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American Journal of Human Genetics

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https://www.readbyqxmd.com/read/29909963/comprehensive-cancer-predisposition-gene-testing-in-an-adult-multiple-primary-tumor-series-shows-a-broad-range-of-deleterious-variants-and-atypical-tumor-phenotypes
#1
James Whitworth, Philip S Smith, Jose-Ezequiel Martin, Hannah West, Andrea Luchetti, Faye Rodger, Graeme Clark, Keren Carss, Jonathan Stephens, Kathleen Stirrups, Chris Penkett, Rutendo Mapeta, Sofie Ashford, Karyn Megy, Hassan Shakeel, Munaza Ahmed, Julian Adlard, Julian Barwell, Carole Brewer, Ruth T Casey, Ruth Armstrong, Trevor Cole, Dafydd Gareth Evans, Florentia Fostira, Lynn Greenhalgh, Helen Hanson, Alex Henderson, Jonathan Hoffman, Louise Izatt, Ajith Kumar, Ava Kwong, Fiona Lalloo, Kai Ren Ong, Joan Paterson, Soo-Mi Park, Rakefet Chen-Shtoyerman, Claire Searle, Lucy Side, Anne-Bine Skytte, Katie Snape, Emma R Woodward, Marc D Tischkowitz, Eamonn R Maher
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families...
June 12, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29909964/neonatal-onset-chronic-diarrhea-caused-by-homozygous-nonsense-wnt2b-mutations
#2
Amy E O'Connell, Fanny Zhou, Manasvi S Shah, Quinn Murphy, Hannah Rickner, Judith Kelsen, John Boyle, Jefferson J Doyle, Bharti Gangwani, Jay R Thiagarajah, Daniel S Kamin, Jeffrey D Goldsmith, Camilla Richmond, David T Breault, Pankaj B Agrawal
Homozygous nonsense mutations in WNT2B were identified in three individuals from two unrelated families with severe, neonatal-onset osmotic diarrhea after whole-exome sequencing was performed on trios from the two families. Intestinal biopsy samples from affected individuals were used for histology and immunofluorescence and to generate enteroids ex vivo. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon. Immunofluorescence demonstrated diminished staining for OLFM4, a marker for intestinal stem cells (ISCs)...
June 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29909962/squalene-synthase-deficiency-clinical-biochemical-and-molecular-characterization-of-a-defect-in-cholesterol-biosynthesis
#3
David Coman, Lisenka E L M Vissers, Lisa G Riley, Michael P Kwint, Roxanna Hauck, Janet Koster, Sinje Geuer, Sarah Hopkins, Barbra Hallinan, Larry Sweetman, Udo F H Engelke, T Andrew Burrow, John Cardinal, James McGill, Anita Inwood, Christine Gurnsey, Hans R Waterham, John Christodoulou, Ron A Wevers, James Pitt
Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect...
June 1, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29887214/using-somatic-mutations-from-tumors-to-classify-variants-in-mismatch-repair-genes
#4
Brian H Shirts, Eric Q Konnick, Sarah Upham, Tom Walsh, John Michael O Ranola, Angela L Jacobson, Mary-Claire King, Rachel Pearlman, Heather Hampel, Colin C Pritchard
Present guidelines for classification of constitutional variants do not incorporate inferences from mutations seen in tumors, even when these are associated with a specific molecular phenotype. When somatic mutations and constitutional mutations lead to the same molecular phenotype, as for the mismatch repair genes, information from somatic mutations may enable interpretation of previously unclassified variants. To test this idea, we first estimated likelihoods that somatic variants in MLH1, MSH2, MSH6, and PMS2 drive microsatellite instability and characteristic IHC staining patterns by calculating likelihoods of high versus low normalized variant read fractions of 153 mutations known to be pathogenic versus those of 760 intronic passenger mutations from 174 paired tumor-normal samples...
