Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse
The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Frederick N. Dong, Amir Amiri-Yekta, Guillaume Martinez, Antoine Saut, Julie Tek, Laurence Stouvenel, Patrick Lor ès, Thomas Karaouzène, Nicolas Thierry-Mieg, Véronique Satre, Sophie Brouillet, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Mélanie Bonhi Tags: Article Source Type: research

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome
In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Patrick R. Blackburn, Zhi Xu, Kathleen E. Tumelty, Rose W. Zhao, William J. Monis, Kimberly G. Harris, Jennifer M. Gass, Margot A. Cousin, Nicole J. Boczek, Mario V. Mitkov, Mark A. Cappel, Clair A. Francomano, Joseph E. Parisi, Eric W. Klee, Eissa Faqeih Tags: Report Source Type: research

Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility
Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in  vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. (Source: The American ...
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang Chen, Ling Wu, Qifeng Lyu, Yonglun Fu, Zheng Yan, Xiaoyan Mao, Yao Xu, Jian Mu, Qiaoli Li, Li Jin, Lin He, Lei Wang Tags: Article Source Type: research

PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses and Clinical Measures across 38,662 Individuals from Geisinger
Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We  calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency> 0.01 for 38,662 individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Anurag Verma, Anastasia Lucas, Shefali S. Verma, Yu Zhang, Navya Josyula, Anqa Khan, Dustin N. Hartzel, Daniel R. Lavage, Joseph Leader, Marylyn D. Ritchie, Sarah A. Pendergrass Tags: Article Source Type: research

Biallelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome
In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Patrick R. Blackburn, Zhi Xu, Kathleen E. Tumelty, Rose W. Zhao, William J. Monis, Kimberly G. Harris, Jennifer M. Gass, Margot A. Cousin, Nicole J. Boczek, Mario V. Mitkov, Mark A. Cappel, Clair A. Francomano, Joseph E. Parisi, Eric W. Klee, Eissa Faqeih Tags: Report Source Type: research

Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse
The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: Frederick N. Dong, Amir Amiri-Yekta, Guillaume Martinez, Antoine Saut, Julie Tek, Laurence Stouvenel, Patrick Lor ès, Thomas Karaouzène, Nicolas Thierry-Mieg, Véronique Satre, Sophie Brouillet, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Mélanie Bonhi Tags: Article Source Type: research

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy
Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: Marisa I. Mendes, Mariana Gutierrez Salazar, Kether Guerrero, Isabelle Thiffault, Gajja S. Salomons, Laurence Gauquelin, Luan T. Tran, Diane Forget, Marie-Soleil Gauthier, Quinten Waisfisz, Desiree E.C. Smith, Cas Simons, Marjo S. van der Knaap, Iris Marq Tags: Report Source Type: research

Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: Thatjana Gardeitchik, Miski Mohamed, Benedetta Ruzzenente, Daniela Karall, Sergio Guerrero-Castillo, Daisy Dalloyaux, Mari ël van den Brand, Sanne van Kraaij, Ellyze van Asbeck, Zahra Assouline, Marlene Rio, Pascale de Lonlay, Sabine Scholl-Buergi, David Tags: Report Source Type: research

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: F.-Nora V ögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossm Tags: Article Source Type: research

Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: Thatjana Gardeitchik, Miski Mohamed, Benedetta Ruzzenente, Daniela Karall, Sergio Guerrero-Castillo, Daisy Dalloyaux, Mari ël van den Brand, Sanne van Kraaij, Ellyze van Asbeck, Zahra Assouline, Marlene Rio, Pascale de Lonlay, Sabine Scholl-Buergi, David Tags: Report Source Type: research

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy
Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: Marisa I. Mendes, Mariana Gutierrez Salazar, Kether Guerrero, Isabelle Thiffault, Gajja S. Salomons, Laurence Gauquelin, Luan T. Tran, Diane Forget, Marie-Soleil Gauthier, Quinten Waisfisz, Desiree E.C. Smith, Cas Simons, Marjo S. van der Knaap, Iris Marq Tags: Report Source Type: research

Biallelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: Thatjana Gardeitchik, Miski Mohamed, Benedetta Ruzzenente, Daniela Karall, Sergio Guerrero-Castillo, Daisy Dalloyaux, Mari ël van den Brand, Sanne van Kraaij, Ellyze van Asbeck, Zahra Assouline, Marlene Rio, Pascale de Lonlay, Sabine Scholl-Buergi, David Tags: Report Source Type: research

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 22, 2018 Category: Genetics & Stem Cells Authors: F.-Nora V ögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossm Tags: Article Source Type: research

Relationship between Deleterious Variation, Genomic Autozygosity, and Disease Risk: Insights from The 1000 Genomes Project
Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations —relatively untouched by purifying selection—being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome se...
Source: The American Journal of Human Genetics - March 15, 2018 Category: Genetics & Stem Cells Authors: Trevor J. Pemberton, Zachary A. Szpiech Tags: Article Source Type: research

Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase
Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB). We investigated the origins of the sickle mutation by using whole-genome-sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Daniel Shriner, Charles N. Rotimi Tags: Article Source Type: research

Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease
Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal- recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Silvia Albert, Alejandro Garanto, Riccardo Sangermano, Mubeen Khan, Nathalie M. Bax, Carel B. Hoyng, Jana Zernant, Winston Lee, Rando Allikmets, Rob W.J. Collin, Frans P.M. Cremers Tags: Article Source Type: research

Outcomes of Counseling after Education about Carrier Results: A Randomized Controlled Trial
In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post-reproductive participants from the ClinSeq cohort within a randomized controlled trial. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Katie L. Lewis, Kendall L. Umstead, Jennifer J. Johnston, Ilana M. Miller, Lydia J. Thompson, Kristen P. Fishler, Leslie G. Biesecker, Barbara B. Biesecker Tags: Article Source Type: research

Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity
Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion ( ≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers>76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (...
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J. Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma ’ayan Semo, Anthony A. Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J. Levis, Pavlina Skalicka, Pirro Hysi, Michael E. Chee Tags: Article Source Type: research

Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease
Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal- recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Silvia Albert, Alejandro Garanto, Riccardo Sangermano, Mubeen Khan, Nathalie M. Bax, Carel B. Hoyng, Jana Zernant, Winston Lee, Rando Allikmets, Rob W.J. Collin, Frans P.M. Cremers Tags: Article Source Type: research

Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase
Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB). We investigated the origins of the sickle mutation by using whole-genome-sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Daniel Shriner, Charles N. Rotimi Tags: Article Source Type: research

Outcomes of Counseling after Education about Carrier Results: A Randomized Controlled Trial
In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post-reproductive participants from the ClinSeq cohort within a randomized controlled trial. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Katie L. Lewis, Kendall L. Umstead, Jennifer J. Johnston, Ilana M. Miller, Lydia J. Thompson, Kristen P. Fishler, Leslie G. Biesecker, Barbara B. Biesecker Tags: Article Source Type: research

Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity
Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion ( ≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers>76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (...
Source: The American Journal of Human Genetics - March 8, 2018 Category: Genetics & Stem Cells Authors: Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J. Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma ’ayan Semo, Anthony A. Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J. Levis, Pavlina Skalicka, Pirro Hysi, Michael E. Chee Tags: Article Source Type: research

2017 William Allan Award Introduction: K ári Stefansson1
It is a great honor for me to introduce the winner of this year ’s William Allan Award, Dr. Kári Stefansson. Mark McCarthy may have put it best when, in preparing Kári’s nomination, he noted that “It is hard to think of any other human geneticist who has played such a singular and transformative role with respect to the evolution and revolution within ou r field.” (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Mark J. Daly Tags: ASHG Awards and Addresses Source Type: research

