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

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Abstract

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.

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Acknowledgments

We thank the patients and their families for participation. This study was supported in part by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) Grant No. HG006542 to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG); the National Institute of Neurological Disorders and Stroke (NINDS) NS058529, the National Institute of General Medical Sciences (NIGMS) GM106373, the National Institute of Child Health and Development (NICHD) HD024064 Intellectual and Developmental Disabilities Research Center (IDDRC), the National Eye Institute (NEI) EY021163 and EY019861, and the Smith-Magenis Syndrome Research Foundation (SMSRF). T.H. was supported by the Medical Genetics Research Fellowship Program NIH/NIGMS NIH T32 GM007526.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Bo Yuan, Juanita Neira, Shen Gu, Tamar Harel, Pengfei Liu, Sarah H. Elsea, Lorraine Potocki & James R. Lupski

  2. Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia

    Ignacio Briceño & Alberto Gómez

  3. Instituto de Referencia Andino, Bogotá, Colombia

    Ignacio Briceño & Alberto Gómez

  4. Facultad de Medicina, Universidad de La Sabana, Chía, Colombia

    Ignacio Briceño

  5. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA

    James R. Lupski

  6. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    James R. Lupski

  7. Texas Children’s Hospital, Houston, TX, 77030, USA

    Lorraine Potocki & James R. Lupski

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Correspondence to James R. Lupski.

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Conflict of interest

JR.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen Inc., is a member of the Scientific Advisory Board of Baylor Miraca Genetics Laboratories, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in the Baylor Miraca Genetics Laboratory.

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Yuan, B., Neira, J., Gu, S. et al. Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith–Magenis syndrome with evident peripheral neuropathy. Hum Genet 135, 1161–1174 (2016). https://doi.org/10.1007/s00439-016-1703-5

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