May 31, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29887215/recessive-myf5-mutations-cause-external-ophthalmoplegia-rib-and-vertebral-anomalies
#5
Silvio Alessandro Di Gioia, Sherin Shaaban, Beyhan Tüysüz, Nursel H Elcioglu, Wai-Man Chan, Caroline D Robson, Kirsten Ecklund, Nicole M Gilette, Azmi Hamzaoglu, Gulsen Akay Tayfun, Elias I Traboulsi, Elizabeth C Engle
MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models...
May 30, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29861108/de-novo-and-inherited-loss-of-function-variants-in-tlk2-clinical-and-genotype-phenotype-evaluation-of-a-distinct-neurodevelopmental-disorder
#6
Margot R F Reijnders, Kerry A Miller, Mohsan Alvi, Jacqueline A C Goos, Melissa M Lees, Anna de Burca, Alex Henderson, Alison Kraus, Barbara Mikat, Bert B A de Vries, Bertrand Isidor, Bronwyn Kerr, Carlo Marcelis, Caroline Schluth-Bolard, Charu Deshpande, Claudia A L Ruivenkamp, Dagmar Wieczorek, Diana Baralle, Edward M Blair, Hartmut Engels, Hermann-Josef Lüdecke, Jacqueline Eason, Gijs W E Santen, Jill Clayton-Smith, Kate Chandler, Katrina Tatton-Brown, Katelyn Payne, Katherine Helbig, Kelly Radtke, Kimberly M Nugent, Kirsten Cremer, Tim M Strom, Lynne M Bird, Margje Sinnema, Maria Bitner-Glindzicz, Marieke F van Dooren, Marielle Alders, Marije Koopmans, Lauren Brick, Mariya Kozenko, Megan L Harline, Merel Klaassens, Michelle Steinraths, Nicola S Cooper, Patrick Edery, Patrick Yap, Paulien A Terhal, Peter J van der Spek, Phillis Lakeman, Rachel L Taylor, Rebecca O Littlejohn, Rolph Pfundt, Saadet Mercimek-Andrews, Alexander P A Stegmann, Sarina G Kant, Scott McLean, Shelagh Joss, Sigrid M A Swagemakers, Sofia Douzgou, Steven A Wall, Sébastien Küry, Eduardo Calpena, Nils Koelling, Simon J McGowan, Stephen R F Twigg, Irene M J Mathijssen, Christoffer Nellaker, Han G Brunner, Andrew O M Wilkie
Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%)...
May 22, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805043/heterozygous-truncating-variants-in-pomp-escape-nonsense-mediated-decay-and-cause-a-unique-immune-dysregulatory-syndrome
#7
M Cecilia Poli, Frédéric Ebstein, Sarah K Nicholas, Marietta M de Guzman, Lisa R Forbes, Ivan K Chinn, Emily M Mace, Tiphanie P Vogel, Alexandre F Carisey, Felipe Benavides, Zeynep H Coban-Akdemir, Richard A Gibbs, Shalini N Jhangiani, Donna M Muzny, Claudia M B Carvalho, Deborah A Schady, Mahim Jain, Jill A Rosenfeld, Lisa Emrick, Richard A Lewis, Brendan Lee, Barbara A Zieba, Sébastien Küry, Elke Krüger, James R Lupski, Bret L Bostwick, Jordan S Orange
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)...
May 22, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805045/landscape-of-conditional-eqtl-in-dorsolateral-prefrontal-cortex-and-co-localization-with-schizophrenia-gwas
#8
Amanda Dobbyn, Laura M Huckins, James Boocock, Laura G Sloofman, Benjamin S Glicksberg, Claudia Giambartolomei, Gabriel E Hoffman, Thanneer M Perumal, Kiran Girdhar, Yan Jiang, Towfique Raj, Douglas M Ruderfer, Robin S Kramer, Dalila Pinto, Schahram Akbarian, Panos Roussos, Enrico Domenici, Bernie Devlin, Pamela Sklar, Eli A Stahl, Solveig K Sieberts
Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations...
