Prader-Willi syndrome - type 1 deletion, a consequence of an unbalanced translocation of chromosomes 13 and 15, easily to be mixed up with a Robertsonian translocation
© Sheth et al. 2015
Received: 21 May 2015
Accepted: 14 July 2015
Published: 22 July 2015
Prader-Willi syndrome, due to microdeletion of proximal 15q, is a well-known cause of syndromic obesity.
A couple with history of repeated first trimester abortions had a son with balanced Robertsonian translocation of chromosomes 13 and 15 according to cytogenetic banding technique.
Chromosomal analysis for the couple was performed. A balanced translocation involving BP1-BP3 region of proximal 15q was observed in the father.
Investigations of the parents is mandatory when a structural rearrangement is detected in a dysmorphic child.
Prader-Willi syndrome (PWS) is a neurobehavioral genetic disorder (OMIM #176270) characterized by hypotonia, poor feeding in infancy, hyperphagia with evolving obesity in later live, hypogonadism, decreased adult height as well as cognitive and behavioural disabilities . PWS can be due to distinct genetic mechanisms: deletion of paternally expressed functional genes, maternal uniparental disomy and imprinting defects of genes in proximal 15q. Micro-deletions in PWS are further subdivided into type-1 (DT1) and type 2 (DT2). Both of them are usually due to a “de novo” event. Type 1 encompasses breakpoints (BP) BP1 to BP3 (~6 Mb) whereas type 2 covers BP2 toBP3 (~5.6 Mb) . However, there are other rare PWS cases where 15q11.2-13 region may be deleted as a result of unbalanced translocation leading to discrepant breakpoints in proximal 15q. Various diagnostic modalities like testing of DNA methylation test or microsatellite analysis, fluorescence in situ hybridization (FISH) or chromosome microarray (CMA) techniques are prerequisite to undoubtedly confirm the clinical diagnosis of PWS.
Here, we present a rare case of PWS arisingas a consequence of paternally inherited unbalanced translocation involving chromosome 13 and 15 resulting in loss of proximal 15q, which can easily be misinterpreted as Robertsonian translocation.
A non-consanguineous elderly couple was referredfor cytogenetic evaluation with repeated first trimester pregnancy losses (n = 3). In addition, there was a history ofa male child with uncontrolled seizures who died at nine months of age. Another male child, the proband of this study, expired at the age of fifteen years due to obesity leading to sleep apnea. This child had intellectual disability and hyperphagia with central obesity. He had all the typical features of PWS along with extreme impairment of language milestones and could only speak few words even at 12 years of age. On cytogenetic evaluation, he had a karyotype of 45,XY, rob (13;15)(q10;q10)[100 %]. There was no history of repeated miscarriages in any other family members; however, intellectual disability was observed in one of the members on the paternal side.
PWS, a contiguous gene disorder results in to functional inactivation of paternally derived genes at 15q11.2-q13 region; this kind of alteration is detected in ~70 % cases. The proximal region of the long arm of chromosome 15 (15q) is rich in duplicons and thus vulnerable to genomic instability . This region further houses six genomic breakpoint (BP) regions, assigned as BP1 to BP6, from the centromeric to telomeric region . Each break point is surrounded by a complex set of low-copy repeats which in turn lead to a variety of genomic imbalances and subsequent rearrangements. A unbalanced translocation involving chromosomes 13 and 15 was inherited from the healthy father in the present case, as the der (15) spanning 15pter to q13.2 harbouring BP1 to BP3 region (DT1) lacked in the proband (Fig. 1b). There exists a controversy between severity of the phenotype of DT1 and DT2 deletions. Approximately, the ratio prevailing between them is 2:3 . Cases with the larger DT1 (~6 Mb) have an estimated difference of 500 kb of genetic material than cases with the smaller type 2 deletion (~5.5 Mb). The BP1-BP2 region of 500 kb harbour four genes: NIPA1, NIPA2, CYFIP and TUBGCP5; those are highly conserved and implicated in developmental delay and psychological consequences since they are expressed in the central nervous system . Butler et al. (2004) found that people with DT1 had more psychological and neurological deficit than people with DT2 . However, Varela et al.  studied 75 individuals and optedthat there was no statistically significant difference between both types of deletions in PWS. Recently, a series of 52 patients reported with developmental delay, behavioural changes, epilepsy and congenital heart disease attributable to 15q11.2 microdeletion (BP1-BP2) analysed by array-CGH . Those authors demonstrated augmentation of severity due to size variations of the deletion (type 1).
The case present under study portraysobesity, cognitive impairment, developmental and speech delay as a major phenotype correlating well with DT1. However, the mode of formation of this deletion involving an sSMC and a derivative chromosome resembling a Robertsonian translocation is unusual.
It is imperative to know the mode of inheritance in caseswhere structural rearrangements in a proband are detected. Additionally, the chances of detecting submicroscopic alterations in child with dysmorphism should not be neglected. This could be attributed to gene/s that has been disrupted at or near the breakpoint region/s using various diagnostic modalities. Also such insights help providing precise genotype-phenotype correlation, management and counselling to patients and families with specific inherited conditions.
Written informed consent was obtained from the patient’s parents for publication of this paper and any accompanying images. A copy of the written consent is available for review bythe Editor-in-Chief of this journal.
Authors are grateful to Dr. Girish Patel for referral and to Dr. Sunil Trivedi for making language corrections. We also thank the patient and the parents for their consent.
- Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91(2):398–402.PubMedGoogle Scholar
- Kim SJ, Miller JL, Kuipers PJ, German JR, Beaudet AL, Sahoo T, et al. Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Eur J Hum Genet. 2012;20(3):283–90.PubMed CentralPubMedView ArticleGoogle Scholar
- Shaffer LG, McGowan-Jordan J, Schmid M. An International System for Human Cytogenetic Nomenclature. Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature. Karger;2013.Google Scholar
- Pujana MA, Nadal M, Guitart M, Armengol L, Gratacos M, Estivill X. Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons. Eur J Hum Genet. 2002;10(1):26–35.PubMedView ArticleGoogle Scholar
- Mignon-Ravix C, Depetris D, Luciani JJ, Cuoco C, Krajewska-Walasek M, Missirian C, et al. Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations. Eur J Hum Genet. 2007;15(4):432–40.PubMedView ArticleGoogle Scholar
- Christian SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH. Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet. 1999;8(6):1025–37.PubMedView ArticleGoogle Scholar
- Chai JH, Locke DP, Greally JM, Knoll JH, Ohta T, Dunai J, et al. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet. 2003;73(4):898–925.PubMed CentralPubMedView ArticleGoogle Scholar
- Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics. 2004;113(3 Pt 1):565–73.PubMedView ArticleGoogle Scholar
- Varela MC, Kok F, Setian N, Kim CA, Koiffmann CP. Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: study of 75 patients. Clin Genet. 2005;67(1):47–52.PubMedView ArticleGoogle Scholar
- Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, et al. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015;58(3):140–7.PubMedView ArticleGoogle Scholar
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