Nonrecurrent PMP22- RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy

Yuan, Bo; Neira, Juanita; Gu, Shen; Harel, Tamar; Liu, Pengfei; Briceño, Ignacio; Elsea, Sarah; Gómez, Alberto; Potocki, Lorraine; Lupski, James
October 2016
Human Genetics;Oct2016, Vol. 135 Issue 10, p1161
Academic Journal
Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22- RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22- RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22- RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.


Related Articles

  • Molecular Analysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17p11.2 Deletion. Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K.; Cox, Gerald F.; Deshpande, Charu; Introne, Wendy J.; Gahl, William A.; Smith, Ann C. M.; Huizing, Marjan // PLoS ONE;2011, Vol. 6 Issue 8, p1 

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype....

  • Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). Walz, Katherina; Paylor, Richard; Jiong Yan; Weimin Bi; Lupski, James R.; Yan, Jiong; Bi, Weimin // Journal of Clinical Investigation;Nov2006, Vol. 116 Issue 11, p3035 

    Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes....

  • How much is too much? Phenotypic consequences of Rai1 overexpression in mice. Girirajan, Santhosh; Patel, Nisha; Slager, Rebecca E; Tokarz, Mary E; Bucan, Maja; Wiley, Jenny L; Elsea, Sarah H // European Journal of Human Genetics;Aug2008, Vol. 16 Issue 8, p941 

    The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith–Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse...

  • Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome. Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K // European Journal of Human Genetics;Feb2012, Vol. 20 Issue 2, p148 

    Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that...

  • Genolype-phenolype correlation of 30 patients with Smith- Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions. Andrieux, J.; Villenet, C.; Quief, S.; Lignon, S.; Geffroy, S.; Roumier, C.; De Leersnyder, H.; M-C De Blois; Manouvrier, S.; Delobel, B.; Benzacken, B.; Bitoun, P.; Attie-Bitach, T.; Thomas, S.; Lyonnet, S.; Vekemans, M.; Kerckaert, J-P. // Journal of Medical Genetics;Aug2007, Vol. 44 Issue 8, p537 

    Background: Smith-Magenis syndrome (SMS) is rare (prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous...

  • A Duplication CNV That Conveys Traits Reciprocal to Metabolic Syndrome and Protects against Diet-Induced Obesity in Mice and Men. Lacaria, Melanie; Saha, Pradip; Potocki, Lorraine; Weimin Bi; Jiong Yan; Girirajan, Santhosh; Burns, Brooke; Elsea, Sarah; Walz, Katherina; Chan, Lawrence; Lupski, James R.; Wenli Gu // PLoS Genetics;May2012, Vol. 8 Issue 5, Special section p1 

    The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a...

  • Smith-Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency. YI ZHOU; YINGJUN XIE; YUNXIAO ZHU; JIANZHU WU; MEIJIAO SHANG; BAOJIANG CHEN; QUN FANG // Molecular Medicine Reports;2016, Vol. 13 Issue 1, p347 

    Smith-Magenis syndrome (SMS) is a rare condition with multiple congenital malformations caused by the haploin-sufficiency of RAI1 (deletion or mutation of RAI1). However, the correlation between genotype and phenotype is not well understood. The present study describes the prenatal diagnosis of...

  • Smith-Magenis Syndrome With West Syndrome in a 5-Year-Old Girl: A Long-Term Follow-Up Study. Hino-Fukuyo, Naomi; Haginoya, Kazuhiro; Uematsu, Mitsugu; Nakayama, Tojo; Kikuchi, Atsuo; Kure, Shigeo; Kamada, Fumiaki; Abe, Yu; Arai, Natsuko; Togashi, Noriko; Onuma, Akira; Tsuchiya, Shigeru // Journal of Child Neurology;Jul2009, Vol. 24 Issue 7, p868 

    Smith-Magenis syndrome is characterized by multiple congenital anomalies and mental retardation caused by the heterozygous deletion of chromosomal region 17p11.2. We present a long-term follow-up study of a girl with Smith-Magenis syndrome and West syndrome. West syndrome became apparent at 7...

  • Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models. Ricard, Guénola; Molina, Jessica; Chrast, Jacqueline; Wenli Gu; Gheldof, Nele; Pradervand, Sylvain; Schütz, Frédéric; Young, Juan I.; Lupski, James R.; Reymond, Alexandre; Walz, Katherina // PLoS Biology;Nov2010, Vol. 8 Issue 11, p1 

    A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and...

  • Surgical treatment of scoliosis in Smith-Magenis syndrome: a case report. Tsirikos, Athanasios I.; Baker, Alexander D. L.; McClean, Claire // Journal of Medical Case Reports;2010, Vol. 4 Issue 1, p1 

    Introduction: Smith-Magenis syndrome is a rare genetic condition associated with scoliosis in approximately 30% of cases. There is limited information in the literature on the treatment of scoliosis and the surgical outcome in patients with this condition. Characteristic features of the...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics