogenesis of ID. Of the two children identified to have interstitial rearrangements using the P064 kit, one subject showed a deletion of the probes in the region (figure 1), which is implicated in the pathogenesis of Prader Willi syndrome (PWS) (Buiting et al. 1992). While PWS is well characterized, our study participant did not show typical features and a diagnosis could not be made with clinical examination alone. The individual was a two and a half-year old male who did not cry at birth and presented with delayed development, microcephaly and seizures. The child was evaluated by a clinical psychologist using the Gesell Children s Behaviour Schedule (GCBS) and Vineland Adaptive Behavior Scale (VABS) techniques and was found to have a developmental age of six months. Also, it is noteworthy that a first cousin of the individual was diagnosed with hemiplegia and seizures. The other subject showed a microduplication of the region, which is reported to be deleted in Williams syndrome. Speech delay is the most significant clinical finding in patients with the microduplication. The participant in Table 1. Demographic study of participants. Proportion of Category study subjects (%) Age group <10 years years to <20 years 18 ID category/dd Mild moderate ID 11 Severe ID 12 DD 77 Dysmorphism 60 Prenatal abnormalities 9 Growth abnormalities 45 Family history of ID/seizures Journal of Genetics, Vol. 95, No. 2, June 2016

3 Genomic imbalances in intellectual disability Figure 1. Subject M1. The ratios indicate a deletion for the five probes in the 15q11 region (deleted in Prader Willi syndrome). MLPA peaks showing deletion/duplication of probes (arrows). Bottom panel and squares represent the ratio or gene dosage for each probe after normalization. Outliers (red squares) indicate a deletion or duplication. The ratios are tabulated on the right. Table 2. Abnormal loci detected and ratios. Individual P064 kit M1 M2 P036 kit S1 S2 S3 S4 S5a S6 S7 Type of abnormality Region Locus Ratio UBE3A MKRN3 NDN UBE3A GABRB3 CLIP2 FZD9 STX1A ELN LIMK1 CLIP pter 17pter 4pter 8pter 6pter 8pter 3qter 7qter 1qter 5pter Ypter Yqter PIGG RPH3AL PIGG FBXO25 IRF4 FBXO25 BDH1 VIPR2 SH3BP5L PDCD6 SHOX VAMP <1.3b <1.3b (missed) (missed) Subjects S1 and S2 showed microdeletions; subjects S3 S7 showed unbalanced translocations. a Figure 2 represents the analysis image; b probes with ratios within the normal threshold. our study was a nine year old male with developmental and speech delay. However, speech delay features as an associated clinical finding in most patients with ID. At least 25% of our study population expressed delayed speech. Both of these abnormalities were not discernible using conventional methods, suggesting that a diagnosis based only on clinical Journal of Genetics, Vol. 95, No. 2, June

