This Month in Genetics
A hallmark of Russell-Silver syndrome (RSS) is the small size of affected individuals. Growth retardation is evident prenatally and continues after birth. One of the genes misregulated in RSS is IGF2, an imprinted gene that encodes insulin-like growth factor II. Although believed to be central to the small size of individuals with this syndrome, Mendelian mutations in this gene have not been described to confirm this prediction—that is, until the recent paper by Begemann et al., who identified related individuals who appeared to have RSS but in whom RSS genetic testing was negative. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors’ Corner Source Type: research

Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans
(The American Journal of Human Genetics 91, 778–793; November 2, 2012) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: David L. Morris, Kimberly E. Taylor, Michelle M.A. Fernando, Joanne Nititham, Marta E. Alarcón-Riquelme, Lisa F. Barcellos, Timothy W. Behrens, Chris Cotsapas, Patrick M. Gaffney, Robert R. Graham, Bernardo A. Pons-Estel, Peter K. Gregersen, Jo Tags: Erratum Source Type: research

This Month in
Craniosynostosis is the premature fusion of the cranial sutures of the skull. In this issue, Twigg and Wilkie review the recent developments in the genetics of craniosynostosis and provide a framework for categorizing the genetic process that can lead to craniosynostosis when defective. In reviewing the genetic defects associated with craniosynostosis, it is notable that mutations causing complete loss of function are rare, and most cases are a result of haploinsufficiency, recessive hypomorphs, and gain-of-function mechanisms. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors’ Corner Source Type: research

Increased Power for Detection of Parent-of-Origin Effects via the Use of Haplotype Estimation
Parent-of-origin (or imprinting) effects relate to the situation in which traits are influenced by the allele inherited from only one parent and the allele from the other parent has little or no effect. Given SNP genotype data from case-parent trios, the parent of origin of each allele in the offspring can often be deduced unambiguously; however, this is not true when all three individuals are heterozygous. Most existing methods for investigating parent-of-origin effects operate on a SNP-by-SNP basis and either perform some sort of averaging over the possible parental transmissions or else discard ambiguous trios. (Source:...
Source: The American Journal of Human Genetics - August 27, 2015 Category: Genetics & Stem Cells Authors: Richard Howey, Chrysovalanto Mamasoula, Ana Töpf, Ron Nudel, Judith A. Goodship, Bernard D. Keavney, Heather J. Cordell Tags: Article Source Type: research

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa
We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 27, 2015 Category: Genetics & Stem Cells Authors: Björn Fischer-Zirnsak, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E. Lin, Inderneel Sahai, Paulina Bahena, Sara L. Reichert, Abigail Loh, Graham D. Wright, Jaron Liu, Elisa Rahikkala, Eniko K. Pivnick, Asim F Tags: Report Source Type: research

Sequence-Level Analysis of the Major European Huntington Disease Haplotype
Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 27, 2015 Category: Genetics & Stem Cells Authors: Jong-Min Lee, Kyung-Hee Kim, Aram Shin, Michael J. Chao, Kawther Abu Elneel, Tammy Gillis, Jayalakshmi Srinidhi Mysore, Julia A. Kaye, Hengameh Zahed, Ian H. Kratter, Aaron C. Daub, Steven Finkbeiner, Hong Li, Jared C. Roach, Nathan Goodman, Leroy Tags: Article Source Type: research

Accurate Non-parametric Estimation of Recent Effective Population Size from Segments of Identity by Descent
We present a non-parametric method for accurately estimating recent effective population size by using inferred long segments of identity by descent (IBD). We found that inferred segments of IBD contain information about effective population size from around 4 generations to around 50 generations ago for SNP array data and to over 200 generations ago for sequence data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 20, 2015 Category: Genetics & Stem Cells Authors: Sharon R. Browning, Brian L. Browning Tags: Article Source Type: research

