Reciprocal Microduplication of the Williams-Beuren Syndrome Chromosome Region in a 9-Year-Old Omani Boy

Case Study Reciprocal Microduplication of the Williams-Beuren Syndrome Chromosome Region in a 9-Year-Old Omani Boy Laboratory Medicine 47:2:171-175 DOI: 10.1093/labmed/lmw005 ABSTRACT Background: Microdeletions of the 7q11.23 Williams-Beuren syndrome chromosome region (WBSCR) are reported with a frequency of 1 in 10,000, whereas microduplications of the region, although expected to occur at the same frequency, are not widely reported. Method: We evaluated a 9-year old Omani boy for idiopathic intellectual disability using genetic methods, including multiplex ligation-dependent probe amplification (MLPA), for detection of microdeletions (P064-B3). Results: MLPA analysis revealed that the boy has a rare microduplication of the WBSCR. Prominent clinical features include global developmental Subtle chromosomal rearrangements are associated with a number of intellectual disability (ID)–related syndromes. Recently, various interstitial and telomeric rearrangements of chromosomes have become well-characterized etiological factors of ID.1,2 These microdeletions and microduplications, also known as copy-number variations, are mediated by lowcopy repeats present in approximately 5% of the human genome;3,4 these entities play a significant role in disease mechanisms by altering the dosage of functional genes. Abbreviations ID, intellectual disability; WBS, Williams-Beuren syndrome; WBSCR, Williams-Beuren syndrome chromosome region; NAHR, nonallelic homologous recombination; MLPA, multiplex ligation-dependent probe amplification; MRI, magnetic resonance imaging; EEG, electroencephalogram; FISH, fluorescence in situ hybridization; PCR, polymerase chain reaction; ADHD, attention-deficit hyperactivity disorder; CAP-Gly; ELN, elastin; LMK1, LIM kinase 1; STX1A, syntaxin delay with pronounced speech delay, dysmorphic facies, and autistic features. Conclusion: Microduplications, in general, are reported at a lesser frequency, perhaps owing to their milder phenotype. Complete genetic assessment in children with idiopathic intellectual disability would help in identifying rare conditions such as duplication of the WBSCR. Keywords: microduplication, 7q11.23, Williams-Beuren syndrome, speech delay, intellectual disability, multiplex ligation-dependent probe amplification Williams-Beuren syndrome (WBS) is one such microdeletion syndrome, with an incidence of approximately 1 in 10,000 live births.5 Although WBS is often associated with a microdeletion in the WBS chromosome region (WBSCR), there been a few reports of microduplications in the region.6-8 In most individuals with a rearrangement in the WBSCR, the region involved in rearrangement is 1.5 Mb in length, encompassing about 26 to 28 genes, between the NSUN5 gene on the centromeric end and GTF2IRD2 gene on the telomeric end.9 Breakpoints vary depending on the extent of rearrangement; however, commonly reported breakpoints lie within the GTF2IP1 and GTF2I genes.10 The phenotypic features of the deletion and duplication syndromes vary, although they occur due to the same molecular mechanism of nonallelic homologous recombination (NAHR).11,12 NAHR results from misalignment due to similarity among low-copy repeats, which are abundant in the pericentromeric and subtelomeric regions.13 1 Department of Human Genetics, Sri Ramachandra University, Chennai, India and 2Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Center, Kochi, India *To whom correspondence should be addressed. Herein, we describe the case of a 9-year-old Omani boy with ID and dysmorphic features, suggestive of chromosomal imbalance as a possible etiology. Multiplex ligation-dependent probe amplification (MLPA) analysis revealed a rare duplication C American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: V 171 Shruthi Mohan, MSc,1 Sheela Nampoothiri, DNB, MSc,2 Dhanya Yesodharan, MD,2 Vettriselvi Venkatesan, PhD,1 Teena Koshy, MSc,1 Solomon F.D. Paul, PhD,1 Venkatachalam Perumal, PhD1* Case Study in the WBSCR. We discuss the observed features of this case in connection with available background information on the syndrome. Case Report Results of ultrasound evaluation of the abdomen, and magnetic resonance imaging (MRI) of the brain and electroencephalogram (EEG) of the proband were normal. A detailed physical examination revealed dysmorphic features, including macrostomia (Image 1A), prominent nose with overhanging nasal tip low-set flared pinna (Image 1B), and down slanted eyes. Other prominent features included fair complexion, brachydactyly of fingers (Image 1C), and bilateral partial cutaneous syndactyly between the second and third toes. He had a right external angular dermoid, which was excised. He showed a few autistic features, and therefore, his specimen was tested for Fragile X syndrome and Angelman syndrome. Further evaluation by karyotyping, fluorescence in situ hybridization (FISH), and MLPA was performed. Results The results of karyotype analysis showed a normal karyotype of 46,XY. The results of the southern blot study for Fragile X and methylation study for Angelman syndrome were normal. FISH testing for subtelomeric rearrangements also yielded a negative result, suggesting the absence of telomeric structural rearrangements. The MLPA peaks were analyzed and the fluorescence intensities were compared between test and control specimens. The results were interpreted based on fluorescence intensity ratios. All 6 probes for the genes, CLIP2 (2 probes), FZD9, ELN, LIMK1, and STX1A in the 1 Mb region within the WBSCR showed ratios greater than 1.3, indicating duplication of the WBS region (Image 2). Materials and Methods Discussion Genetic testing was performed on the boy after obtaining informed consent from his parents. FISH was performed using the Vysis ToTelVysion kit (Abbott Laboratories, Inc) on chromosomes obtained from cultured lymphocytes, to rule out Less than 100 cases of microduplication of the WBSCR have been described in the literature.14 Although the prevalence of the WBSCR duplication is estimated to be similar to that of the WBS microdeletion, the population frequency is not 172 Lab Medicine 2016;47:2;171–175 172 DOI: 10.1093/labmed/lmw005 www.labmedicine.com The proband was a 9-year-old Omani boy born to a fourthdegree consanguineous couple; he had weighed 3 kg at birth. He was the firstborn; his 2 younger siblings did not have any of the health problems that he had experienced. The boy had had 4 episodes of seizures, with uprolling of eyes that lasted for approximately 15 minutes, at the age of 5 months. Occasional blackouts while playing had also been observed by his parents. He showed overall developmental delay, with prominent speech delay disproportionate to his motor delay. The boy had started to speak only at age 5 years, and at age 9 years, he was still not toilet trained. His height was 132 cm (25th to 50th percentile), his weigh (...truncated)