4 Shruthi Mohan et al. Figure 2. Subject S5. The ratios show a duplication in the 3q39 telomeric region and a deletion in the 7q36.3 telomeric region. examination or testing a few target loci is insufficient. Further, our results imply that although, common microdeletion syndromes have been described with characteristic features, the varying degree of severity and complexity of ID make a thorough genetic assessment of the individual essential. Another aspect of our study was to compare the detection of subtelomeric alterations previously identified by FISH in seven children using MLPA. Subtelomeric rearrangements detected by MLPA were reported at a frequency of 6.7% earlier by Koolen et al. (2004). Of the two studies using the P036 kit, Mundhofir et al. (2013) reported a subtelomeric rearrangement rate of 3.7% in an Indonesian population, while no rearrangements were detected in an Indian population (John et al. 2013). However, our previous study reported subtelomeric rearrangements at a frequency of 7.8% in an Indian population using FISH (Mohan et al. 2016). Subsequently, using MLPA, we found 100% detection of microdeletions. However, only three of five microduplications (60%) were accurately detected. The results of the subtelomeric screening with MLPA suggest that the technique has a high accuracy for the detection of deletions; however, the duplications may be occasionally missed. Although, our observation is based on a small number of positive samples, the results stress the need to interpret MLPA data with caution. In general, studies on submicroscopic rearrangements report a greater number of deletions than duplications (Menten et al. 2006), which is thought to be due to the possible milder phenotype associated with duplication abnormalities or the apparent low frequency of random duplication events in the human genome (van Ommen 2005). In addition, the detection of duplications may be limited by the chosen threshold cut-offs in the analysis of fluorescence intensities. 472 Similar to other techniques, such as microarray, which rely on threshold algorithms for data analysis, a higher likelihood of false negatives in case of duplications is possible with MLPA. Menten et al. (2006) commented that since the fluorescence intensity ratios of deletions are more distant from the mean than that of duplications, they are likely to be detected more accurately, even if the cut-off is determined at equal distance from the mean for both deletions and duplications. Also, it is possible that a reduced amount of MLPA product may result from improper probe hybridization or ligation due to the occurrence of point mutations at target sequences, which may cause reduced fluorescence intensities to be interpreted as false positive deletions (Holla et al. 2005) or false negative duplications. At present, various technologies are available for genetic diagnosis. FISH is highly sensitive and can detect balanced rearrangements; however, it remains labour-intensive and unaffordable for routine screening. Whole-exome sequencing and array CGH offer wider coverage, however, they need confirmation by standard methods and are not a costeffective screening tool, especially in developing countries. MLPA is a reliable and cost-effective technique that can screen multiple targets in a number of samples simultaneously. Nevertheless, it has a few limitations including inability to detect balanced rearrangements. Also, since it is not a whole genome approach, imbalances in genomic regions other than the ones targeted will not be detected. Therefore, weighing the advantages and limitations of the technique, it is a likely candidate to be adopted as a preliminary screening technique that may be followed up with further analysis using other methods. The latest recommendation for genetic evaluation of ID is to adopt microarray as the initial screening Journal of Genetics, Vol. 95, No. 2, June 2016

5 Genomic imbalances in intellectual disability Medical history Clinical examination Psychological evaluation Recommended approach, 2006 Recommended approach, (Moeschler and Shevell 2006) Cytogenetic evaluation Fragile x screening or other molecular testing FISH for subtelomeres Metabolic testing Recommended approach, 2006 Suggested approach based on present study Cytogenetic evaluation MLPA for subtelomeres/microdeletions Fragile x screening or other molecular testing Metabolic testing (when needed) Recommended approach, (Moeschler and Shevell 2014) Microarray Fragile X testing Metabolic testing Follow up with gene panels For confirmation of diagnosis For further diagnostic investigation MLPA follow-up kits FISH for subtelomeres Metabolic testing Microarray Whole exome sequencing Figure 3. Schematic of diagnostic workflow in the genetic evaluation of children with ID/DD. Based on the present study, we propose that MLPA R for subtelomeres (using kits P036/P069/P070) and/or interstitial rearrangements (using kits: P064/P245) may be performed to initially screen children for a number of disorders. This, in conjunction with cytogenetic analysis at high resolution may reveal the underlying aetiology. To delineate the abnormality further, follow-up kits for subtelomeric (kit: TELO) and interstitial (kits: P371 P374) microdeletion/microduplication abnormalities are available from MRC, Holland, which contain more number of probes for each region. In addition, using subtelomeric FISH in the case of unbalanced translocations (Vysis ToTelVysion R /CytoCell Chromoprobe Multiprobe R - T probes) for confirmation or parental testing is highly recommended as it has important implications in genetic counselling. When an abnormality is not detected in the initial screening, further metabolic or molecular testing is warranted. Fragile X screening by PCR serves as a rapid screening method. Microarray and whole-genome sequencing which can scan the entire genome are attractive screening options; however, their utility in routine diagnostics is limited due to their high cost and thus may be reserved for cases where the aetiology has not been established by initial testing. technique (Moeschler and Shevell 2014). However, since microarray is yet to become affordable in developing countries, we suggest that MLPA (figure 3) may be employed as the first-tier diagnostic tool in the evaluation of ID and may be followed up with more panels or other techniques if need be. Conclusion There is a need for more studies on ID in Asian populations. The elucidation of genomic abnormalities in 2% of the study population, despite the lack of stringent preselection of study subjects, suggests that genetic evaluation is important in all children with idiopathic ID, even when the observed phenotype is mild. Acknowledgements We thank Dr Ashwin Dalal, Centre for DNA Fingerprinting and Diagnostics, for his valuable inputs. We are grateful to Dr Sheela Nampoothiri, AIMS; Dr Kalpana Gowrishankar, KKCTH and Dr Latha Ravichandran, SRU for evaluation of study participants. We also thank Ms Mohanapriya, SRU for her assistance. References Buiting K., Greger V. and Brownstein B. H A putative gene family in 15q11.13 and 16p11.2: possible implications for Prader Willi and Angelman syndromes. Proc. Natl. Acad. Sci. USA 89, Curry C. J., Stevenson R. E., Aughton D., Byrne J., Carey J. C., Cassidy S. et al Evaluation of mental retardation: recommendations of a consensus conference. Am.J.Med.Genet.72, de Luca A., Bottillo I., Dasdia M. C., Morella A., Lanari V., Bernardini L. et al s of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. J. Med. Genet. 44, de Vries B. B. A., White S. M., Knight S. J. L., Regan R., Homfray T., Young I. D. et al Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J. Med. Genet. 38, Holla Ø. L., Teie C., Berge K. E. and Leren T. P Identification of deletions and duplications in the low density lipoprotein receptor gene by MLPA. Clin. Chim. Acta 356, Homig-Holzel C. and Savola S Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. Diagn. Mol. Pathol. 21, Janowski S., Currie-Fraser E., Xu L. and Coffa J Multiplex ligation-dependent probe amplification analysis on capillary Journal of Genetics, Vol. 95, No. 2, June