Mutations in Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss
Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 20, 2015 Category: Genetics & Stem Cells Authors: Akemi J. Tanaka, Megan T. Cho, Francisca Millan, Jane Juusola, Kyle Retterer, Charuta Joshi, Dmitriy Niyazov, Adolfo Garnica, Edward Gratz, Matthew Deardorff, Alisha Wilkins, Xilma Ortiz-Gonzalez, Katherine Mathews, Karin Panzer, Eva Brilstra, Koen L.I Tags: Report Source Type: research

Heterozygous Loss-of-Function Mutations in Cause Adams-Oliver Syndrome
Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pa...
Source: The American Journal of Human Genetics - August 20, 2015 Category: Genetics & Stem Cells Authors: Josephina A.N. Meester, Laura Southgate, Anna-Barbara Stittrich, Hanka Venselaar, Sander J.A. Beekmans, Nicolette den Hollander, Emilia K. Bijlsma, Appolonia Helderman-van den Enden, Joke B.G.M. Verheij, Gustavo Glusman, Jared C. Roach, Anna Lehma Tags: Report Source Type: research

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency
Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed ...
Source: The American Journal of Human Genetics - August 13, 2015 Category: Genetics & Stem Cells Authors: Manfred Fliegauf, Vanessa L. Bryant, Natalie Frede, Charlotte Slade, See-Tarn Woon, Klaus Lehnert, Sandra Winzer, Alla Bulashevska, Thomas Scerri, Euphemia Leung, Anthony Jordan, Baerbel Keller, Esther de Vries, Hongzhi Cao, Fang Yang, Alejandro A. Sch Tags: Article Source Type: research

A Point Mutation in Causes Autosomal-Dominant Penttinen Syndrome
Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Val665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor β. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 13, 2015 Category: Genetics & Stem Cells Authors: Jennifer J. Johnston, Monica Y. Sanchez-Contreras, Kim M. Keppler-Noreuil, Julie Sapp, Molly Crenshaw, NiCole A. Finch, Valerie Cormier-Daire, Rosa Rademakers, Virginia P. Sybert, Leslie G. Biesecker Tags: Report Source Type: research

This Month in Genetics
The idea that creative genius and mental illness can go hand-in-hand is not a new one, but exploring this link from the point of view of overlapping common variation is. Power et al. established a risk-scoring system for schizophrenia and bipolar disorder by using markers identified in multiple prior genome-wide association studies. They next sought an association between these same risk scores and creativity, defined by membership in national artistic societies for endeavors such as dance and visual arts. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 6, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

This Month in
Copy-number variation (CNV) at the 7q11.23 locus results in two distinct neurodevelopmental disorders: deletions give rise to Williams syndrome (WS), whereas the reciprocal CNV causes 7q11.23 duplication syndrome (Dup7). Because the same genes are altered in each, the study of these two disorders can provide insight into the ways in which gene dosage influences human development. In this issue, Strong et al. question whether DNA-methylation changes occur in children with WS and Dup7. Their analyses identified genome-wide, dose-dependent alterations in DNA methylation in both groups of children. (Source: The American J...
Source: The American Journal of Human Genetics - August 6, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Leveraging Functional-Annotation Data in Trans-ethnic Fine-Mapping Studies
(The American Journal of Human Genetics 97, 260–271; August 6, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 6, 2015 Category: Genetics & Stem Cells Authors: Gleb Kichaev, Bogdan Pasaniuc Tags: Erratum Source Type: research

Mutations in Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome
(The American Journal of Human Genetics 97, 311–318; August 6, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 6, 2015 Category: Genetics & Stem Cells Authors: Caroline Alby, Kevin Piquand, Céline Huber, André Megarbané, Amale Ichkou, Marine Legendre, Fanny Pelluard, Ferechté Encha-Ravazi, Georges Abi-Tayeh, Bettina Bessières, Salima El Chehadeh-Djebbar, Nicole Laurent, Laurence Faivre, László Sztriha, M Tags: Erratum Source Type: research