2017 Victor A. McKusick Leadership Award1
It is an extraordinary honor to receive this award. I want to thank the ASHG Board and all who had any part in making the award possible. I first encountered Victor McKusick in 1967 while I was a pediatric resident, and I would like to recognize the recent passing of his always present partner, Anne. I view this award as recognition for my participation in building a medical genetics program at Baylor College of Medicine in Houston. This effort has involved hundreds of individuals and 46 years. So the recognition goes to a team effort. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Arthur L. Beaudet Tags: ASHG Awards and Addresses Source Type: research

2017 William Allan Award1
Thank you, thank you for giving me this award. My understanding is that it is given for having contributed to human genetics over a long period of time. My assumption is that I am given this award for what is considered to be a good story that can be told with my work in human genetics. And please do not correct me if I am wrong. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: K ári Stefansson Tags: ASHG Awards and Addresses Source Type: research

2017 Curt Stern Award Introduction: Nico Katsanis1
Dear colleagues, (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Han G. Brunner Tags: ASHG Awards and Addresses Source Type: research

2017 ASHG Awards and Addresses
Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Tags: ASHG Awards and Addresses Source Type: research

2017 Victor A. McKusick Leadership Award Introduction: Arthur L. Beaudet1
I am delighted to introduce Dr. Arthur Beaudet as this year ’s recipient of the ASHG Victor A. McKusick Leadership Award. The award is in recognition of individuals who “exemplify the enduring leadership and vision required to ensure that the field of human genetics will flourish and successfully assimilate into the broader context of science, medicine, and health.” There is no better individual who exemplifies these ideals than Arthur L. Beaudet. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Brendan Lee Tags: ASHG Awards and Addresses Source Type: research

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more  than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way—by combining data from seven countries on four continents—we were able to define mutations in ATP1A1, which encode s the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Petra Lassuthova, Adriana P. Rebelo, Gianina Ravenscroft, Phillipa J. Lamont, Mark R. Davis, Fiore Manganelli, Shawna M. Feely, Chelsea Bacon, Dana Šafka Brožková, Jana Haberlova, Radim Mazanec, Feifei Tao, Cima Saghira, Lisa Abreu, Steve Courel, Eric Tags: Report Source Type: research

Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease
Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Paul W. Hook, Sarah A. McClymont, Gabrielle H. Cannon, William D. Law, A. Jennifer Morton, Loyal A. Goff, Andrew S. McCallion Tags: Article Source Type: research

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4
In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3 –q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected f...
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidso Tags: Article Source Type: research

2017 Curt Stern Award: The Complexity of Simple Genetics1
Leo Tolstoy famously remarked that happy families are all alike but that every unhappy family is unhappy in its own way. The adage that applied to Anna Karenina is just as apt a description for most Ph.D. students. A smooth transition to a doctorate can be described uniformly as one where experiments work more frequently than not, papers get published in high-quality journals, and students matriculate on time and with a minimum of stress or fuss. Alas, that utopian journey is seldom found, and such was the case when I found myself struggling a year or two into my Ph.D. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Nicholas Katsanis Tags: ASHG Awards and Addresses Source Type: research

Arno G. Motulsky (1923 –2018): A Founder of Medical Genetics, Creator of Pharmacogenetics, and Former ASHG President
Arno G. Motulsky, MD, a father of our field, was born in Germany on July 5, 1923, and died in Seattle on January 17, 2018, at 94 years of age. Through his research, writing, and mentoring, he was one of the founders of modern human and medical genetics. He created the field of pharmacogenetics. His life and career were in every way remarkable. His contributions as a scientist, physician, and mentor cannot be overstated. But first, he was a refugee. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Gail P. Jarvik, Mary-Claire King Tags: Obituary Source Type: research

