Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program
(The American Journal of Human Genetics 108, 874 –893; May 6, 2021) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 3, 2021 Category: Genetics & Stem Cells Authors: Yao Hu, Adrienne M. Stilp, Caitlin P. McHugh, Shuquan Rao, Deepti Jain, Xiuwen Zheng, John Lane, S ébastian Méric de Bellefon, Laura M. Raffield, Ming-Huei Chen, Lisa R. Yanek, Marsha Wheeler, Yao Yao, Chunyan Ren, Jai Broome, Jee-Young Moon, Paul S. de Tags: Correction Source Type: research

A form of muscular dystrophy associated with pathogenic variants in JAG2
(The American Journal of Human Genetics 108, 840 –856; May 6, 2021) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 3, 2021 Category: Genetics & Stem Cells Authors: Sandra Coppens, Alison M. Barnard, Sanna Puusepp, Sander Pajusalu, Katrin Õunap, Dorianmarie Vargas-Franco, Christine C. Bruels, Sandra Donkervoort, Lynn Pais, Katherine R. Chao, Julia K. Goodrich, Eleina M. England, Ben Weisburd, Vijay S. Ganesh, Sanna Tags: Correction Source Type: research

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
(The American Journal of Human Genetics 106, 356 –370; March 5, 2020) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 3, 2021 Category: Genetics & Stem Cells Authors: Erfan Aref-Eshghi, Jennifer Kerkhof, Victor P. Pedro, Groupe DI France, Mouna Barat-Houari, Nathalie Ruiz-Pallares, Jean-Christophe Andrau, Didier Lacombe, Julien Van-Gils, Patricia Fergelot, Christ éle Dubourg, Valerie Cormier-Daire, Sophie Rondeau, Fra Tags: Correction Source Type: research

This month in The Journal
Next-generation sequencing has enabled tremendous progress in identifying genetic causes of epilepsy, a neurological disorder with a range of causes and health complications. Ever-larger studies make it clear that variants in a given gene can cause both mild and severe epilepsies. This, in turn, poses challenges for the interpretation of variants identified in affected individuals. Now, in this issue, the Epi25 Collaborative seek to better understand the differential impact of variants in epilepsy-associated genes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 3, 2021 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5 ′ untranslated regions (5′ UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 21, 2021 Category: Genetics & Stem Cells Authors: Caroline F. Wright, Nicholas M. Quaife, Laura Ramos-Hern ández, Petr Danecek, Matteo P. Ferla, Kaitlin E. Samocha, Joanna Kaplanis, Eugene J. Gardner, Ruth Y. Eberhardt, Katherine R. Chao, Konrad J. Karczewski, Joannella Morales, Giuseppe Gallone, Meena Tags: Article Source Type: research

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder
We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 21, 2021 Category: Genetics & Stem Cells Authors: Holger Hengel, Shabab B. Hannan, Sarah Dyack, Sara B. MacKay, Ulrich Schatz, Martin Fleger, Andreas Kurringer, Ghassan Balousha, Zaid Ghanim, Fowzan S. Alkuraya, Hamad Alzaidan, Hessa S. Alsaif, Tadahiro Mitani, Sevcan Bozdogan, Davut Pehlivan, James R. L Tags: Article Source Type: research

A computational approach for detecting physiological homogeneity in the midst of genetic heterogeneity
The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious varian...
Source: The American Journal of Human Genetics - May 19, 2021 Category: Genetics & Stem Cells Authors: Peng Zhang, Aur élie Cobat, Yoon-Seung Lee, Yiming Wu, Cigdem Sevim Bayrak, Clémentine Boccon-Gibod, Daniela Matuozzo, Lazaro Lorenzo, Aayushee Jain, Soraya Boucherit, Louis Vallée, Burkhard Stüve, Stéphane Chabrier, Jean-Laurent Casanova, Laurent Ab Tags: Article Source Type: research

Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation
Dysregulated transforming growth factor TGF- β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyp erlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 18, 2021 Category: Genetics & Stem Cells Authors: Alban Ziegler, R émi Duclaux-Loras, Céline Revenu, Fabienne Charbit-Henrion, Bernadette Begue, Karine Duroure, Linda Grimaud, Anne Laure Guihot, Valérie Desquiret-Dumas, Mohammed Zarhrate, Nicolas Cagnard, Emmanuel Mas, Anne Breton, Thomas Edouard, Cla Tags: Report Source Type: research

A human importin- β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8
Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin- β protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-β signaling components such as SMAD1–4 have been suggested to be among them . Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 18, 2021 Category: Genetics & Stem Cells Authors: Ilse Van Gucht, Josephina A.N. Meester, Jotte Rodrigues Bento, Maaike Bastiaansen, Jarl Bastianen, Ilse Luyckx, Lotte Van Den Heuvel, C édric H.G. Neutel, Pieter-Jan Guns, Mandy Vermont, Erik Fransen, Melanie H.A.M. Perik, Joe Davis Velchev, Maaike Alaer Tags: Report Source Type: research

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism
Revertant mosaicism, or “natural gene therapy,” refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline muta tion. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via ...
Source: The American Journal of Human Genetics - May 17, 2021 Category: Genetics & Stem Cells Authors: Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, Toshifumi Nomura Tags: Article Source Type: research

Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome
Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 14, 2021 Category: Genetics & Stem Cells Authors: Lore Pottie, Christin S. Adamo, Aude Beyens, Steffen L ütke, Piyanoot Tapaneeyaphan, Adelbert De Clercq, Phil L. Salmon, Riet De Rycke, Alper Gezdirici, Elif Yilmaz Gulec, Naz Khan, Jill E. Urquhart, William G. Newman, Kay Metcalfe, Stephanie Efthymiou, Tags: Article Source Type: research

Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder
We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencin...
Source: The American Journal of Human Genetics - May 11, 2021 Category: Genetics & Stem Cells Authors: Eva Morava, Ulrich A. Schatz, Pernille M. Torring, Mary-Alice Abbott, Matthias Baumann, Charlotte Brasch-Andersen, Nathalie Chevalier, Ulrike Dunkhase-Heinl, Martin Fleger, Tobias B. Haack, Stephen Nelson, Sven Potelle, Silvia Radenkovic, Guido T. Bommer, Tags: Report Source Type: research

A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction
We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423 ∗), in SLC37A4; the affected individuals were from four unrelated families. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 7, 2021 Category: Genetics & Stem Cells Authors: Bobby G. Ng, Paulina Sosicka, Fran çois Fenaille, Annie Harroche, Sandrine Vuillaumier-Barrot, Mindy Porterfield, Zhi-Jie Xia, Shannon Wagner, Michael J. Bamshad, Marie-Christine Vergnes-Boiteux, Sophie Cholet, Stephen Dalton, Anne Dell, Thierry Dupré, Tags: Article Source Type: research

Leveraging both individual-level genetic data and GWAS summary statistics increases polygenic prediction
The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet  been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 7, 2021 Category: Genetics & Stem Cells Authors: Clara Albi ñana, Jakob Grove, John J. McGrath, Esben Agerbo, Naomi R. Wray, Cynthia M. Bulik, Merete Nordentoft, David M. Hougaard, Thomas Werge, Anders D. Børglum, Preben Bo Mortensen, Florian Privé, Bjarni J. Vilhjálmsson Tags: Article Source Type: research

Estimation of non-additive genetic variance in human complex traits from a large sample of unrelated individuals
(The American Journal of Human Genetics 108, 786 –798; May 6, 2021) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 6, 2021 Category: Genetics & Stem Cells Authors: Valentin Hivert, Julia Sidorenko, Florian Rohart, Michael E. Goddard, Jian Yang, Naomi R. Wray, Loic Yengo, Peter M. Visscher Tags: Correction Source Type: research

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associat...
Source: The American Journal of Human Genetics - May 6, 2021 Category: Genetics & Stem Cells Authors: Norine Voisin, Rhonda E. Schnur, Sofia Douzgou, Susan M. Hiatt, Cecilie F. Rustad, Natasha J. Brown, Dawn L. Earl, Boris Keren, Olga Levchenko, Sinje Geuer, Sarah Verheyen, Diana Johnson, Yuri A. Zarate, Miroslava Han čárová, David J. Amor, E. Martina Tags: Article Source Type: research