May 21, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805044/risks-and-recommendations-in-prenatally-detected-de-novo-balanced-chromosomal-rearrangements-from-assessment-of-long-term-outcomes
#9
Christina Halgren, Nete M Nielsen, Lusine Nazaryan-Petersen, Asli Silahtaroglu, Ryan L Collins, Chelsea Lowther, Susanne Kjaergaard, Morten Frisch, Maria Kirchhoff, Karen Brøndum-Nielsen, Allan Lind-Thomsen, Yuan Mang, Zahra El-Schich, Claire A Boring, Mana M Mehrjouy, Peter K A Jensen, Christina Fagerberg, Lotte N Krogh, Jan Hansen, Thue Bryndorf, Claus Hansen, Michael E Talkowski, Mads Bak, Niels Tommerup, Iben Bache
The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19...
May 17, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29779563/association-of-polygenic-risk-scores-for-multiple-cancers-in-a-phenome-wide-study-results-from-the-michigan-genomics-initiative
#10
Lars G Fritsche, Stephen B Gruber, Zhenke Wu, Ellen M Schmidt, Matthew Zawistowski, Stephanie E Moser, Victoria M Blanc, Chad M Brummett, Sachin Kheterpal, Gonçalo R Abecasis, Bhramar Mukherjee
Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine...
May 17, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805042/mutations-in-the-epithelial-cadherin-p120-catenin-complex-cause-mendelian-non-syndromic-cleft-lip-with-or-without-cleft-palate
#11
Liza L Cox, Timothy C Cox, Lina M Moreno Uribe, Ying Zhu, Chika T Richter, Nichole Nidey, Jennifer M Standley, Mei Deng, Elizabeth Blue, Jessica X Chong, Yueqin Yang, Russ P Carstens, Deepti Anand, Salil A Lachke, Joshua D Smith, Michael O Dorschner, Bruce Bedell, Edwin Kirk, Anne V Hing, Hanka Venselaar, Luz C Valencia-Ramirez, Michael J Bamshad, Ian A Glass, Jonathan A Cooper, Eric Haan, Deborah A Nickerson, Hans van Bokhoven, Huiqing Zhou, Katy N Krahn, Michael F Buckley, Jeffrey C Murray, Andrew C Lidral, Tony Roscioli
Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance...
May 16, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805041/recessive-spondylocarpotarsal-synostosis-syndrome-due-to-compound-heterozygosity-for-variants-in-myh3
#12
Sophia R Cameron-Christie, Constance F Wells, Marleen Simon, Marja Wessels, Candy Z N Tang, Wenhua Wei, Riku Takei, Coranne Aarts-Tesselaar, Sarah Sandaradura, David O Sillence, Marie-Pierre Cordier, Hermine E Veenstra-Knol, Matteo Cassina, Kathrin Ludkig, Eva Trevisson, Melanie Bahlo, David M Markie, Zandra A Jenkins, Stephen P Robertson
Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype...
May 16, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29754768/mutations-in-ppcs-encoding-phosphopantothenoylcysteine-synthetase-cause-autosomal-recessive-dilated-cardiomyopathy
#13
Arcangela Iuso, Marit Wiersma, Hans-Joachim Schüller, Ben Pode-Shakked, Dina Marek-Yagel, Mathias Grigat, Thomas Schwarzmayr, Riccardo Berutti, Bader Alhaddad, Bart Kanon, Nicola A Grzeschik, Jürgen G Okun, Zeev Perles, Yishay Salem, Ortal Barel, Amir Vardi, Marina Rubinshtein, Tal Tirosh, Gal Dubnov-Raz, Ana C Messias, Caterina Terrile, Iris Barshack, Alex Volkov, Camilla Avivi, Eran Eyal, Elisa Mastantuono, Muhamad Kumbar, Shachar Abudi, Matthias Braunisch, Tim M Strom, Thomas Meitinger, Georg F Hoffmann, Holger Prokisch, Tobias B Haack, Bianca J J M Brundel, Dorothea Haas, Ody C M Sibon, Yair Anikster
Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration...
May 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29754767/preconception-carrier-screening-by-genome-sequencing-results-from-the-clinical-laboratory
#14
Sumit Punj, Yassmine Akkari, Jennifer Huang, Fei Yang, Allison Creason, Christine Pak, Amiee Potter, Michael O Dorschner, Deborah A Nickerson, Peggy D Robertson, Gail P Jarvik, Laura M Amendola, Jennifer Schleit, Dana Kostiner Simpson, Alan F Rope, Jacob Reiss, Tia Kauffman, Marian J Gilmore, Patricia Himes, Benjamin Wilfond, Katrina A B Goddard, C Sue Richards
Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported...
