@article {855, title = {Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {40}, year = {2020}, month = {2020 11}, pages = {2738-2746}, abstract = {

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malm{\"o} Diet and Cancer Study, of whom 4122 (14.4\%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16\% for those in the lowest GPS decile to 48\% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

CONCLUSIONS: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

}, keywords = {Adult, Aged, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Heredity, Humans, Incidence, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Prognosis, Risk Assessment, Sweden, Time Factors, United Kingdom}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.120.314856}, author = {Hindy, George and Aragam, Krishna G and Ng, Kenney and Chaffin, Mark and Lotta, Luca A and Baras, Aris and Drake, Isabel and Orho-Melander, Marju and Melander, Olle and Kathiresan, Sekar and Khera, Amit V} } @article {921, title = {Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {158-163}, abstract = {

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

}, keywords = {Aspartic Acid Endopeptidases, Heredity, Heterozygote, Humans, Ichthyosis, Lamellar, Intermediate Filament Proteins, Mutation, Missense, Phenotype, Skin Diseases, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.013}, author = {Boyden, Lynn M and Zhou, Jing and Hu, Ronghua and Zaki, Theodore and Loring, Erin and Scott, Jared and Traupe, Heiko and Paller, Amy S and Lifton, Richard P and Choate, Keith A} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {423, title = {Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {789-802}, abstract = {

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0~{\texttimes} 10 for novel LOF, increased to p = 4.1~{\texttimes} 10 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3~{\texttimes} 10). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

}, keywords = {Alleles, Animals, Case-Control Studies, Clustered Regularly Interspaced Short Palindromic Repeats, Congenital Abnormalities, Exome, Female, Genetic Heterogeneity, Genome-Wide Association Study, Genotype, Heredity, Homozygote, Humans, Kidney, Kidney Diseases, Male, Membrane Proteins, Mice, Mutation, Neoplasm Proteins, Phenotype, RNA, Long Noncoding, Urinary Tract, Urogenital Abnormalities, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.018}, author = {Sanna-Cherchi, Simone and Khan, Kamal and Westland, Rik and Krithivasan, Priya and Fievet, Lorraine and Rasouly, Hila Milo and Ionita-Laza, Iuliana and Capone, Valentina P and Fasel, David A and Kiryluk, Krzysztof and Kamalakaran, Sitharthan and Bodria, Monica and Otto, Edgar A and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Vukojevic, Katarina and Pediaditakis, Igor and Makar, Gabriel S and Mitrotti, Adele and Verbitsky, Miguel and Martino, Jeremiah and Liu, Qingxue and Na, Young-Ji and Goj, Vinicio and Ardissino, Gianluigi and Gigante, Maddalena and Gesualdo, Loreto and Janezcko, Magdalena and Zaniew, Marcin and Mendelsohn, Cathy Lee and Shril, Shirlee and Hildebrandt, Friedhelm and van Wijk, Joanna A E and Arapovic, Adela and Saraga, Marijan and Allegri, Landino and Izzi, Claudia and Scolari, Francesco and Tasic, Velibor and Ghiggeri, Gian Marco and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Mane, Shrikant and Goldstein, David B and Lifton, Richard P and Katsanis, Nicholas and Davis, Erica E and Gharavi, Ali G} } @article {317, title = {Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Dec}, pages = {1370-4}, abstract = {

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

}, keywords = {Adult, Aged, Chromosomal Proteins, Non-Histone, Chromosomes, Human, Pair 18, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Haplotypes, Heredity, Homeodomain Proteins, Humans, Male, Middle Aged, Muscular Dystrophy, Facioscapulohumeral, Mutation}, issn = {1546-1718}, doi = {10.1038/ng.2454}, author = {Lemmers, Richard J L F and Tawil, Rabi and Petek, Lisa M and Balog, Judit and Block, Gregory J and Santen, Gijs W E and Amell, Amanda M and van der Vliet, Patrick J and Almomani, Rowida and Straasheijm, Kirsten R and Krom, Yvonne D and Klooster, Rinse and Sun, Yu and den Dunnen, Johan T and Helmer, Quinta and Donlin-Smith, Colleen M and Padberg, George W and van Engelen, Baziel G M and de Greef, Jessica C and Aartsma-Rus, Annemieke M and Frants, Rune R and de Visser, Marianne and Desnuelle, Claude and Sacconi, Sabrina and Filippova, Galina N and Bakker, Bert and Bamshad, Michael J and Tapscott, Stephen J and Miller, Daniel G and van der Maarel, Silv{\`e}re M} }