@article {41,
	title = {Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.},
	journal = {Hum Genet},
	volume = {135},
	year = {2016},
	month = {2016 Oct},
	pages = {1161-74},
	abstract = {<p>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.</p>},
	keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Copy Number Variations, DNA Replication, Female, Gene Deletion, Haploinsufficiency, Homologous Recombination, Humans, Intellectual Disability, Male, Mutation, Myelin Proteins, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors},
	issn = {1432-1203},
	doi = {10.1007/s00439-016-1703-5},
	author = {Yuan, Bo and Neira, Juanita and Gu, Shen and Harel, Tamar and Liu, Pengfei and Brice{\~n}o, Ignacio and Elsea, Sarah H and G{\'o}mez, Alberto and Potocki, Lorraine and Lupski, James R}
}
@article {229,
	title = {Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.},
	journal = {Am J Hum Genet},
	volume = {95},
	year = {2014},
	month = {2014 Aug 07},
	pages = {173-82},
	abstract = {<p>New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics. </p>},
	keywords = {Cell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2014.07.003},
	author = {Campbell, Ian M and Yuan, Bo and Robberecht, Caroline and Pfundt, Rolph and Szafranski, Przemyslaw and McEntagart, Meriel E and Nagamani, Sandesh C S and Erez, Ayelet and Bartnik, Magdalena and Wi{\'s}niowiecka-Kowalnik, Barbara and Plunkett, Katie S and Pursley, Amber N and Kang, Sung-Hae L and Bi, Weimin and Lalani, Seema R and Bacino, Carlos A and Vast, Mala and Marks, Karen and Patton, Michael and Olofsson, Peter and Patel, Ankita and Veltman, Joris A and Cheung, Sau Wai and Shaw, Chad A and Vissers, Lisenka E L M and Vermeesch, Joris R and Lupski, James R and Stankiewicz, Pawe{\l}}
}
