@article {49, title = {Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jun 02}, pages = {1146-1158}, abstract = {

Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in~vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

}, keywords = {Adolescent, Adult, Cerebellar Ataxia, Child, Chromosome Aberrations, Chromosomes, Human, Pair 7, Exome, Female, Genetic Linkage, Genotype, High-Throughput Nucleotide Sequencing, Humans, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Male, Middle Aged, Mutation, Missense, Pancytopenia, Pedigree, Proteins, Tumor Suppressor Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.009}, author = {Chen, Dong-Hui and Below, Jennifer E and Shimamura, Akiko and Keel, Sioban B and Matsushita, Mark and Wolff, John and Sul, Youngmee and Bonkowski, Emily and Castella, Maria and Taniguchi, Toshiyasu and Nickerson, Deborah and Papayannopoulou, Thalia and Bird, Thomas D and Raskind, Wendy H} } @article {639, title = {Keratoacanthoma Shares Driver Mutations with Cutaneous Squamous Cell Carcinoma.}, journal = {J Invest Dermatol}, volume = {136}, year = {2016}, month = {2016 08}, pages = {1737-1741}, keywords = {Aged, Aged, 80 and over, Biomarkers, Tumor, Biopsy, Carcinoma, Squamous Cell, Cohort Studies, Diagnosis, Differential, Exome, Female, Humans, Keratoacanthoma, Loss of Heterozygosity, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Skin, Skin Neoplasms, Whole Exome Sequencing}, issn = {1523-1747}, doi = {10.1016/j.jid.2016.04.002}, author = {Lim, Young H and Fisher, Jonathan M and Bosenberg, Marcus W and Choate, Keith A and Ko, Christine J} } @article {185, title = {Absence of heterozygosity due to template switching during replicative rearrangements.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 02}, pages = {555-64}, abstract = {

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

}, keywords = {Base Sequence, DNA Copy Number Variations, DNA Repair, DNA Replication, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Models, Genetic, Molecular Sequence Data, Netherlands, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uniparental Disomy}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.021}, author = {Carvalho, Claudia M B and Pfundt, Rolph and King, Daniel A and Lindsay, Sarah J and Zuccherato, Luciana W and Macville, Merryn V E and Liu, Pengfei and Johnson, Diana and Stankiewicz, Pawel and Brown, Chester W and Shaw, Chad A and Hurles, Matthew E and Ira, Grzegorz and Hastings, P J and Brunner, Han G and Lupski, James R} } @article {187, title = {Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Apr}, pages = {1703-7}, abstract = {

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Cell Line, Tumor, Cell Nucleus, Child, Child, Preschool, Chromosomes, Human, Pair 12, Cytoskeleton, Frameshift Mutation, Humans, Ichthyosis, Intermediate Filaments, Keratin-1, Keratinocytes, Loss of Heterozygosity, Male, Molecular Sequence Data, Mosaicism, Phenotype, Polymorphism, Single Nucleotide, Protein Transport, Transfection}, issn = {1558-8238}, doi = {10.1172/JCI64415}, author = {Choate, Keith A and Lu, Yin and Zhou, Jing and Elias, Peter M and Zaidi, Samir and Paller, Amy S and Farhi, Anita and Nelson-Williams, Carol and Crumrine, Debra and Milstone, Leonard M and Lifton, Richard P} }