May 3, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29754769/a-statistical-framework-for-mapping-risk-genes-from-de-novo-mutations-in-whole-genome-sequencing-studies
#15
Yuwen Liu, Yanyu Liang, A Ercument Cicek, Zhongshan Li, Jinchen Li, Rebecca A Muhle, Martina Krenzer, Yue Mei, Yan Wang, Nicholas Knoblauch, Jean Morrison, Siming Zhao, Yi Jiang, Evan Geller, Iuliana Ionita-Laza, Jinyu Wu, Kun Xia, James P Noonan, Zhong Sheng Sun, Xin He
Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWASs) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is challenging, however, because the functional significance of non-coding mutations is difficult to predict...
April 30, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29754766/estimation-of-genetic-correlation-via-linkage-disequilibrium-score-regression-and-genomic-restricted-maximum-likelihood
#16
Guiyan Ni, Gerhard Moser, Naomi R Wray, S Hong Lee
Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC...
April 26, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29861107/trpv6-variants-interfere-with-maternal-fetal-calcium-transport-through-the-placenta-and-cause-transient-neonatal-hyperparathyroidism
#17
Yoshiro Suzuki, David Chitayat, Hirotake Sawada, Matthew A Deardorff, Heather M McLaughlin, Amber Begtrup, Kathryn Millar, Jennifer Harrington, Karen Chong, Maian Roifman, Katheryn Grand, Makoto Tominaga, Fumio Takada, Shirley Shuster, Megumi Obara, Hiroshi Mutoh, Reiko Kushima, Gen Nishimura
Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+ -selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent...
June 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29861106/quantifying-the-impact-of-rare-and-ultra-rare-coding-variation-across-the-phenotypic-spectrum
#18
Andrea Ganna, F Kyle Satterstrom, Seyedeh M Zekavat, Indraniel Das, Mitja I Kurki, Claire Churchhouse, Jessica Alfoldi, Alicia R Martin, Aki S Havulinna, Andrea Byrnes, Wesley K Thompson, Philip R Nielsen, Konrad J Karczewski, Elmo Saarentaus, Manuel A Rivas, Namrata Gupta, Olli Pietiläinen, Connor A Emdin, Francesco Lescai, Jonas Bybjerg-Grauholm, Jason Flannick, Josep M Mercader, Miriam Udler, Markku Laakso, Veikko Salomaa, Christina Hultman, Samuli Ripatti, Eija Hämäläinen, Jukka S Moilanen, Jarmo Körkkö, Outi Kuismin, Merete Nordentoft, David M Hougaard, Ole Mors, Thomas Werge, Preben Bo Mortensen, Daniel MacArthur, Mark J Daly, Patrick F Sullivan, Adam E Locke, Aarno Palotie, Anders D Børglum, Sekar Kathiresan, Benjamin M Neale
There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment...
June 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29861105/%C3%AE-iv-spectrinopathies-cause-profound-intellectual-disability-congenital-hypotonia-and-motor-axonal-neuropathy
#19
Chih-Chuan Wang, Xilma R Ortiz-González, Sabrina W Yum, Sara M Gill, Amy White, Erin Kelter, Laurie H Seaver, Sansan Lee, Graham Wiley, Patrick M Gaffney, Klaas J Wierenga, Matthew N Rasband
βIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into βIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding...
June 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29805046/functional-assays-are-essential-for-interpretation-of-missense-variants-associated-with-variable-expressivity
#20
Karen S Raraigh, Sangwoo T Han, Emily Davis, Taylor A Evans, Matthew J Pellicore, Allison F McCague, Anya T Joynt, Zhongzhou Lu, Melis Atalar, Neeraj Sharma, Molly B Sheridan, Patrick R Sosnay, Garry R Cutting
Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression...
June 7, 2018: American Journal of Human Genetics
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