Mutations in Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. (Sou...
Source: The American Journal of Human Genetics - July 30, 2015 Category: Genetics & Stem Cells Authors: Asaf Vivante, Marc-Jens Kleppa, Julian Schulz, Stefan Kohl, Amita Sharma, Jing Chen, Shirlee Shril, Daw-Yang Hwang, Anna-Carina Weiss, Michael M. Kaminski, Rachel Shukrun, Markus J. Kemper, Anja Lehnhardt, Rolf Beetz, Simone Sanna-Cherchi, Miguel Verbit Tags: Article Source Type: research

Incorporating Functional Information in Tests of Excess De Novo Mutational Load
A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 30, 2015 Category: Genetics & Stem Cells Authors: Yu Jiang, Yujun Han, Slavé Petrovski, Kouros Owzar, David B. Goldstein, Andrew S. Allen Tags: Article Source Type: research

Correcting for Sample Contamination in Genotype Calling of DNA Sequence Data
DNA sample contamination is a frequent problem in DNA sequencing studies and can result in genotyping errors and reduced power for association testing. We recently described methods to identify within-species DNA sample contamination based on sequencing read data, showed that our methods can reliably detect and estimate contamination levels as low as 1%, and suggested strategies to identify and remove contaminated samples from sequencing studies. Here we propose methods to model contamination during genotype calling as an alternative to removal of contaminated samples from further analyses. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 30, 2015 Category: Genetics & Stem Cells Authors: Matthew Flickinger, Goo Jun, Gonçalo R. Abecasis, Michael Boehnke, Hyun Min Kang Tags: Article Source Type: research

Mutations in Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling
In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 30, 2015 Category: Genetics & Stem Cells Authors: Lot Snijders Blok, Erik Madsen, Jane Juusola, Christian Gilissen, Diana Baralle, Margot R.F. Reijnders, Hanka Venselaar, Céline Helsmoortel, Megan T. Cho, Alexander Hoischen, Lisenka E.L.M. Vissers, Tom S. Koemans, Willemijn Wissink-Lindhout, Evan E Tags: Report Source Type: research

Long-Range Modulation of Expression by 8q21 Allergy Risk Variants
The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the...
Source: The American Journal of Human Genetics - July 23, 2015 Category: Genetics & Stem Cells Authors: Cristina T. Vicente, Stacey L. Edwards, Kristine M. Hillman, Susanne Kaufmann, Hayley Mitchell, Lisa Bain, Dylan M. Glubb, Jason S. Lee, Juliet D. French, Manuel A.R. Ferreira Tags: Report Source Type: research

A Functional SNP in Is Associated with Adolescent Idiopathic Scoliosis
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10−13; odds ratio = 1.21). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 23, 2015 Category: Genetics & Stem Cells Authors: Yoji Ogura, Ikuyo Kou, Shigenori Miura, Atsushi Takahashi, Leilei Xu, Kazuki Takeda, Yohei Takahashi, Katsuki Kono, Noriaki Kawakami, Koki Uno, Manabu Ito, Shohei Minami, Ikuho Yonezawa, Haruhisa Yanagida, Hiroshi Taneichi, Zezhang Zhu, Taichi Tsuji, Tepp Tags: Report Source Type: research

Decoding Intragenic Copy-Number Variations
Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 16, 2015 Category: Genetics & Stem Cells Authors: Meng-Chang Hsiao, Arkadiusz Piotrowski, Tom Callens, Chuanhua Fu, Katharina Wimmer, Kathleen B.M. Claes, Ludwine Messiaen Tags: Article Source Type: research

