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Response to Grosse et  al.
To the Editor: We thank Dr. Grosse and colleagues for two corrections to the introduction of our recent description of a genome-sequencing system for universal newborn screening (NBS), diagnosis, and precision medicine for severe childhood genetic diseases that currently have effective therapeutic interventions.1 Firstly, that between 2006 and 2022, the number of core disorders recommended for NBS of dried blood spots (DBSs) in the United States —the Recommended Uniform Screening Panel (RUSP)—increased by six and not eight, as we had stated. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2023 Category: Genetics & Stem Cells Authors: Stephen F. Kingsmore, Laurie D. Smith, Chris M. Kunard, Matthew Bainbridge, Sergey Batalov, Wendy Benson, Eric Blincow, Sara Caylor, Christina Chambers, Guillermo Del Angel, David P. Dimmock, Yan Ding, Katarzyna Ellsworth, Annette Feigenbaum, Erwin Frise, Tags: Letter to the editor Source Type: research

Progress in expanding newborn screening in the United States
To the Editor: We read with interest the recent article by Kingsmore et  al., who suggest that universal newborn rapid whole-genome sequencing is attractive for “comprehensive” newborn screening (NBS).1 Existing US NBS programs are based on mandated routine testing of newborns; evidence-based decision-making processes exist for this testing.2 Whether policy makers also consider routine rapid whole-genome sequencing of newborns to be warranted may depend on the resolution of a number of evidentiary, ethical, legal, social, and economic issues. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2023 Category: Genetics & Stem Cells Authors: Scott D. Grosse, Carla Cuthbert, Marcus Gaffney, Amy Gaviglio, Cynthia F. Hinton, Yvonne Kellar-Guenther, Alex R. Kemper, Sarah McKasson, Jelili Ojodu, Catharine Riley, Sikha Singh, Marci K. Sontag, Stuart K. Shapira Tags: Letter to the editor Source Type: research

eXclusionarY: 10 years later, where are the sex chromosomes in GWASs?
A decade ago, paucity of GWAS signals on the X chromosome was noted, in part because only 1/3 of GWASs included the X chromosome. Revisiting this topic, we find that the situation has become even worse: only 1/4 GWASs analyzed the X chromosome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2023 Category: Genetics & Stem Cells Authors: Lei Sun, Zhong Wang, Tianyuan Lu, Teri A. Manolio, Andrew D. Paterson Tags: Technology review Source Type: research

This month in The Journal
The omnigenic hypothesis, which contextualizes the highly polygenic nature of complex traits, proposes that a broad, interconnected gene regulatory network coalesces on a set of core effector genes in relevant tissues. Most heritability, therefore, can be attributed to so-called peripheral pathways comprising the additive trans-effects  of many common variants. In this issue, Iakovliev et al. explore a key component of the omnigenic hypothesis by seeking to identify core (or, per the authors’ terminology, sparse effector) genes for type 1 diabetes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Estimating clinical risk in gene regions from population sequencing cohort data
Methods to identify regions of genes that are most functionally impactful have relied on structural, evolutionary, and population data. We extend these approaches with REGatta, a method to estimate the clinical risk conferred by variants in regions of genes with established disease phenotypes using diagnostic and population cohort data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 25, 2023 Category: Genetics & Stem Cells Authors: James D. Fife, Christopher A. Cassa Tags: Article Source Type: research

Impact of cross-ancestry genetic architecture on GWASs in admixed populations
Genome-wide association studies (GWASs) are an important tool for disease mapping but are under-explored for populations of individuals with mixed genetic ancestries (admixed populations). We provide considerations for method selection and show that differences in allele frequency and/or causal effects by ancestry impact statistical power for GWASs in admixed populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 23, 2023 Category: Genetics & Stem Cells Authors: Rachel Mester, Kangcheng Hou, Yi Ding, Gillian Meeks, Kathryn S. Burch, Arjun Bhattacharya, Brenna M. Henn, Bogdan Pasaniuc Tags: Article Source Type: research

Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene ’s candidacy in 6q16.1 deletions
Monogenic forms of obesity have taught us about central nervous system dysregulation of food intake as a disease mechanism. We associate ultra-rare variants in POU3F2, encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopmental delay in 12 individuals. Additionally, we demonstrate variant pathogenicity through in  vitro analysis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 18, 2023 Category: Genetics & Stem Cells Authors: Ria Sch önauer, Wenjun Jin, Christin Findeisen, Irene Valenzuela, Laura Alice Devlin, Jill Murrell, Emma C. Bedoukian, Linda Pöschla, Elena Hantmann, Korbinian M. Riedhammer, Julia Hoefele, Konrad Platzer, Ronald Biemann, Philipp M. Campeau, Johannes M� Tags: Report Source Type: research