2020 McKusick Award address
This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 6, 2021 Category: Genetics & Stem Cells Authors: Peter H. Byers Tags: ASHG Awards and Addresses Source Type: research

This month in The Journal
Tandem repeats make up ~3% of the human genome, but owing to their repetitive, mutagenic, and polymorphic nature, these elements have been largely overlooked in high-throughput genomic studies. Although the contribution of tandem repeats to human disease has been recognized for decades, only recently have researchers been able to explore in a genome-wide fashion the phenotypic consequences of variation within tandem repeats. In this issue, Garg et  al. assess the putative functional effects of copy-number variation in variable number tandem repeats (VNTRs). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 6, 2021 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generaliz...
Source: The American Journal of Human Genetics - April 30, 2021 Category: Genetics & Stem Cells Authors: Epi25 Collaborative Tags: Article Source Type: research

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism
ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 27, 2021 Category: Genetics & Stem Cells Authors: Maya Chopra, Meriel McEntagart, Jill Clayton-Smith, Konrad Platzer, Anju Shukla, Katta M. Girisha, Anupriya Kaur, Parneet Kaur, Rolph Pfundt, Hermine Veenstra-Knol, Grazia M.S. Mancini, Gerarda Cappuccio, Nicola Brunetti-Pierri, Fanny Kort üm, Maja Hempe Tags: Report Source Type: research

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric...
Source: The American Journal of Human Genetics - April 27, 2021 Category: Genetics & Stem Cells Authors: Dmitrijs Rots, Eric Chater-Diehl, Alexander J.M. Dingemans, Sarah J. Goodman, Michelle T. Siu, Cheryl Cytrynbaum, Sanaa Choufani, Ny Hoang, Susan Walker, Zain Awamleh, Joshua Charkow, Stephen Meyn, Rolph Pfundt, Tuula Rinne, Thatjana Gardeitchik, Bert B.A Tags: Article Source Type: research

EPISPOT: An epigenome-driven approach for detecting and interpreting hotspots in molecular QTL studies
We present EPISPOT, a fully joint framework which exploits large panels of epigenetic annotations as variant-level information to enhance molecular quantitative trait locus (QTL) mapping. Thanks to a purpose-built Bayesian inferential algorithm, EPISPOT accommodates functional information for both cis and trans actions, including QTL hotspot effects. It effectively couples simultaneous QTL analysis of thousands of genetic variants and molecular traits with hypothesis-free selection of biologically interpretable annotations which directly contribute to the QTL effects. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 27, 2021 Category: Genetics & Stem Cells Authors: H élène Ruffieux, Benjamin P. Fairfax, Isar Nassiri, Elena Vigorito, Chris Wallace, Sylvia Richardson, Leonardo Bottolo Tags: Article Source Type: research

Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration
Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 27, 2021 Category: Genetics & Stem Cells Authors: Yi-Ting Tsai, Yao Li, Joseph Ryu, Pei-Yin Su, Chia-Hua Cheng, Wen-Hsuan Wu, Yong-Shi Li, Peter M.J. Quinn, Kam W. Leong, Stephen H. Tsang Tags: Article Source Type: research

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormaliti...
Source: The American Journal of Human Genetics - April 23, 2021 Category: Genetics & Stem Cells Authors: M édéric Jeanne, Hélène Demory, Aubin Moutal, Marie-Laure Vuillaume, Sophie Blesson, Rose-Anne Thépault, Sylviane Marouillat, Judith Halewa, Saskia M. Maas, M. Mahdi Motazacker, Grazia M.S. Mancini, Marjon A. van Slegtenhorst, Avgi Andreou, Helene Co Tags: Report Source Type: research

Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation
Cerebral cavernous malformations (CCMs) are vascular disorders that affect up to 0.5% of the total population. About 20% of CCMs are inherited because of familial mutations in CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10, whereas the etiology of a majority of simplex CCM-affected individuals remains unclear. Here, we report somatic mutations of MAP3K3, PIK3CA, MAP2K7, and CCM genes in CCM lesions. In particular, somatic hotspot mutations of PIK3CA are found in 11 of 38 individuals with CCMs, and a MAP3K3 somatic mutation (c.1323C>G [p.Ile441Met]) is detected in 37.0% (34 of 92) of the simplex CCM-affec...
Source: The American Journal of Human Genetics - April 22, 2021 Category: Genetics & Stem Cells Authors: Jiancong Weng, Yingxi Yang, Dong Song, Ran Huo, Hao Li, Yiyun Chen, Yoonhee Nam, Qiuxia Zhou, Yuming Jiao, Weilun Fu, Zihan Yan, Jie Wang, Hongyuan Xu, Lin Di, Jie Li, Shuo Wang, Jizong Zhao, Jiguang Wang, Yong Cao Tags: Report Source Type: research

Engagement and return of results preferences among a primarily African American genomic sequencing research cohort
Genomics researchers are increasingly interested in what constitutes effective engagement of individuals from underrepresented groups. This is critical for longitudinal projects needed to inform the implementation of precision medicine. Return of results is one opportunity for engagement. The aims of this study were to determine participant perspectives on optimal engagement strategies and priorities for return of results and the extent to which focus groups were an effective modality for gathering input on these topics. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 21, 2021 Category: Genetics & Stem Cells Authors: Katie L. Lewis, Erin Turbitt, Priscilla A. Chan, Sandra Epps, Barbara B. Biesecker, Lori A.H. Erby, Grace-Ann Fasaye, Leslie G. Biesecker Tags: Article Source Type: research

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program
Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 21, 2021 Category: Genetics & Stem Cells Authors: Yao Hu, Adrienne M. Stilp, Caitlin P. McHugh, Shuquan Rao, Deepti Jain, Xiuwen Zheng, John Lane, S ébastian Méric de Bellefon, Laura M. Raffield, Ming-Huei Chen, Lisa R. Yanek, Marsha Wheeler, Yao Yao, Chunyan Ren, Jai Broome, Jee-Young Moon, Paul S. de Tags: Article Source Type: research

A form of muscular dystrophy associated with pathogenic variants in JAG2
JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. (Source: T...
Source: The American Journal of Human Genetics - April 15, 2021 Category: Genetics & Stem Cells Authors: Sandra Coppens, Alison M. Barnard, Sanna Puusepp, Sander Pajusalu, Katrin Õunap, Dorianmarie Vargas-Franco, Christine C. Bruels, Sandra Donkervoort, Lynn Pais, Katherine R. Chao, Julia K. Goodrich, Eleina M. England, Ben Weisburd, Vijay S. Ganesh, Sanna Tags: Article Source Type: research

Efficient mixed model approach for large-scale genome-wide association studies of ordinal categorical phenotypes
In genome-wide association studies, ordinal categorical phenotypes are widely used to measure human behaviors, satisfaction, and preferences. However, because of the lack of analysis tools, methods designed for binary or quantitative traits are commonly used inappropriately to analyze categorical phenotypes. To accurately model the dependence of an ordinal categorical phenotype on covariates, we propose an efficient mixed model association test, proportional odds logistic mixed model (POLMM). POLMM is computationally efficient to analyze large datasets with hundreds of thousands of samples, can control type I error rates a...
Source: The American Journal of Human Genetics - April 8, 2021 Category: Genetics & Stem Cells Authors: Wenjian Bi, Wei Zhou, Rounak Dey, Bhramar Mukherjee, Joshua N. Sampson, Seunggeun Lee Tags: Article Source Type: research

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder
Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spec...
Source: The American Journal of Human Genetics - April 2, 2021 Category: Genetics & Stem Cells Authors: Xenia Latypova, Marie Vincent, Alice Moll é, Oluwadamilare A. Adebambo, Cynthia Fourgeux, Tahir N. Khan, Alfonso Caro, Monica Rosello, Carmen Orellana, Dmitriy Niyazov, Damien Lederer, Marie Deprez, Yline Capri, Peter Kannu, Anne Claude Tabet, Jonathan L Tags: Report Source Type: research