A Fast Method that Uses Polygenic Scores to Estimate the Variance Explained by Genome-wide Marker Panels and the Proportion of Variants Affecting a Trait
Several methods have been proposed to estimate the variance in disease liability explained by large sets of genetic markers. However, current methods do not scale up well to large sample sizes. Linear mixed models require solving high-dimensional matrix equations, and methods that use polygenic scores are very computationally intensive. Here we propose a fast analytic method that uses polygenic scores, based on the formula for the non-centrality parameter of the association test of the score. We estimate model parameters from the results of multiple polygenic score tests based on markers with p values in different interval...
Source: The American Journal of Human Genetics - July 16, 2015 Category: Genetics & Stem Cells Authors: Luigi Palla, Frank Dudbridge Tags: Article Source Type: research

Leveraging Functional-Annotation Data in Trans-ethnic Fine-Mapping Studies
Localization of causal variants underlying known risk loci is one of the main research challenges following genome-wide association studies. Risk loci are typically dissected through fine-mapping experiments in trans-ethnic cohorts for leveraging the variability in the local genetic structure across populations. More recent works have shown that genomic functional annotations (i.e., localization of tissue-specific regulatory marks) can be integrated for increasing fine-mapping performance within single-population studies. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 16, 2015 Category: Genetics & Stem Cells Authors: Gleb Kichaev, Bogdan Pasaniuc Tags: Article Source Type: research

Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies
Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. (Source: The A...
Source: The American Journal of Human Genetics - July 16, 2015 Category: Genetics & Stem Cells Authors: Christopher A. Powell, Robert Kopajtich, Aaron R. D’Souza, Joanna Rorbach, Laura S. Kremer, Ralf A. Husain, Cristina Dallabona, Claudia Donnini, Charlotte L. Alston, Helen Griffin, Angela Pyle, Patrick F. Chinnery, Tim M. Strom, Thomas Meitinger, Tags: Report Source Type: research

Symmetrical Dose-Dependent DNA-Methylation Profiles in Children with Deletion or Duplication of 7q11.23
Epigenetic dysfunction has been implicated in a growing list of disorders that include cancer, neurodevelopmental disorders, and neurodegeneration. Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders with broad phenotypic spectra caused by deletion and duplication, respectively, of a 1.5-Mb region that includes several genes with a role in epigenetic regulation. We have identified striking differences in DNA methylation across the genome between blood cells from children with WS or Dup7 and blood cells from typically developing (TD) children. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 9, 2015 Category: Genetics & Stem Cells Authors: Emma Strong, Darci T. Butcher, Rajat Singhania, Carolyn B. Mervis, Colleen A. Morris, Daniel De Carvalho, Rosanna Weksberg, Lucy R. Osborne Tags: Article Source Type: research

Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability
Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 9, 2015 Category: Genetics & Stem Cells Authors: Raman Kumar, Mark A. Corbett, Bregje W.M. van Bon, Joshua A. Woenig, Lloyd Weir, Evelyn Douglas, Kathryn L. Friend, Alison Gardner, Marie Shaw, Lachlan A. Jolly, Chuan Tan, Matthew F. Hunter, Anna Hackett, Michael Field, Elizabeth E. Palmer, Melan Tags: Report Source Type: research

Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages
Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4–0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10−9)....
Source: The American Journal of Human Genetics - July 9, 2015 Category: Genetics & Stem Cells Authors: Paraskevi Christofidou, Christopher P. Nelson, Majid Nikpay, Liming Qu, Mingyao Li, Christina Loley, Radoslaw Debiec, Peter S. Braund, Matthew Denniff, Fadi J. Charchar, Ares Rocanin Arjo, David-Alexandre Trégouët, Alison H. Goodall, Francois Cambi Tags: Article Source Type: research

Mutations in Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome
KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 ...
Source: The American Journal of Human Genetics - July 9, 2015 Category: Genetics & Stem Cells Authors: Caroline Alby, Kevin Piquand, Céline Huber, André Megarbané, Amale Ichkou, Marine Legendre, Fanny Pelluard, Ferechté Encha-Ravazi, Georges Abi Tayeh, Bettina Bessières, Salima El Chehadeh-Djebbar, Nicole Laurent, Laurence Faivre, László Sztriha, Tags: Report Source Type: research

