CELL PRESS 已被美国人类遗传学会选中从 2008 年 1 月开始出版其首屈一指的月刊。美国人类遗传学杂志 (AJHG) 是 CELL PRESS 作为其第一个社会所有期刊的一项令人兴奋的新冒险。美国人类遗传学会 (ASHG) 和 CELL PRESS 预计 AJHG 的内容与 CELL PRESS 的 12 个标题（包括 CELL、MOLECULAR CELL、CURRENT BIOLOGY 和 IMMUNITY）之间会产生巨大的协同作用。自 1948 年成立以来，THE AMERICAN JOURNAL OF HUMAN遗传学提供了与人类遗传相关的研究和评论记录，以及遗传原理在医学和公共政策中的应用，以及分子和细胞生物学的相关领域。

The American Journal of Human Genetics (AJHG) is a premier monthly journal published by the American Society of Human Genetics (ASHG) in collaboration with CELL PRESS, starting from January 2008. This journal represents an exciting new venture for CELL PRESS as its first society-owned journal, aiming to create significant synergies with CELL PRESS's other titles, including CELL, MOLECULAR CELL, CURRENT BIOLOGY, and IMMUNITY. Since its establishment in 1948, the American Journal of Human Genetics has provided a record of research and reviews related to human genetics, as well as the application of genetic principles in medicine and public policy, alongside relevant fields of molecular and cellular biology.

《美国人类遗传学杂志》（American Journal of Human Genetics）是由美国人类遗传学会（ASHG）与CELL PRESS合作出版的月刊，自2008年1月起发行。该杂志是CELL PRESS作为其首个社会所有期刊的一项重要尝试，旨在促进与CELL PRESS旗下其他期刊（如CELL、MOLECULAR CELL、CURRENT BIOLOGY和IMMUNITY）之间的协同作用。自1948年创刊以来，《美国人类遗传学杂志》一直致力于发布与人类遗传学相关的研究和评论，涵盖遗传学原理在医学和公共政策中的应用，以及分子和细胞生物学的相关领域。

American Journal of Human Genetics

Perrault syndrome is a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations. No genes for Perrault syndrome have heretofore been identified. A small family of mixed European ancestry includes two sisters with well-characterized Perrault syndrome. Whole-exome sequencing of genomic DNA from one of these sisters revealed exactly one gene with two rare functional variants: HSD17B4, which encodes 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4), also known as D-bifunctional protein (DBP). HSD17B4/DBP is a multifunctional peroxisomal enzyme involved in fatty acid beta-oxidation and steroid metabolism. Both sisters are compound heterozygotes for HSD17B4 c.650A>G (p.Y217C) (maternal allele) and HSB17B4 c.1704T>A (p.Y568X) (paternal allele). The missense mutation is predicted by structural analysis to destabilize the HSD17B4 dehydrogenase domain. The nonsense mutation leads to very low levels of HSD17B4 transcript. Expression of mutant HSD17B4 protein in a compound heterozygote was severely reduced. Mutations in HSD17B4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid beta-oxidation that is generally fatal within the first two years of life. No females with DBP deficiency surviving past puberty have been reported, and ovarian dysgenesis has not previously been associated with this illness. Six other families with Perrault syndrome have wild-type sequences of HSD17B4. These results indicate that Perrault syndrome and DBP deficiency overlap clinically; that Perrault syndrome is genetically heterogeneous; that DBP deficiency may be underdiagnosed; and that whole-exome sequencing can reveal critical genes in small, nonconsanguineous families.

Sarah B Pierce

Tom Walsh

Karen M Chisholm

Ming K Lee

Anne M Thornton

Agata Fiumara

John M Opitz

Ephrat Levy-Lahad

Rachel E Klevit

Mary-Claire King

American journal of human genetics

Am J Hum Genet

Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome.

DBP缺陷蛋白HSD17B4的突变导致Perrault综合征的卵巢发育不全、听力损失和共济失调。

Ossification of the posterior longitudinal ligament of the spine (OPLL) is recognized as a common disorder among Japanese and throughout Asia. Estimates of its prevalence are in the range of 1. 9%-4.3%. Although its etiology is thought to involve a multiplicity of factors, epidemiological and family studies strongly implicate genetic susceptibility in the pathogenesis of OPLL. In this study we report an identification of a predisposing locus for OPLL, on chromosome 6p, close to the HLA complex. The evidence for this localization is provided by a genetic-linkage study of 91 affected sib pairs from 53 Japanese families. In this sib-pair study, D6S276, a marker lying close to the HLA complex, gives evidence for strongly significant linkage (P = .000006) to the OPLL locus. A candidate gene in the region, that for collagen 11A2, was analyzed for the presence of molecular variants in affected probands. Of 19 distinct variants identified, 4 showed strong statistical associations with OPLL (highest P = .0004). These observations of linkage and association, taken together, show that a genetic locus for OPLL lies close to the HLA region, on chromosome 6p.