Quantifying the contribution of dominance deviation effects to complex trait variation in biobank-scale data
We present an efficient method to estimate the variation in a complex trait that can be attributed to additive (additive heritability) and dominance deviation (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2021 Category: Genetics & Stem Cells Authors: Ali Pazokitoroudi, Alec M. Chiu, Kathryn S. Burch, Bogdan Pasaniuc, Sriram Sankararaman Tags: Article Source Type: research

Estimation of non-additive genetic variance in human complex traits from a large sample of unrelated individuals
Non-additive genetic variance for complex traits is traditionally estimated from data on relatives. It is notoriously difficult to estimate without bias in non-laboratory species, including humans, because of possible confounding with environmental covariance among relatives. In principle, non-additive variance attributable to common DNA variants can be estimated from a random sample of unrelated individuals with genome-wide SNP data. Here, we jointly estimate the proportion of variance explained by additive (hSNP2), dominance ( δSNP2) and additive-by-additive (ηSNP2) genetic variance in a single analysis model. ...
Source: The American Journal of Human Genetics - April 2, 2021 Category: Genetics & Stem Cells Authors: Valentin Hivert, Julia Sidorenko, Florian Rohart, Michael E. Goddard, Jian Yang, Naomi R. Wray, Loic Yengo, Peter M. Visscher Tags: Article Source Type: research

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?
Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or ge...
Source: The American Journal of Human Genetics - April 2, 2021 Category: Genetics & Stem Cells Authors: Christel Depienne, Jean-Louis Mandel Tags: Review Source Type: research

Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease
(The American Journal of Human Genetics 107, 539 –543; September 3, 2020) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Marta Vergnano, Maja Mockenhaupt, Natashia Benzian-Olsson, Maren Paulmann, Katarzyna Grys, Satveer K. Mahil, Charlotte Chaloner, Ines A. Barbosa, Suzannah August, A. David Burden, Siew-Eng Choon, Hywel Cooper, Alex A. Navarini, Nick J. Reynolds, Shyamal W Tags: Correction Source Type: research

Progressive myoclonus epilepsies —Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes
Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Carolina Courage, Karen L. Oliver, Eon Joo Park, Jillian M. Cameron, Kariona A. Grabi ńska, Mikko Muona, Laura Canafoglia, Antonio Gambardella, Edith Said, Zaid Afawi, Betul Baykan, Christian Brandt, Carlo di Bonaventura, Hui Bein Chew, Chiara Criscuolo, Tags: Article Source Type: research

Association of structural variation with cardiometabolic traits in Finns
The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 indi...
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Lei Chen, Haley J. Abel, Indraniel Das, David E. Larson, Liron Ganel, Krishna L. Kanchi, Allison A. Regier, Erica P. Young, Chul Joo Kang, Alexandra J. Scott, Colby Chiang, Xinxin Wang, Shuangjia Lu, Ryan Christ, Susan K. Service, Charleston W.K. Chiang, Tags: Article Source Type: research

A catalog of GWAS fine-mapping efforts in autoimmune disease
Genome-wide association studies (GWASs) have enabled unbiased identification of genetic loci contributing to common complex diseases. Because GWAS loci often harbor many variants and genes, it remains a major challenge to move from GWASs ’ statistical associations to the identification of causal variants and genes that underlie these association signals. Researchers have applied many statistical and functional fine-mapping strategies to prioritize genetic variants and genes as potential candidates. There is no gold standard in fin e-mapping approaches, but consistent results across different approaches can improve co...
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Minal Caliskan, Christopher D. Brown, Joseph C. Maranville Tags: Review Source Type: research

Opportunities and challenges for the computational interpretation of rare variation in clinically important genes
Genome sequencing is enabling precision medicine —tailoring treatment to the unique constellation of variants in an individual’s genome. The impact of recurrent pathogenic variants is often understood, leaving a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when i t occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous c...
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Gregory McInnes, Andrew G. Sharo, Megan L. Koleske, Julia E.H. Brown, Matthew Norstad, Aashish N. Adhikari, Sheng Wang, Steven E. Brenner, Jodi Halpern, Barbara A. Koenig, David C. Magnus, Renata C. Gallagher, Kathleen M. Giacomini, Russ B. Altman Tags: Perspective Source Type: research

