@article {562, title = {Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 11 01}, pages = {794-807}, abstract = {

Ca signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca store, and dysregulation of ER Ca signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In~vitro cellular experiments showed decreased total ER Ca storage, impaired Ca signaling mediated by the IPR Ca release channel, and reduced ER Ca refilling via store-operated Ca entry. These results, together with the previously described role of CCDC47 in Ca signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.014}, author = {Morimoto, Marie and Waller-Evans, Helen and Ammous, Zineb and Song, Xiaofei and Strauss, Kevin A and Pehlivan, Davut and Gonzaga-Jauregui, Claudia and Puffenberger, Erik G and Holst, Charles R and Karaca, Ender and Brigatti, Karlla W and Maguire, Emily and Coban-Akdemir, Zeynep H and Amagata, Akiko and Lau, C Christopher and Chepa-Lotrea, Xenia and Macnamara, Ellen and Tos, Tulay and Isikay, Sedat and Nehrebecky, Michele and Overton, John D and Klein, Matthew and Markello, Thomas C and Posey, Jennifer E and Adams, David R and Lloyd-Evans, Emyr and Lupski, James R and Gahl, William A and Malicdan, May Christine V} } @article {121, title = {Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.}, journal = {Neuron}, volume = {88}, year = {2015}, month = {2015 Nov 04}, pages = {499-513}, abstract = {

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85\% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

}, keywords = {Brain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.09.048}, author = {Karaca, Ender and Harel, Tamar and Pehlivan, Davut and Jhangiani, Shalini N and Gambin, Tomasz and Coban Akdemir, Zeynep and Gonzaga-Jauregui, Claudia and Erdin, Serkan and Bayram, Yavuz and Campbell, Ian M and Hunter, Jill V and Atik, Mehmed M and Van Esch, Hilde and Yuan, Bo and Wiszniewski, Wojciech and Isikay, Sedat and Yesil, G{\"o}zde and Yuregir, Ozge O and Tug Bozdogan, Sevcan and Aslan, Huseyin and Aydin, Hatip and Tos, Tulay and Aksoy, Ayse and De Vivo, Darryl C and Jain, Preti and Geckinli, B Bilge and Sezer, Ozlem and Gul, Davut and Durmaz, Burak and Cogulu, Ozgur and Ozkinay, Ferda and Topcu, Vehap and Candan, Sukru and Cebi, Alper Han and Ikbal, Mevlit and Yilmaz Gulec, Elif and Gezdirici, Alper and Koparir, Erkan and Ekici, Fatma and Coskun, Salih and Cicek, Salih and Karaer, Kadri and Koparir, Asuman and Duz, Mehmet Bugrahan and Kirat, Emre and Fenercioglu, Elif and Ulucan, Hakan and Seven, Mehmet and Guran, Tulay and Elcioglu, Nursel and Yildirim, Mahmut Selman and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Ture, Mehmet and Yakut, Tahsin and Overton, John D and Yuksel, Adnan and Ozen, Mustafa and Muzny, Donna M and Adams, David R and Boerwinkle, Eric and Chung, Wendy K and Gibbs, Richard A and Lupski, James R} } @article {289, title = {Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jan 15}, pages = {397-407}, abstract = {

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

}, keywords = {Adolescent, Child, Exome, Female, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, GTP Phosphohydrolases, Humans, Hypophosphatemia, Male, Membrane Proteins, Mutation, Nevus, Nevus, Pigmented, Osteomalacia, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, Skin, Skin Neoplasms}, issn = {1460-2083}, doi = {10.1093/hmg/ddt429}, author = {Lim, Young H and Ovejero, Diana and Sugarman, Jeffrey S and Deklotz, Cynthia M C and Maruri, Ann and Eichenfield, Lawrence F and Kelley, Patrick K and J{\"u}ppner, Harald and Gottschalk, Michael and Tifft, Cynthia J and Gafni, Rachel I and Boyce, Alison M and Cowen, Edward W and Bhattacharyya, Nisan and Guthrie, Lori C and Gahl, William A and Golas, Gretchen and Loring, Erin C and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Levy, Moise L and Collins, Michael T and Choate, Keith A} } @article {286, title = {Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.}, journal = {J Invest Dermatol}, volume = {134}, year = {2014}, month = {2014 Apr}, pages = {1149-1152}, keywords = {Adherens Junctions, Child, Exome, Female, Genes, ras, Hair, Hair Diseases, Hair Follicle, Humans, Intermediate Filaments, Mosaicism, Mutation, Nevus, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction}, issn = {1523-1747}, doi = {10.1038/jid.2013.430}, author = {Levinsohn, Jonathan L and Teng, Joyce and Craiglow, Brittany G and Loring, Erin C and Burrow, T Andrew and Mane, Shrikant S and Overton, John D and Lifton, Richard P and McNiff, Jennifer M and Lucky, Anne W and Choate, Keith A} } @article {302, title = {De novo mutations in histone-modifying genes in congenital heart disease.}, journal = {Nature}, volume = {498}, year = {2013}, month = {2013 Jun 13}, pages = {220-3}, abstract = {

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8\% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes {\textquoteright}poised{\textquoteright} promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10\% of severe CHD.

