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May 03, 2018

Volume 102Issue 5p715-1008
Open Archive

Editors' Corner

  • This Month in The Journal

    • Sarah Ratzel,
    • Sara B. Cullinan
    Large-scale sequencing projects have provided great insights into human genetic diversity, disease susceptibility, and demographic history. To a large extent, however, such studies have focused on individuals of European descent. Recent efforts, including the H3Africa Initiative, aim to expand genomic studies of African populations with a view toward improving health outcomes as well as our overall understanding of human genetic diversity. In this issue, Retshabile et al. report their findings of a whole-exome sequencing project focused on residents of the southern African nation of Botswana.

Review

  • The Post-GWAS Era: From Association to Function

    • Michael D. Gallagher,
    • Alice S. Chen-Plotkin
    During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. We highlight the evidence suggesting that causal variants underlying disease risk often function through regulatory effects on the expression of target genes and that these expression effects might be modest and cell-type specific.

Articles

  • Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana

    • Gaone Retshabile,
    • Busisiwe C. Mlotshwa,
    • Lesedi Williams,
    • Savannah Mwesigwa,
    • Gerald Mboowa,
    • Zhuoyi Huang,
    • Navin Rustagi,
    • Shanker Swaminathan,
    • Eric Katagirya,
    • Samuel Kyobe,
    • Misaki Wayengera,
    • Grace P. Kisitu,
    • David P. Kateete,
    • Eddie M. Wampande,
    • Koketso Maplanka,
    • Ishmael Kasvosve,
    • Edward D. Pettitt,
    • Mogomotsi Matshaba,
    • Betty Nsangi,
    • Marape Marape,
    • Masego Tsimako-Johnstone,
    • Chester W. Brown,
    • Fuli Yu,
    • Adeodata Kekitiinwa,
    • Moses Joloba,
    • Sununguko W. Mpoloka,
    • Graeme Mardon,
    • Gabriel Anabwani,
    • Neil A. Hanchard
    • for the Collaborative African Genomics Network (CAfGEN) of the H3Africa Consortium
    Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana—a Southern African country that is regionally underrepresented in genomic databases.
  • Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

    • Claire Guissart,
    • Xenia Latypova,
    • Paul Rollier,
    • Tahir N. Khan,
    • Hannah Stamberger,
    • Kirsty McWalter,
    • Megan T. Cho,
    • Susanne Kjaergaard,
    • Sarah Weckhuysen,
    • Gaetan Lesca,
    • Thomas Besnard,
    • Katrin Õunap,
    • Lynn Schema,
    • Andreas G. Chiocchetti,
    • Marie McDonald,
    • Julitta de Bellescize,
    • Marie Vincent,
    • Hilde Van Esch,
    • Shannon Sattler,
    • Irman Forghani,
    • Isabelle Thiffault,
    • Christine M. Freitag,
    • Deborah Sara Barbouth,
    • Maxime Cadieux-Dion,
    • Rebecca Willaert,
    • Maria J. Guillen Sacoto,
    • Nicole P. Safina,
    • Christèle Dubourg,
    • Lauren Grote,
    • Wilfrid Carré,
    • Carol Saunders,
    • Sander Pajusalu,
    • Emily Farrow,
    • Anne Boland,
    • Danielle Hays Karlowicz,
    • Jean-François Deleuze,
    • Monica H. Wojcik,
    • Rena Pressman,
    • Bertrand Isidor,
    • Annick Vogels,
    • Wim Van Paesschen,
    • Lihadh Al-Gazali,
    • Aisha Mohamed Al Shamsi,
    • Mireille Claustres,
    • Aurora Pujol,
    • Stephan J. Sanders,
    • François Rivier,
    • Nicolas Leboucq,
    • Benjamin Cogné,
    • Souphatta Sasorith,
    • Damien Sanlaville,
    • Kyle Retterer,
    • Sylvie Odent,
    • Nicholas Katsanis,
    • Stéphane Bézieau,
    • Michel Koenig,
    • Erica E. Davis,
    • Laurent Pasquier,
    • Sébastien Küry
    RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy.
  • Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland

    • Alicia R. Martin,
    • Konrad J. Karczewski,
    • Sini Kerminen,
    • Mitja I. Kurki,
    • Antti-Pekka Sarin,
    • Mykyta Artomov,
    • Johan G. Eriksson,
    • Tõnu Esko,
    • Giulio Genovese,
    • Aki S. Havulinna,
    • Jaakko Kaprio,
    • Alexandra Konradi,
    • László Korányi,
    • Anna Kostareva,
    • Minna Männikkö,
    • Andres Metspalu,
    • Markus Perola,
    • Rashmi B. Prasad,
    • Olli Raitakari,
    • Oxana Rotar,
    • Veikko Salomaa,
    • Leif Groop,
    • Aarno Palotie,
    • Benjamin M. Neale,
    • Samuli Ripatti,
    • Matti Pirinen,
    • Mark J. Daly
    Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories.
  • An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation

    • Xiao-Feng Chen,
    • Dong-Li Zhu,
    • Man Yang,
    • Wei-Xin Hu,
    • Yuan-Yuan Duan,
    • Bing-Jie Lu,
    • Yu Rong,
    • Shan-Shan Dong,
    • Ruo-Han Hao,
    • Jia-Bin Chen,
    • Yi-Xiao Chen,
    • Shi Yao,
    • Hlaing Nwe Thynn,
    • Yan Guo,
    • Tie-Lin Yang
    Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region.
  • Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

    • Dong Wang,
    • Yu Fan,
    • Mahadev Malhi,
    • Rui Bi,
    • Yong Wu,
    • Min Xu,
    • Xiu-Feng Yu,
    • Heng Long,
    • Yu-Ye Li,
    • Deng-Feng Zhang,
    • Yong-Gang Yao
    Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China.
  • Patterns of Genetic Coding Variation in a Native American Population before and after European Contact

    • John Lindo,
    • Mary Rogers,
    • Elizabeth K. Mallott,
    • Barbara Petzelt,
    • Joycelynn Mitchell,
    • David Archer,
    • Jerome S. Cybulski,
    • Ripan S. Malhi,
    • Michael DeGiorgio
    The effects of European colonization on the genomes of Native Americans may have produced excesses of potentially deleterious features, mainly due to the severe reductions in population size and corresponding losses of genetic diversity. This assumption, however, neither considers actual genomic patterns that existed before colonization nor does it adequately capture the effects of admixture. In this study, we analyze the whole-exome sequences of modern and ancient individuals from a Northwest Coast First Nation, with a demographic history similar to other indigenous populations from the Americas.
  • Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms

    • Thomas A. Forbes,
    • Sara E. Howden,
    • Kynan Lawlor,
    • Belinda Phipson,
    • Jovana Maksimovic,
    • Lorna Hale,
    • Sean Wilson,
    • Catherine Quinlan,
    • Gladys Ho,
    • Katherine Holman,
    • Bruce Bennetts,
    • Joanna Crawford,
    • Peter Trnka,
    • Alicia Oshlack,
    • Chirag Patel,
    • Andrew Mallett,
    • Cas Simons,
    • Melissa H. Little
    Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies.
  • Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease

    • Emilie Cornec-Le Gall,
    • Rory J. Olson,
    • Whitney Besse,
    • Christina M. Heyer,
    • Vladimir G. Gainullin,
    • Jessica M. Smith,
    • Marie-Pierre Audrézet,
    • Katharina Hopp,
    • Binu Porath,
    • Beili Shi,
    • Saurabh Baheti,
    • Sarah R. Senum,
    • Jennifer Arroyo,
    • Charles D. Madsen,
    • Claude Férec,
    • Dominique Joly,
    • François Jouret,
    • Oussamah Fikri-Benbrahim,
    • Christophe Charasse,
    • Jean-Marie Coulibaly,
    • Alan S. Yu,
    • Korosh Khalili,
    • York Pei,
    • Stefan Somlo,
    • Yannick Le Meur,
    • Vicente E. Torres,
    • Genkyst Study Group,
    • the HALT Progression of Polycystic Kidney Disease Group,
    • the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease,
    • Peter C. Harris
    Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts.
  • The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance

    • Fleur C. Garton,
    • Peter J. Houweling,
    • Damjan Vukcevic,
    • Lyra R. Meehan,
    • Fiona X.Z. Lee,
    • Monkol Lek,
    • Kelly N. Roeszler,
    • Marshall W. Hogarth,
    • Chrystal F. Tiong,
    • Diana Zannino,
    • Nan Yang,
    • Stephen Leslie,
    • Paul Gregorevic,
    • Stewart I. Head,
    • Jane T. Seto,
    • Kathryn N. North
    Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3–1.6) but substantial heterogeneity in heterozygotes.
  • Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

    • David T. Burns,
    • Sandra Donkervoort,
    • Juliane S. Müller,
    • Ellen Knierim,
    • Diana Bharucha-Goebel,
    • Eissa Ali Faqeih,
    • Stephanie K. Bell,
    • Abdullah Y. AlFaifi,
    • Dorota Monies,
    • Francisca Millan,
    • Kyle Retterer,
    • Sarah Dyack,
    • Sara MacKay,
    • Susanne Morales-Gonzalez,
    • Michele Giunta,
    • Benjamin Munro,
    • Gavin Hudson,
    • Mena Scavina,
    • Laura Baker,
    • Tara C. Massini,
    • Monkol Lek,
    • Ying Hu,
    • Daniel Ezzo,
    • Fowzan S. AlKuraya,
    • Peter B. Kang,
    • Helen Griffin,
    • A. Reghan Foley,
    • Markus Schuelke,
    • Rita Horvath,
    • Carsten G. Bönnemann
    The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals’ fibroblasts and skeletal muscle and in vivo in zebrafish.
  • Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes

    • Jeffrey Staples,
    • Evan K. Maxwell,
    • Nehal Gosalia,
    • Claudia Gonzaga-Jauregui,
    • Christopher Snyder,
    • Alicia Hawes,
    • John Penn,
    • Ricardo Ulloa,
    • Xiaodong Bai,
    • Alexander E. Lopez,
    • Cristopher V. Van Hout,
    • Colm O’Dushlaine,
    • Tanya M. Teslovich,
    • Shane E. McCarthy,
    • Suganthi Balasubramanian,
    • H. Lester Kirchner,
    • Joseph B. Leader,
    • Michael F. Murray,
    • David H. Ledbetter,
    • Alan R. Shuldiner,
    • George D. Yancoupolos,
    • Frederick E. Dewey,
    • David J. Carey,
    • John D. Overton,
    • Aris Baras,
    • Lukas Habegger,
    • Jeffrey G. Reid
    Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in line with expectations given the underlying population and ascertainment approach.
  • A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies

    • Xingyi Guo,
    • Weiqiang Lin,
    • Jiandong Bao,
    • Qiuyin Cai,
    • Xiao Pan,
    • Mengqiu Bai,
    • Yuan Yuan,
    • Jiajun Shi,
    • Yaqiong Sun,
    • Mi-Ryung Han,
    • Jing Wang,
    • Qi Liu,
    • Wanqing Wen,
    • Bingshan Li,
    • Jirong Long,
    • Jianghua Chen,
    • Wei Zheng
    Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05.
  • A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics

    • Yu-Ru Su,
    • Chongzhi Di,
    • Stephanie Bien,
    • Licai Huang,
    • Xinyuan Dong,
    • Goncalo Abecasis,
    • Sonja Berndt,
    • Stephane Bezieau,
    • Hermann Brenner,
    • Bette Caan,
    • Graham Casey,
    • Jenny Chang-Claude,
    • Stephen Chanock,
    • Sai Chen,
    • Charles Connolly,
    • Keith Curtis,
    • Jane Figueiredo,
    • Manish Gala,
    • Steven Gallinger,
    • Tabitha Harrison,
    • Michael Hoffmeister,
    • John Hopper,
    • Jeroen R. Huyghe,
    • Mark Jenkins,
    • Amit Joshi,
    • Loic Le Marchand,
    • Polly Newcomb,
    • Deborah Nickerson,
    • John Potter,
    • Robert Schoen,
    • Martha Slattery,
    • Emily White,
    • Brent Zanke,
    • Ulrike Peters,
    • Li Hsu
    Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach.
  • FUN-LDA: A Latent Dirichlet Allocation Model for Predicting Tissue-Specific Functional Effects of Noncoding Variation: Methods and Applications

    • Daniel Backenroth,
    • Zihuai He,
    • Krzysztof Kiryluk,
    • Valentina Boeva,
    • Lynn Petukhova,
    • Ekta Khurana,
    • Angela Christiano,
    • Joseph D. Buxbaum,
    • Iuliana Ionita-Laza
    We describe a method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell-type- and/or tissue-specific way (FUN-LDA). Using this unsupervised approach, we predict tissue-specific functional effects for every position in the human genome in 127 different tissues and cell types. We demonstrate the usefulness of our predictions by using several validation experiments. Using eQTL data from several sources, including the GTEx project, Geuvadis project, and TwinsUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted functional variants in relevant tissues in Roadmap.
  • A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships

    • Taylor L. Mighell,
    • Sara Evans-Dutson,
    • Brian J. O’Roak
    Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible).
  • C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia

    • Mahmoud R. Fassad,
    • Amelia Shoemark,
    • Pierrick le Borgne,
    • France Koll,
    • Mitali Patel,
    • Mellisa Dixon,
    • Jane Hayward,
    • Charlotte Richardson,
    • Emily Frost,
    • Lucy Jenkins,
    • Thomas Cullup,
    • Eddie M.K. Chung,
    • Michel Lemullois,
    • Anne Aubusson-Fleury,
    • Claire Hogg,
    • David R. Mitchell,
    • Anne-Marie Tassin,
    • Hannah M. Mitchison
    Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder characterized by destructive respiratory disease and laterality abnormalities due to randomized left-right body asymmetry. PCD is mostly caused by mutations affecting the core axoneme structure of motile cilia that is essential for movement. Genes that cause PCD when mutated include a group that encode proteins essential for the assembly of the ciliary dynein motors and the active transport process that delivers them from their cytoplasmic assembly site into the axoneme.

Reports

  • Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

    • Inga M. Höben,
    • Rim Hjeij,
    • Heike Olbrich,
    • Gerard W. Dougherty,
    • Tabea Nöthe-Menchen,
    • Isabella Aprea,
    • Diana Frank,
    • Petra Pennekamp,
    • Bernd Dworniczak,
    • Julia Wallmeier,
    • Johanna Raidt,
    • Kim G. Nielsen,
    • Maria C. Philipsen,
    • Francesca Santamaria,
    • Laura Venditto,
    • Israel Amirav,
    • Huda Mussaffi,
    • Freerk Prenzel,
    • Kaman Wu,
    • Zeineb Bakey,
    • Miriam Schmidts,
    • Niki T. Loges,
    • Heymut Omran
    Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms.
  • Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