This month in The Journal
Like many traits evaluated by genome-wide association studies (GWASs), height has been characterized primarily in European populations. As larger, more diverse cohorts become available, there is a strong push to determine the generalizability of previously identified loci. Additionally, owing to differences in allele frequencies and linkage disequilibrium structure across populations, new opportunities arise to better refine previously identified signals. In this issue, Graff et  al. use African Ancestry Anthropometry Genetics Consortium data to enrich European cohorts, conduct a meta-analysis for height, and fine map...
Source: The American Journal of Human Genetics - April 1, 2021 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Pervasive cis effects of variation in copy number of large tandem repeats on local DNA methylation and gene expression
Variable number tandem repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, because of their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole-genome sequencing to perform association analysis between copy number of ∼70,000 VNTRs (motif size ≥ 10 bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (...
Source: The American Journal of Human Genetics - March 31, 2021 Category: Genetics & Stem Cells Authors: Paras Garg, Alejandro Martin-Trujillo, Oscar L. Rodriguez, Scott J. Gies, Elina Hadelia, Bharati Jadhav, Miten Jain, Benedict Paten, Andrew J. Sharp Tags: Article Source Type: research

Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies
Virtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and medical genetic initiatives are reliant upon short-read whole-genome sequencing (srWGS), which presents challenges for the detection of structural variants (SVs) relative to emerging long-read WGS (lrWGS) technologies. Given this ubiquity of srWGS in large-scale genomics initiatives, we sought to establish expectations for routine SV detection from this data type by comparison with lrWGS assembly, as well as to quantify the genomic properties and added value of SVs uniquely accessible to each technology. (Source: The A...
Source: The American Journal of Human Genetics - March 30, 2021 Category: Genetics & Stem Cells Authors: Xuefang Zhao, Ryan L. Collins, Wan-Ping Lee, Alexandra M. Weber, Yukyung Jun, Qihui Zhu, Ben Weisburd, Yongqing Huang, Peter A. Audano, Harold Wang, Mark Walker, Chelsea Lowther, Jack Fu, Human Genome Structural Variation Consortium, Mark B. Gerstein, Sco Tags: Report Source Type: research

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations
Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 25, 2021 Category: Genetics & Stem Cells Authors: Alicia R. Martin, Elizabeth G. Atkinson, Sin éad B. Chapman, Anne Stevenson, Rocky E. Stroud, Tamrat Abebe, Dickens Akena, Melkam Alemayehu, Fred K. Ashaba, Lukoye Atwoli, Tera Bowers, Lori B. Chibnik, Mark J. Daly, Timothy DeSmet, Sheila Dodge, Abebaw F Tags: Article Source Type: research

A unified framework for cross-population trait prediction by leveraging the genetic correlation of polygenic traits
The development of polygenic risk scores (PRSs) has proved useful to stratify the general European population into different risk groups. However, PRSs are less accurate in non-European populations due to genetic differences across different populations. To improve the prediction accuracy in non-European populations, we propose a cross-population analysis framework for PRS construction with both individual-level (XPA) and summary-level (XPASS) GWAS data. By leveraging trans-ancestry genetic correlation, our methods can borrow information from the Biobank-scale European population data to improve risk prediction in the non-...
Source: The American Journal of Human Genetics - March 25, 2021 Category: Genetics & Stem Cells Authors: Mingxuan Cai, Jiashun Xiao, Shunkang Zhang, Xiang Wan, Hongyu Zhao, Gang Chen, Can Yang Tags: Article Source Type: research

Machine learning-based reclassification of germline variants of unknown significance: The RENOVO algorithm
The increasing scope of genetic testing allowed by next-generation sequencing (NGS) dramatically increased the number of genetic variants to be interpreted as pathogenic or benign for adequate patient management. Still, the interpretation process often fails to deliver a clear classification, resulting in either variants of unknown significance (VUSs) or variants with conflicting interpretation of pathogenicity (CIP); these represent a major clinical problem because they do not provide useful information for decision-making, causing a large fraction of genetically determined disease to remain undertreated. (Source: The Ame...
Source: The American Journal of Human Genetics - March 23, 2021 Category: Genetics & Stem Cells Authors: Valentina Favalli, Giulia Tini, Emanuele Bonetti, Gianluca Vozza, Alessandro Guida, Sara Gandini, Pier Giuseppe Pelicci, Luca Mazzarella Tags: Article Source Type: research