The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. (Source: The Ame...
Source: The American Journal of Human Genetics - July 9, 2015 Category: Genetics & Stem Cells Authors: Jessica X. Chong, Kati J. Buckingham, Shalini N. Jhangiani, Corinne Boehm, Nara Sobreira, Joshua D. Smith, Tanya M. Harrell, Margaret J. McMillin, Wojciech Wiszniewski, Tomasz Gambin, Zeynep H. Coban Akdemir, Kimberly Doheny, Alan F. Scott, Dimit Tags: Review Source Type: research

A Joint Location-Scale Test Improves Power to Detect Associated SNPs, Gene Sets, and Pathways
Gene-based, pathway, and other multivariate association methods are motivated by the possibility of GxG and GxE interactions; however, accounting for such interactions is limited by the challenges associated with adequate modeling information. Here we propose an easy-to-implement joint location-scale (JLS) association testing framework for single-variant and multivariate analysis that accounts for interactions without explicitly modeling them. We apply the JLS method to a gene-set analysis of cystic fibrosis (CF) lung disease, which is influenced by multiple environmental and genetic factors. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: David Soave, Harriet Corvol, Naim Panjwani, Jiafen Gong, Weili Li, Pierre-Yves Boëlle, Peter R. Durie, Andrew D. Paterson, Johanna M. Rommens, Lisa J. Strug, Lei Sun Tags: Article Source Type: research

Disentangling the Effects of Colocalizing Genomic Annotations to Functionally Prioritize Non-coding Variants within Complex-Trait Loci
Identifying genomic annotations that differentiate causal from trait-associated variants is essential to fine mapping disease loci. Although many studies have identified non-coding functional annotations that overlap disease-associated variants, these annotations often colocalize, complicating the ability to use these annotations for fine mapping causal variation. We developed a statistical approach (Genomic Annotation Shifter [GoShifter]) to assess whether enriched annotations are able to prioritize causal variation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: Gosia Trynka, Harm-Jan Westra, Kamil Slowikowski, Xinli Hu, Han Xu, Barbara E. Stranger, Robert J. Klein, Buhm Han, Soumya Raychaudhuri Tags: Article Source Type: research

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents
In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: Jeffrey R. Botkin, John W. Belmont, Jonathan S. Berg, Benjamin E. Berkman, Yvonne Bombard, Ingrid A. Holm, Howard P. Levy, Kelly E. Ormond, Howard M. Saal, Nancy B. Spinner, Benjamin S. Wilfond, Joseph D. McInerney Tags: ASHG Position Statement Source Type: research

This Month in Genetics
Our initial view of genetic syndromes is often biased by the collection of the most severely affected individuals as a syndrome is first described. For genomic disorders, which are caused by copy-number variation (CNV), reduced penetrance and variable expression are almost the rule rather than the exception, and fully delineating this phenotypic variability is difficult, yet it is crucial for genetic counseling. The design of a recent survey by Männik et al. gets around some of these issues through the use of an unselected Estonian population for which they had extensive health and education information. (Source:...
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors’ Corner Source Type: research

This Month in
Efforts aimed at gaining insight into the genetic architecture of complex-trait disorders turn, with increasing frequency, to rare-variant association studies (RVASs). Indeed, in recent years, many methods have been developed to detect rare variants that influence human traits. The increase in large-scale sequencing studies suggests that like genome-wide association studies (GWASs), which study the association between common variants and complex phenotypes, successful implementation of RVASs might rely on the integration of data obtained from multiple groups. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors’ Corner Source Type: research

F. Clarke Fraser (1920–2014)
In the summer of 1967, I was lucky enough to spend the summer as a medical student in the laboratory of Dr. Charles Scriver at the Montreal Children’s Hospital. It was at this time that I had the privilege of first interacting with the other legend of human genetics in Canada, F. Clarke Fraser. McGill University was indeed fortunate to have these two giants in the same institution at the same time. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2015 Category: Genetics & Stem Cells Authors: David S. Rosenblatt Tags: Obituary Source Type: research

Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations
We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the vari...
Source: The American Journal of Human Genetics - June 25, 2015 Category: Genetics & Stem Cells Authors: Sonia Shah, Marc J. Bonder, Riccardo E. Marioni, Zhihong Zhu, Allan F. McRae, Alexandra Zhernakova, Sarah E. Harris, Dave Liewald, Anjali K. Henders, Michael M. Mendelson, Chunyu Liu, Roby Joehanes, Liming Liang, BIOS Consortium, Daniel Levy, Nichol Tags: Article Source Type: research

Recurrent Mutations in the Basic Domain of Cause Ablepharon Macrostomia and Barber-Say Syndromes
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 25, 2015 Category: Genetics & Stem Cells Authors: Shannon Marchegiani, Taylor Davis, Federico Tessadori, Gijs van Haaften, Francesco Brancati, Alexander Hoischen, Haigen Huang, Elise Valkanas, Barbara Pusey, Denny Schanze, Hanka Venselaar, Anneke T. Vulto-van Silfhout, Lynne A. Wolfe, Cynthia J. Tif Tags: Article Source Type: research

A Powerful Pathway-Based Adaptive Test for Genetic Association with Common or Rare Variants
In spite of the success of genome-wide association studies (GWASs), only a small proportion of heritability for each complex trait has been explained by identified genetic variants, mainly SNPs. Likely reasons include genetic heterogeneity (i.e., multiple causal genetic variants) and small effect sizes of causal variants, for which pathway analysis has been proposed as a promising alternative to the standard single-SNP-based analysis. A pathway contains a set of functionally related genes, each of which includes multiple SNPs. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 25, 2015 Category: Genetics & Stem Cells Authors: Wei Pan, Il-Youp Kwak, Peng Wei Tags: Article Source Type: research

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease
The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 25, 2015 Category: Genetics & Stem Cells Authors: Tudor Groza, Sebastian Köhler, Dawid Moldenhauer, Nicole Vasilevsky, Gareth Baynam, Tomasz Zemojtel, Lynn Marie Schriml, Warren Alden Kibbe, Paul N. Schofield, Tim Beck, Drashtti Vasant, Anthony J. Brookes, Andreas Zankl, Nicole L. Washington, Chris Tags: Article Source Type: research

Meta-analysis for Discovering Rare-Variant Associations: Statistical Methods and Software Programs
There is heightened interest in using next-generation sequencing technologies to identify rare variants that influence complex human diseases and traits. Meta-analysis is essential to this endeavor because large sample sizes are required for detecting associations with rare variants. In this article, we provide a comprehensive overview of statistical methods for meta-analysis of sequencing studies for discovering rare-variant associations. Specifically, we discuss the calculation of relevant summary statistics from participating studies, the construction of gene-level association tests, the choice of transformation for qua...
Source: The American Journal of Human Genetics - June 18, 2015 Category: Genetics & Stem Cells Authors: Zheng-Zheng Tang, Dan-Yu Lin Tags: Article Source Type: research

Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation
Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 18, 2015 Category: Genetics & Stem Cells Authors: Harrison Brand, Ryan L. Collins, Carrie Hanscom, Jill A. Rosenfeld, Vamsee Pillalamarri, Matthew R. Stone, Fontina Kelley, Tamara Mason, Lauren Margolin, Stacey Eggert, Elyse Mitchell, Jennelle C. Hodge, James F. Gusella, Stephan J. Sanders, Michael Tags: Report Source Type: research

Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy
Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 18, 2015 Category: Genetics & Stem Cells Authors: Aurelio Reyes, Laura Melchionda, Alessia Nasca, Franco Carrara, Eleonora Lamantea, Alice Zanolini, Costanza Lamperti, Mingyan Fang, Jianguo Zhang, Dario Ronchi, Sara Bonato, Gigliola Fagiolari, Maurizio Moggio, Daniele Ghezzi, Massimo Zeviani Tags: Report Source Type: research