The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder
Clinical and molecular analysis of the KDM6B-related neurodevelopmental disorder highlights inaccuracies in its current OMIM definition and demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants for an unbiased, accurate, and comprehensive definition of rare genetic disorders. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 16, 2023 Category: Genetics & Stem Cells Authors: Dmitrijs Rots, Taryn E. Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, Rolph Pfundt, Bert B.A. de Vries, Richard H. van Jaarsveld, Saskia M.J. Hopman, Ellen van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kort üm, Francois Le Tags: Article Source Type: research

Declining autozygosity over time: An exploration in over 1 million individuals from three diverse cohorts
This study found that genome-wide autozygosity is decreasing over generational time in three large cohorts of diverse genetic ancestries, though the rate of this decline varies by country and ancestry. This trend is most likely attributable to increases in urbanization and panmixia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 12, 2023 Category: Genetics & Stem Cells Authors: Sarah M.C. Colbert, Frank R. Wendt, Gita A. Pathak, Drew A. Helmer, Elizabeth R. Hauser, Matthew C. Keller, Renato Polimanti, Emma C. Johnson Tags: Report Source Type: research

Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy
We identified rare bi-allelic variants in HMGCR in nine individuals with muscular dystrophy and no genetic diagnosis. Functional and in silico studies implicate HMGCR dysfunction in muscular dystrophy pathogenesis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 10, 2023 Category: Genetics & Stem Cells Authors: Joel A. Morales-Rosado, Tanya L. Schwab, Sarah K. Macklin-Mantia, A. Reghan Foley, Filippo Pinto e Vairo, Davut Pehlivan, Sandra Donkervoort, Jill A. Rosenfeld, Grace E. Boyum, Ying Hu, Anh T.Q. Cong, Timothy E. Lotze, Carrie A. Mohila, Dimah Saade, Diana Tags: Report Source Type: research

A joint transcriptome-wide association study across multiple tissues identifies candidate breast cancer susceptibility genes
Gao and colleagues identify eight loci of breast cancer susceptibility in a genome-wide association study. By leveraging gene expression data from multiple tissues, they also discover 309 breast cancer susceptibility genes in a transcriptome-wide association study. Known genetic risk variants could act on these genes to cause breast cancer. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 9, 2023 Category: Genetics & Stem Cells Authors: Guimin Gao, Peter N. Fiorica, Julian McClellan, Alvaro N. Barbeira, James L. Li, Olufunmilayo I. Olopade, Hae Kyung Im, Dezheng Huo Tags: Article Source Type: research

Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the “omnigenic” sparse effector hypothesis of complex trait genetics
Iakovliev et  al. investigate whether the effects of common SNPs on risk of type 1 diabetes are mediated through trans-effects on expression of core genes. By testing for association with genotypic scores that aggregate predicted trans-effects, they identify a set of putative core genes for type 1 diabetes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 9, 2023 Category: Genetics & Stem Cells Authors: Andrii Iakovliev, Stuart J. McGurnaghan, Caroline Hayward, Marco Colombo, Debby Lipschutz, Athina Spiliopoulou, Helen M. Colhoun, Paul M. McKeigue Tags: Article Source Type: research

The functional impact of 1,570 individual amino acid substitutions in human OTC
OTC deficiency is the most common urea cycle disorder. Here, we measure the functional impact of 1,570 single-nucleotide-variant-accessible amino acid substitutions in human OTC. Our assay distinguishes benign from pathogenic variants and neonatal from late-onset disease variants, supporting its use as PS3 evidence under the current ACMG guidelines. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 4, 2023 Category: Genetics & Stem Cells Authors: Russell S. Lo, Gareth A. Cromie, Michelle Tang, Kevin Teng, Katherine Owens, Amy Sirr, J. Nathan Kutz, Hiroki Morizono, Ljubica Caldovic, Nicholas Ah Mew, Andrea Gropman, Aim ée M. Dudley Tags: Article Source Type: research

Kurt Hirschhorn (1926 –2022)
Kurt Hirschhorn, M.D., died peacefully on November 22, 2022, after a short illness. He is survived by his wife, Rochelle Hirschhorn, and son, Joel, both human geneticists; his two daughters, Melanie (a former attorney and now writing coach) and Lisa (a physician-scientist working on HIV and global health); and seven grandchildren. Kurt was a leader in medical genetics as the specialty was first developed in the late 1950s. He was a productive physician-scientist, advancing a critical immunological assay, the mixed lymphocyte culture, and cytogenetics early in its development, leading to his description of the Wolf-Hirschho...
Source: The American Journal of Human Genetics - May 4, 2023 Category: Genetics & Stem Cells Authors: Bruce D. Gelb, Robert J. Desnick Tags: Obituary Source Type: research

This month in The Journal
Complications stemming from atherosclerosis, the hardening of arteries due to a buildup of fats and cholesterol, is the leading cause of death in the United States. Although large-scale genomics studies have identified hundreds of risk loci and nominated critical cell types, a clear picture of relevant gene signatures and cell states has yet to emerge. One complicating factor is the difficulty of obtaining sufficient human tissue samples, especially those from unaffected individuals. In this issue, Örd et al. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 4, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research