A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome
The DNA damage-binding protein 1 (DDB1) is part of the CUL4 –DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. (...
Source: The American Journal of Human Genetics - March 19, 2021 Category: Genetics & Stem Cells Authors: Susan M. White, Elizabeth Bhoj, Christoffer Nell åker, Augusta M.A. Lachmeijer, Aren E. Marshall, Kym M. Boycott, Dong Li, Wendy Smith, Taila Hartley, Arran McBride, Michelle E. Ernst, Alison S. May, Dagmar Wieczorek, Rami Abou Jamra, Margarete Koch-Hogr Tags: Report Source Type: research

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation
The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 19, 2021 Category: Genetics & Stem Cells Authors: Rebecca Truty, Karen Ouyang, Susan Rojahn, Sarah Garcia, Alexandre Colavin, Barbara Hamlington, Mary Freivogel, Robert L. Nussbaum, Keith Nykamp, Swaroop Aradhya Tags: Article Source Type: research

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects
The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8% –1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their dist...
Source: The American Journal of Human Genetics - March 18, 2021 Category: Genetics & Stem Cells Authors: Hila Fridman, Helger G. Yntema, Reedik M ägi, Reidar Andreson, Andres Metspalu, Massimo Mezzavila, Chris Tyler-Smith, Yali Xue, Shai Carmi, Ephrat Levy-Lahad, Christian Gilissen, Han G. Brunner Tags: Article Source Type: research

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia
The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic implications for treatment of β-thalassemia and sickle cell anemia, two major global health problems. Although significant progress has been made in our understanding of the molecular mechanism of the fetal-to-adult hemoglobin switch, the mechanism of epigenetic regulation of HbF silencing remains to be fully defined. Here, we performed whole-genome bisulfite sequencing and RNA sequencing analysis of the bone marrow-derived GYPA+ erythroid cells from β-thalassemia-a...
Source: The American Journal of Human Genetics - March 17, 2021 Category: Genetics & Stem Cells Authors: Xiuqin Bao, Xinhua Zhang, Liren Wang, Zhongju Wang, Jin Huang, Qianqian Zhang, Yuhua Ye, Yongqiong Liu, Diyu Chen, Yangjin Zuo, Qifa Liu, Peng Xu, Binbin Huang, Jianpei Fang, Jinquan Lao, Xiaoqin Feng, Yafeng Li, Ryo Kurita, Yukio Nakamura, Weiwei Yu, Cun Tags: Article Source Type: research

A powerful subset-based method identifies gene set associations and improves interpretation in UK Biobank
Tests of association between a phenotype and a set of genes in a biological pathway can provide insights into the genetic architecture of complex phenotypes beyond those obtained from single-variant or single-gene association analysis. However, most existing gene set tests have limited power to detect gene set-phenotype association when a small fraction of the genes are associated with the phenotype and cannot identify the potentially “active” genes that might drive a gene set-based association. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 16, 2021 Category: Genetics & Stem Cells Authors: Diptavo Dutta, Peter VandeHaar, Lars G. Fritsche, Sebastian Z öllner, Michael Boehnke, Laura J. Scott, Seunggeun Lee Tags: Article Source Type: research

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry
Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. (Source: The Ameri...
Source: The American Journal of Human Genetics - March 12, 2021 Category: Genetics & Stem Cells Authors: Mariaelisa Graff, Anne E. Justice, Kristin L. Young, Eirini Marouli, Xinruo Zhang, Rebecca S. Fine, Elise Lim, Victoria Buchanan, Kristin Rand, Mary F. Feitosa, Mary K. Wojczynski, Lisa R. Yanek, Yaming Shao, Rebecca Rohde, Adebowale A. Adeyemo, Melinda C Tags: Article Source Type: research