    • Hanyin Cheng,
    • Avinash V. Dharmadhikari,
    • Sylvia Varland,
    • Ning Ma,
    • Deepti Domingo,
    • Robert Kleyner,
    • Alan F. Rope,
    • Margaret Yoon,
    • Asbjørg Stray-Pedersen,
    • Jennifer E. Posey,
    • Sarah R. Crews,
    • Mohammad K. Eldomery,
    • Zeynep Coban Akdemir,
    • Andrea M. Lewis,
    • Vernon R. Sutton,
    • Jill A. Rosenfeld,
    • Erin Conboy,
    • Katherine Agre,
    • Fan Xia,
    • Magdalena Walkiewicz,
    • Mauro Longoni,
    • Frances A. High,
    • Marjon A. van Slegtenhorst,
    • Grazia M.S. Mancini,
    • Candice R. Finnila,
    • Arie van Haeringen,
    • Nicolette den Hollander,
    • Claudia Ruivenkamp,
    • Sakkubai Naidu,
    • Sonal Mahida,
    • Elizabeth E. Palmer,
    • Lucinda Murray,
    • Derek Lim,
    • Parul Jayakar,
    • Michael J. Parker,
    • Stefania Giusto,
    • Emanuela Stracuzzi,
    • Corrado Romano,
    • Jennifer S. Beighley,
    • Raphael A. Bernier,
    • Sébastien Küry,
    • Mathilde Nizon,
    • Mark A. Corbett,
    • Marie Shaw,
    • Alison Gardner,
    • Christopher Barnett,
    • Ruth Armstrong,
    • Karin S. Kassahn,
    • Anke Van Dijck,
    • Geert Vandeweyer,
    • Tjitske Kleefstra,
    • Jolanda Schieving,
    • Marjolijn J. Jongmans,
    • Bert B.A. de Vries,
    • Rolph Pfundt,
    • Bronwyn Kerr,
    • Samantha K. Rojas,
    • Kym M. Boycott,
    • Richard Person,
    • Rebecca Willaert,
    • Evan E. Eichler,
    • R. Frank Kooy,
    • Yaping Yang,
    • Joseph C. Wu,
    • James R. Lupski,
    • Thomas Arnesen,
    • Gregory M. Cooper,
    • Wendy K. Chung,
    • Jozef Gecz,
    • Holly A.F. Stessman,
    • Linyan Meng,
    • Gholson J. Lyon
    N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15.
  • A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

    • Heather E. Olson,
    • Nolwenn Jean-Marçais,
    • Edward Yang,
    • Delphine Heron,
    • Katrina Tatton-Brown,
    • Paul A. van der Zwaag,
    • Emilia K. Bijlsma,
    • Bryan L. Krock,
    • E. Backer,
    • Erik-Jan Kamsteeg,
    • Margje Sinnema,
    • Margot R.F. Reijnders,
    • David Bearden,
    • Amber Begtrup,
    • Aida Telegrafi,
    • Roelineke J. Lunsing,
    • Lydie Burglen,
    • Gaetan Lesca,
    • Megan T. Cho,
    • Lacey A. Smith,
    • Beth R. Sheidley,
    • Christelle Moufawad El Achkar,
    • Phillip L. Pearl,
    • Annapurna Poduri,
    • Cara M. Skraban,
    • Jennifer Tarpinian,
    • Addie I. Nesbitt,
    • Dietje E. Fransen van de Putte,
    • Claudia A.L. Ruivenkamp,
    • Patrick Rump,
    • Nicolas Chatron,
    • Isabelle Sabatier,
    • Julitta De Bellescize,
    • Laurent Guibaud,
    • David A. Sweetser,
    • Jessica L. Waxler,
    • Klaas J. Wierenga,
    • DDD Study,
    • Jean Donadieu,
    • Vinodh Narayanan,
    • Keri M. Ramsey,
    • C4RCD Research Group,
    • Caroline Nava,
    • Jean-Baptiste Rivière,
    • Antonio Vitobello,
    • Frédéric Tran Mau-Them,
    • Christophe Philippe,
    • Ange-Line Bruel,
    • Yannis Duffourd,
    • Laurel Thomas,
    • Stefan H. Lelieveld,
    • Janneke Schuurs-Hoeijmakers,
    • Han G. Brunner,
    • Boris Keren,
    • Julien Thevenon,
    • Laurence Faivre,
    • Gary Thomas,
    • Christel Thauvin-Robinet
    Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals.
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