@article {231,
	title = {The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.},
	journal = {Am J Hum Genet},
	volume = {95},
	year = {2014},
	month = {2014 Aug 07},
	pages = {143-61},
	abstract = {<p>Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70\%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22\%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects{\textquoteright} genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.</p>},
	keywords = {Adenosine Triphosphatases, Alu Elements, Base Sequence, Cation Transport Proteins, Cell Line, Transformed, DNA Copy Number Variations, Genotype, Humans, Protein Isoforms, Recombinant Fusion Proteins, Sequence Analysis, DNA, Sequence Deletion, Spastic Paraplegia, Hereditary, Spastin},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2014.06.014},
	author = {Boone, Philip M and Yuan, Bo and Campbell, Ian M and Scull, Jennifer C and Withers, Marjorie A and Baggett, Brett C and Beck, Christine R and Shaw, Christine J and Stankiewicz, Pawel and Moretti, Paolo and Goodwin, Wendy E and Hein, Nichole and Fink, John K and Seong, Moon-Woo and Seo, Soo Hyun and Park, Sung Sup and Karbassi, Izabela D and Batish, Sat Dev and Ord{\'o}{\~n}ez-Ugalde, Andr{\'e}s and Quint{\'a}ns, Beatriz and Sobrido, Mar{\'\i}a-Jes{\'u}s and Stemmler, Susanne and Lupski, James R}
}
@article {272,
	title = {Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.},
	journal = {Eur J Hum Genet},
	volume = {22},
	year = {2014},
	month = {2014 Sep},
	pages = {1145-8},
	abstract = {<p>Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM$\#$213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM$\#$614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD. </p>},
	keywords = {Abnormalities, Multiple, Exome, Humans, Infant, Intellectual Disability, Male, Membrane Proteins, Mutation, Protein Isoforms},
	issn = {1476-5438},
	doi = {10.1038/ejhg.2013.291},
	author = {Pehlivan, Davut and Karaca, Ender and Aydin, Hatip and Beck, Christine R and Gambin, Tomasz and Muzny, Donna M and Bilge Geckinli, B and Karaman, Ali and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R}
}