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate Expression
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 11, 2015 Category: Genetics & Stem Cells Authors: Hatef Darabi, Karen McCue, Jonathan Beesley, Kyriaki Michailidou, Silje Nord, Siddhartha Kar, Keith Humphreys, Deborah Thompson, Maya Ghoussaini, Manjeet K. Bolla, Joe Dennis, Qin Wang, Sander Canisius, Christopher G. Scott, Carmel Apicella, John L. Ho Tags: Article Source Type: research

Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes
Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive condition resulting from structural and/or functional defects of the axoneme in motile cilia and sperm flagella. The great majority of mutations identified so far involve genes whose defects result in dynein-arm anomalies. By contrast, PCD due to CC/RS defects (those in the central complex [CC] and radial spokes [RSs]), which might be difficult to diagnose, remains mostly unexplained. We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 11, 2015 Category: Genetics & Stem Cells Authors: Ludovic Jeanson, Bruno Copin, Jean-François Papon, Florence Dastot-Le Moal, Philippe Duquesnoy, Guy Montantin, Jacques Cadranel, Harriet Corvol, André Coste, Julie Désir, Anissa Souayah, Esther Kott, Nathalie Collot, Sylvie Tissier, Bruno Louis, Aline Tags: Report Source Type: research

A 3.4-kb Copy-Number Deletion near Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p
Source: The American Journal of Human Genetics - June 11, 2015 Category: Genetics & Stem Cells Authors: Haiyi Lou, Yan Lu, Dongsheng Lu, Ruiqing Fu, Xiaoji Wang, Qidi Feng, Sijie Wu, Yajun Yang, Shilin Li, Longli Kang, Yaqun Guan, Boon-Peng Hoh, Yeun-Jun Chung, Li Jin, Bing Su, Shuhua Xu Tags: Article Source Type: research

Biallelic Mutations in Cause Recurrent Acute Liver Failure with Onset in Infancy
Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 11, 2015 Category: Genetics & Stem Cells Authors: Tobias B. Haack, Christian Staufner, Marlies G. Köpke, Beate K. Straub, Stefan Kölker, Christian Thiel, Peter Freisinger, Ivo Baric, Patrick J. McKiernan, Nicola Dikow, Inga Harting, Flemming Beisse, Peter Burgard, Urania Kotzaeridou, Joachim Kühr, Tags: Report Source Type: research

Loss-of-Function Mutations in in Familial Diabetes Mellitus
Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552∗] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing ...
Source: The American Journal of Human Genetics - June 11, 2015 Category: Genetics & Stem Cells Authors: Sabrina Prudente, Prapaporn Jungtrakoon, Antonella Marucci, Ornella Ludovico, Patinut Buranasupkajorn, Tommaso Mazza, Timothy Hastings, Teresa Milano, Eleonora Morini, Luana Mercuri, Diego Bailetti, Christine Mendonca, Federica Alberico, Giorgio Basile, M Tags: Report Source Type: research

Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation
De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 5, 2015 Category: Genetics & Stem Cells Authors: Rocio Acuna-Hidalgo, Tan Bo, Michael P. Kwint, Maartje van de Vorst, Michele Pinelli, Joris A. Veltman, Alexander Hoischen, Lisenka E.L.M. Vissers, Christian Gilissen Tags: Article Source Type: research

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations
Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 4, 2015 Category: Genetics & Stem Cells Authors: Jennifer J. Johnston, Katie L. Lewis, David Ng, Larry N. Singh, Jamila Wynter, Carmen Brewer, Brian P. Brooks, Isaac Brownell, Fabio Candotti, Steven G. Gonsalves, Suzanne P. Hart, Heidi H. Kong, Kristina I. Rother, Robert Sokolic, Benjamin D. So Tags: Article Source Type: research