@article {380, title = {Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 11}, pages = {1246-1252}, abstract = {

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

}, keywords = {Adult, Aged, Antigens, CD, Cadherins, Early Detection of Cancer, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Male, Middle Aged, Sequence Analysis, DNA, Stomach Neoplasms}, issn = {1476-5438}, doi = {10.1038/ejhg.2017.138}, author = {Vogelaar, Ingrid P and van der Post, Rachel S and van Krieken, J Han Jm and Spruijt, Liesbeth and van Zelst-Stams, Wendy Ag and Kets, C Marleen and Lubinski, Jan and Jakubowska, Anna and Teodorczyk, Urszula and Aalfs, Cora M and van Hest, Liselotte P and Pinheiro, Hugo and Oliveira, Carla and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and de Ligt, Joep and Vissers, Lisenka E L M and Hoischen, Alexander and Gilissen, Christian and van de Vorst, Maartje and Goeman, Jelle J and Schackert, Hans K and Ranzani, Guglielmina N and Molinaro, Valeria and G{\'o}mez Garc{\'\i}a, Encarna B and Hes, Frederik J and Holinski-Feder, Elke and Genuardi, Maurizio and Ausems, Margreet G E M and Sijmons, Rolf H and Wagner, Anja and van der Kolk, Lizet E and Bj{\o}rnevoll, Inga and H{\o}berg-Vetti, Hildegunn and van Kessel, Ad Geurts and Kuiper, Roland P and Ligtenberg, Marjolijn J L and Hoogerbrugge, Nicoline} } @article {67, title = {Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 May}, pages = {569-586}, abstract = {

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

}, keywords = {Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Female, Forkhead Transcription Factors, Genes, Lethal, Genome, Human, Genomic Imprinting, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Pedigree, Persistent Fetal Circulation Syndrome, Pulmonary Alveoli, Pulmonary Veins, Sequence Deletion}, issn = {1432-1203}, doi = {10.1007/s00439-016-1655-9}, author = {Szafranski, Przemyslaw and Gambin, Tomasz and Dharmadhikari, Avinash V and Akdemir, Kadir Caner and Jhangiani, Shalini N and Schuette, Jennifer and Godiwala, Nihal and Yatsenko, Svetlana A and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Surti, Urvashi and Abellar, Rosanna G and Bateman, David A and Wilson, Ashley L and Markham, Melinda H and Slamon, Jill and Santos-Simarro, Fernando and Palomares, Mar{\'\i}a and Nevado, Juli{\'a}n and Lapunzina, Pablo and Chung, Brian Hon-Yin and Wong, Wai-Lap and Chu, Yoyo Wing Yiu and Mok, Gary Tsz Kin and Kerem, Eitan and Reiter, Joel and Ambalavanan, Namasivayam and Anderson, Scott A and Kelly, David R and Shieh, Joseph and Rosenthal, Taryn C and Scheible, Kristin and Steiner, Laurie and Iqbal, M Anwar and McKinnon, Margaret L and Hamilton, Sara Jane and Schlade-Bartusiak, Kamilla and English, Dawn and Hendson, Glenda and Roeder, Elizabeth R and DeNapoli, Thomas S and Littlejohn, Rebecca Okashah and Wolff, Daynna J and Wagner, Carol L and Yeung, Alison and Francis, David and Fiorino, Elizabeth K and Edelman, Morris and Fox, Joyce and Hayes, Denise A and Janssens, Sandra and De Baere, Elfride and Menten, Bj{\"o}rn and Loccufier, Anne and Vanwalleghem, Lieve and Moerman, Philippe and Sznajer, Yves and Lay, Amy S and Kussmann, Jennifer L and Chawla, Jasneek and Payton, Diane J and Phillips, Gael E and Brosens, Erwin and Tibboel, Dick and de Klein, Annelies and Maystadt, Isabelle and Fisher, Richard and Sebire, Neil and Male, Alison and Chopra, Maya and Pinner, Jason and Malcolm, Girvan and Peters, Gregory and Arbuckle, Susan and Lees, Melissa and Mead, Zoe and Quarrell, Oliver and Sayers, Richard and Owens, Martina and Shaw-Smith, Charles and Lioy, Janet and McKay, Eileen and de Leeuw, Nicole and Feenstra, Ilse and Spruijt, Liesbeth and Elmslie, Frances and Thiruchelvam, Timothy and Bacino, Carlos A and Langston, Claire and Lupski, James R and Sen, Partha and Popek, Edwina and Stankiewicz, Pawe{\l}} } @article {122, title = {Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {647-60}, abstract = {

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In~vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In~vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

}, keywords = {Alleles, Animals, Female, Fluorescent Antibody Technique, Genetic Linkage, Hearing Loss, Unilateral, Humans, Male, Mice, Mutation, NIH 3T3 Cells, Pedigree, Phenotype, Prognosis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Stem Cell Factor, Waardenburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.09.011}, author = {Zazo Seco, Celia and Serr{\~a}o de Castro, Luciana and van Nierop, Josephine W and Mor{\'\i}n, Mat{\'\i}as and Jhangiani, Shalini and Verver, Eva J J and Schraders, Margit and Maiwald, Nadine and Wesdorp, Mieke and Venselaar, Hanka and Spruijt, Liesbeth and Oostrik, Jaap and Schoots, Jeroen and van Reeuwijk, Jeroen and Lelieveld, Stefan H and Huygen, Patrick L M and Insenser, Mar{\'\i}a and Admiraal, Ronald J C and Pennings, Ronald J E and Hoefsloot, Lies H and Arias-V{\'a}squez, Alejandro and de Ligt, Joep and Yntema, Helger G and Jansen, Joop H and Muzny, Donna M and Huls, Gerwin and van Rossum, Michelle M and Lupski, James R and Moreno-Pelayo, Miguel Angel and Kunst, Henricus P M and Kremer, Hannie} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} }