6 Shruthi Mohan et al. electrophoresis instruments for a rapid gene copy number study. J. Biomol. Tech. 19, John N., Rajasekhar M., Girisha K. M., Sharma P. S. V. N. and Gopinath P. M Multiplex ligation-dependent probe amplification study of children with idiopathic mental retardation in south India. India. J. Hum. Genet. 19, Koolen D. A., Nillesen W. M., Versteeg M. H., Merkx G. F., Knoers N. V., Kets M. et al Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation-dependent probe amplification (MLPA). J. Med. Genet. 41, Menten B., Maas N., Thienpont B., Buysse K., Vandesompele J., Melotte C. et al Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J. Med. Genet. 43, Moeschler J. B. and Shevell M Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134, e903 e918. Moeschler J. B. and Shevell M Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 117, Mohan S., Koshy T., Perumal V., Nampoothiri S., Yesodharan D., Gowrishankar K. et al Subtelomeric rearrangements in Indian children with idiopathic intellectual disability/ developmental delay: frequency estimation and clinical correlation using FISH. Indian J. Med. Res. (in press). Mundhofir F. E. P., Nillesen W. M., Van Bon B. W. M., Smeets D., Pfundt R., van de Ven-Schobers G. et al Subtelomeric chromosomal rearrangements in a large cohort of unexplained intellectually disabled individuals in Indonesia: a clinical and molecular study. Indian J. Hum. Genet. 19, Murugesan S., Chandramohan A. and Lakshmi B. R Use of multiplex ligation-dependent probe amplification (MLPA) for Duchenne muscular dystrophy (DMD) gene mutation analysis. Indian J. Med. Res. 132, Raynham H., Gibbons R., Flint R. and Higgs D The genetic basis for mental retardation. Q. J. Med. 89, Rio M., Molinari F., Heuertz S., Ozilou C., Gosset P., Raoul O. et al Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromicmental retardation. J. Med. Genet. 39, Schouten J. P., McElgunn C. J., Waaijer R., Zwijnenburg D., Diepvens F. and Pals G Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57. van Ommen G. J Frequency of new copy number variation in humans. Nat. Genet. 37, Verma I. C Burden of genetic disorders in India. Indian J. Pediatr. 67, Received 27 June 2015, in final revised form 16 October 2015; accepted 20 October 2015 Unedited version published online: 19 November 2015 Final version published online: 5 May Journal of Genetics, Vol. 95, No. 2, June 2016

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