2017 Presidential Address: Checking, Balancing, and Celebrating Diversity: Celebrating Some of the Women Who Paved the Way1
Given that the verbal presentation and slides of the 2017  ASHG presidential address are available on the ASHG website, it seemed appropriate to take the opportunity in this article to provide more detailed information on some of the women—highlighted in the presentation—who have made contributions to the science of human genetics. Among those highlig hted, I will focus on the subset of women who I have known personally. Human genetics has a long history of strong female scientists who not only contributed greatly to science but also paved—and smoothed—the way for those who came after. (Source:...
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Nancy J. Cox Tags: ASHG Awards and Addresses Source Type: research

This Month in The Journal
Elevated blood pressure is a well-recognized risk factor for conditions such as heart disease, heart failure, and stroke. Blood pressure, in turn, is influenced by several factors, both genetic and non-genetic. However, there is a lack of understanding regarding the potential for lifestyle (e.g., choices related to smoking, alcohol consumption, diet, and exercise) to modulate how genetic variation influences blood pressure. To gain insight into this issue, Sung et  al. incorporated smoking status into a genome-wide meta-analysis of systolic and diastolic blood pressure in over 600,000 individuals spanning multiple anc...
Source: The American Journal of Human Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Inherited DNA-Repair Defects in Colorectal Cancer
Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. (Source: ...
Source: The American Journal of Human Genetics - February 22, 2018 Category: Genetics & Stem Cells Authors: Saud H. AlDubayan, Marios Giannakis, Nathanael D. Moore, G. Celine Han, Brendan Reardon, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Reiko Nishihara, Zhirong Qian, Li Liu, Matthew B. Yurgelun, Sapna Syngal, Levi A. Garraway, Shuji Ogino, Charles S. Fuchs, Elieze Tags: Article Source Type: research

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder
ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acido sis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute ...
Source: The American Journal of Human Genetics - February 22, 2018 Category: Genetics & Stem Cells Authors: Monika Ol áhová, Wan Hee Yoon, Kyle Thompson, Sharayu Jangam, Liliana Fernandez, Jean M. Davidson, Jennifer E. Kyle, Megan E. Grove, Dianna G. Fisk, Jennefer N. Kohler, Matthew Holmes, Annika M. Dries, Yong Huang, Chunli Zhao, Kévin Contrepois, Zachary Tags: Report Source Type: research

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children
Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 22, 2018 Category: Genetics & Stem Cells Authors: Anu Bashamboo, Caroline Eozenou, Anne Jorgensen, Joelle Bignon-Topalovic, Jean-Pierre Siffroi, Capucine Hyon, Attila Tar, P éter Nagy, Janos Sólyom, Zita Halász, Annnabel Paye-Jaouen, Sophie Lambert, David Rodriguez-Buritica, Rita Bertalan, Laetitia Ma Tags: Report Source Type: research

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promisin...
Source: The American Journal of Human Genetics - February 15, 2018 Category: Genetics & Stem Cells Authors: Yun J. Sung, Thomas W. Winkler, Lisa de las Fuentes, Amy R. Bentley, Michael R. Brown, Aldi T. Kraja, Karen Schwander, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K. Mu Tags: Article Source Type: research

Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures
The spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and provides insight into the functional importance of protein regions and the potential pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of human germline and somatic variation in 6,604 experimentally derived protein structures and 33,144 computationally derived homology models covering 77% of all human proteins. Using a systematic approach, we quantify differences in the spatial distributions of neutral germline variants, disease-causing germline variants, and recurrent somatic...
Source: The American Journal of Human Genetics - February 15, 2018 Category: Genetics & Stem Cells Authors: R. Michael Sivley, Xiaoyi Dou, Jens Meiler, William S. Bush, John A. Capra Tags: Article Source Type: research

Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: S...
Source: The American Journal of Human Genetics - February 15, 2018 Category: Genetics & Stem Cells Authors: Kazutoshi Cho, Masafumi Yamada, Kazunaga Agematsu, Hirokazu Kanegane, Noriko Miyake, Masahiro Ueki, Takuma Akimoto, Norimoto Kobayashi, Satoru Ikemoto, Mishie Tanino, Atsushi Fujita, Itaru Hayasaka, Satoshi Miyamoto, Mari Tanaka-Kubota, Koh Nakata, Masaak Tags: Report Source Type: research

NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy
Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. (Source: The American...
Source: The American Journal of Human Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Dorota Piekutowska-Abramczuk, Zahra Assouline, Lavinija Matakovi ć, René G. Feichtinger, Eliška Koňařiková, Elżbieta Jurkiewicz, Piotr Stawiński, Mirjana Gusic, Andreas Koller, Agnieszka Pollak, Piotr Gasperowicz, Joanna Trubicka, Elżbieta Ciara, Tags: Report Source Type: research

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in  vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolis...
Source: The American Journal of Human Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aur élie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugela Tags: Article Source Type: research

Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome
Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Georgia Vasileiou, Silvia Vergarajauregui, Sabine Endele, Bernt Popp, Christian B üttner, Arif B. Ekici, Marion Gerard, Nuria C. Bramswig, Beate Albrecht, Jill Clayton-Smith, Jenny Morton, Susan Tomkins, Karen Low, Astrid Weber, Maren Wenzel, Janine Altm Tags: Report Source Type: research

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Laura Bozal-Basterra, Itziar Mart ín-Ruíz, Lucia Pirone, Yinwen Liang, Jón Otti Sigurðsson, Maria Gonzalez-Santamarta, Immacolata Giordano, Estibaliz Gabicagogeascoa, Angela de Luca, Jose A. Rodríguez, Andrew O.M. Wilkie, Jürgen Kohlhase, Deborah Ea Tags: Article Source Type: research

Bible Says Israelites Didn't Exterminate Sidonians
To the Editor: In an otherwise excellent and well-sourced article, Haber et  al.1 stated, “Uncertainties also surround the fate of the Canaanites: the Bible reports the destruction of the Canaanite cities and the annihilation of its people; if true, the Canaanites could not have directly contributed genetically to present-day populations. However, no archaeological evide nce has so far been found to support widespread destruction of Canaanite cities between the Bronze and Iron Ages: cities on the Levant coast such as Sidon and Tyre show continuity of occupation until the present day.” No references are pro...
Source: The American Journal of Human Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Paul Giem Tags: Letter to the Editor Source Type: research

Response to Giem
To the Editor: Giem suggests1 that our statement “the Bible reports the destruction of the Canaanite cities and the annihilation of its people”2 is inaccurate and not supported by references. The Bible reports “And Israel vowed a vow unto the Lord, and said, If thou wilt indeed deliver this people into my hand, then I will utterly destroy th eir cities. And the Lord hearkened to the voice of Israel, and delivered up the Canaanites; and they utterly destroyed them and their cities: and he called the name of the place Hormah.”3 Within a longer account, it further reports “And the Lord delivered ...
Source: The American Journal of Human Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Micha ł Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas K Tags: Letter to the Editor Source Type: research

Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation
Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Anthony Drecourt, Jo ël Babdor, Michael Dussiot, Floriane Petit, Nicolas Goudin, Meriem Garfa-Traoré, Florence Habarou, Christine Bole-Feysot, Patrick Nitschké, Chris Ottolenghi, Metodi D. Metodiev, Valérie Serre, Isabelle Desguerre, Nathalie Boddaert Tags: Article Source Type: research

Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome
15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Jiani Yin, Wu Chen, Eugene S. Chao, Sirena Soriano, Li Wang, Wei Wang, Steven E. Cummock, Huifang Tao, Kaifang Pang, Zhandong Liu, Fred A. Pereira, Rodney C. Samaco, Huda Y. Zoghbi, Mingshan Xue, Christian P. Schaaf Tags: Article Source Type: research