}, keywords = {Adult, Case-Control Studies, Child, Chromatin, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Female, Genes, Developmental, Heart Diseases, Histones, Humans, Lysine, Male, Methylation, Mutation, Odds Ratio, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/nature12141}, author = {Zaidi, Samir and Choi, Murim and Wakimoto, Hiroko and Ma, Lijiang and Jiang, Jianming and Overton, John D and Romano-Adesman, Angela and Bjornson, Robert D and Breitbart, Roger E and Brown, Kerry K and Carriero, Nicholas J and Cheung, Yee Him and Deanfield, John and DePalma, Steve and Fakhro, Khalid A and Glessner, Joseph and Hakonarson, Hakon and Italia, Michael J and Kaltman, Jonathan R and Kaski, Juan and Kim, Richard and Kline, Jennie K and Lee, Teresa and Leipzig, Jeremy and Lopez, Alexander and Mane, Shrikant M and Mitchell, Laura E and Newburger, Jane W and Parfenov, Michael and Pe{\textquoteright}er, Itsik and Porter, George and Roberts, Amy E and Sachidanandam, Ravi and Sanders, Stephan J and Seiden, Howard S and State, Mathew W and Subramanian, Sailakshmi and Tikhonova, Irina R and Wang, Wei and Warburton, Dorothy and White, Peter S and Williams, Ismee A and Zhao, Hongyu and Seidman, Jonathan G and Brueckner, Martina and Chung, Wendy K and Gelb, Bruce D and Goldmuntz, Elizabeth and Seidman, Christine E and Lifton, Richard P} } @article {306, title = {Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {531-6}, abstract = {

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.

}, keywords = {Acute Kidney Injury, Atypical Hemolytic Uremic Syndrome, Child, Child, Preschool, Diacylglycerol Kinase, Exome, Female, Genes, Recessive, Hemolytic-Uremic Syndrome, Humans, Immunoenzyme Techniques, Infant, Male, Molecular Sequence Data, Mutation, Renal Insufficiency, Chronic, Thrombocytopenia, Thrombotic Microangiopathies}, issn = {1546-1718}, doi = {10.1038/ng.2590}, author = {Lemaire, Mathieu and Fremeaux-Bacchi, Veronique and Schaefer, Franz and Choi, Murim and Tang, Wai Ho and Le Quintrec, Moglie and Fakhouri, Fadi and Taque, Sophie and Nobili, Fran{\c c}ois and Martinez, Frank and Ji, Weizhen and Overton, John D and Mane, Shrikant M and N{\"u}rnberg, Gudrun and Altm{\"u}ller, Janine and Thiele, Holger and Morin, Denis and Deschenes, Georges and Baudouin, V{\'e}ronique and Llanas, Brigitte and Collard, Laure and Majid, Mohammed A and Simkova, Eva and N{\"u}rnberg, Peter and Rioux-Leclerc, Nathalie and Moeckel, Gilbert W and Gubler, Marie Claire and Hwa, John and Loirat, Chantal and Lifton, Richard P} } @article {293, title = {Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Sep}, pages = {1050-4}, abstract = {

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause \~{}40\% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

}, keywords = {Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Aldosterone, Amino Acid Sequence, Calcium Channels, L-Type, Cell Line, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Hyperaldosteronism, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment}, issn = {1546-1718}, doi = {10.1038/ng.2695}, author = {Scholl, Ute I and Goh, Gerald and St{\"o}lting, Gabriel and de Oliveira, Regina Campos and Choi, Murim and Overton, John D and Fonseca, Annabelle L and Korah, Reju and Starker, Lee F and Kunstman, John W and Prasad, Manju L and Hartung, Erum A and Mauras, Nelly and Benson, Matthew R and Brady, Tammy and Shapiro, Jay R and Loring, Erin and Nelson-Williams, Carol and Libutti, Steven K and Mane, Shrikant and Hellman, Per and Westin, Gunnar and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Fahlke, Christoph and Hidalgo, Patricia and Lifton, Richard P} } @article {318, title = {Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 Mar}, pages = {827-830}, keywords = {Adolescent, Adult, Amino Acid Sequence, Biopsy, Child, Child, Preschool, Cohort Studies, Epidermis, Exome, Humans, Infant, Middle Aged, Molecular Sequence Data, Mutation, Nevus, Sebaceous of Jadassohn, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Sequence Analysis, DNA, Young Adult}, issn = {1523-1747}, doi = {10.1038/jid.2012.379}, author = {Levinsohn, Jonathan L and Tian, Li C and Boyden, Lynn M and McNiff, Jennifer M and Narayan, Deepak and Loring, Erin S and Yun, Duri and Sugarman, Jeffrey L and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Paller, Amy S and Wagner, Annette M and Antaya, Richard J and Choate, Keith A} }