Hiroaki Koga

Takashi Sakou

Eiji Taketomi

Kyouji Hayashi

Takuya Numasawa

Seiko Harata

Kazunori Yone

Shunji Matsunaga

Brith Otterud

Ituro Inoue

Mark Leppert

The American Journal of Human Genetics

Genetic Mapping of Ossification of the Posterior Longitudinal Ligament of the Spine

脊柱后纵韧带骨化的基因定位

Spinal muscular atrophy (SMA) is a neuromuscular disease causing the most frequent genetic childhood lethality. Recently, nusinersen, an antisense oligonucleotide (ASO) that corrects SMN2 splicing and thereby increases full-length SMN protein, has been approved by the FDA and EMA for SMA therapy. However, the administration of nusinersen in severe and/or post-symptomatic SMA-affected individuals is insufficient to counteract the disease. Therefore, additional SMN-independent therapies are needed to support the function of motoneurons and neuromuscular junctions. We recently identified asymptomatic SMN1-deleted individuals who were protected against SMA by reduced expression of neurocalcin delta (NCALD). NCALD reduction is proven to be a protective modifier of SMA across species, including worm, zebrafish, and mice. Here, we identified Ncald-ASO3-out of 450 developed Ncald ASOs-as the most efficient and non-toxic ASO for the CNS, by applying a stepwise screening strategy in cortical neurons and adult and neonatal mice. In a randomized-blinded preclinical study, a single subcutaneous low-dose SMN-ASO and a single intracerebroventricular Ncald-ASO3 or control-ASO injection were presymptomatically administered in a severe SMA mouse model. NCALD reduction of >70% persisted for about 1 month. While low-dose SMN-ASO rescues multiorgan impairment, additional NCALD reduction significantly ameliorated SMA pathology including electrophysiological and histological properties of neuromuscular junctions and muscle at P21 and motoric deficits at 3 months. The present study shows the additional benefit of a combinatorial SMN-dependent and SMN-independent ASO-based therapy for SMA. This work illustrates how a modifying gene, identified in some asymptomatic individuals, helps to develop a therapy for all SMA-affected individuals.

Laura Torres-Benito

Svenja Schneider

Roman Rombo

Karen K Ling

Vanessa Grysko

Aaradhita Upadhyay

Natalia L Kononenko

Frank Rigo

C Frank Bennett

Brunhilde Wirth

NCALD Antisense Oligonucleotide Therapy in Addition to Nusinersen further Ameliorates Spinal Muscular Atrophy in Mice.

NCALD反义寡核苷酸疗法联合nusinersen进一步改善小鼠脊髓性肌萎缩。

Sébastien Küry

Thomas Besnard

Frédéric Ebstein

Tahir N Khan

Tomasz Gambin

Jessica Douglas

Carlos A Bacino

William J Craigen

Stephan J Sanders

Andrea Lehmann

Xénia Latypova

Kamal Khan

Mathilde Pacault

Stephanie Sacharow

Kimberly Glaser

Eric Bieth

Laurence Perrin-Sabourin

Marie-Line Jacquemont

Megan T Cho

Elizabeth Roeder

Anne-Sophie Denommé-Pichon

Kristin G Monaghan

Bo Yuan

Fan Xia

Sylvain Simon

Dominique Bonneau

Philippe Parent

Brigitte Gilbert-Dussardier

Sylvie Odent

Annick Toutain

Laurent Pasquier

Deborah Barbouth

Chad A Shaw

Ankita Patel

Janice L Smith

Weimin Bi

Sébastien Schmitt

Wallid Deb

Mathilde Nizon

Sandra Mercier

Marie Vincent

Caroline Rooryck

Valérie Malan

Ignacio Briceño

Alberto Gómez

Kimberly M Nugent

James B Gibson

Benjamin Cogné

James R Lupski

Holly A F Stessman

Evan E Eichler

Kyle Retterer

Yaping Yang

Richard Redon

Nicholas Katsanis

Jill A Rosenfeld

Peter-Michael Kloetzel

Christelle Golzio

Stéphane Bézieau

Paweł Stankiewicz

Bertrand Isidor

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

蛋白酶体调节亚基PSMD12的新发破坏导致一种综合征性神经发育障碍。

SummaryVery–long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid β-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established. Very–long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid β-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.

Brage Storstein Andresen

Simon Olpin

Ben J.H.M. Poorthuis

Hans R. Scholte

Christine Vianey-Saban

Ronald Wanders

Lodewijk Ijlst

Andrew Morris

Morteza Pourfarzam

Kim Bartlett

E. Regula Baumgartner

Johannis B.C. deKlerk

Lisbeth Dahl Schroeder

Thomas J. Corydon

Hans Lund

Vibeke Winter

Peter Bross

Lars Bolund

Niels Gregersen

Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency

长链酰基辅酶A脱氢酶缺乏症中基因型与疾病表型的明确关联

Cancer incidence and mortality differ among individuals of different ages, but the functional consequences of genetic alterations remain largely unknown. We systematically characterized genetic alterations within protein domains stratified by affected individual's age and showed that the mutational effects on domains varied with age. We further identified potential age-associated driver genes with hotspots across 33 cancers. The candidate drivers involved numerous cancer-related genes that participate in various oncogenic pathways and play central roles in human protein-protein interaction (PPI) networks. We found widespread age biases in protein domains and identified the associations between hotspots and age. Age-stratified PPI networks perturbed by hotspots were constructed to illustrate the function of mutations enriched in domains. We found that hotspots in young adults were associated with premature senescence. In summary, we provided a catalog of age-associated hotspots and their perturbed networks, which may facilitate precision diagnostics and treatments for cancer.

Haozhe Zou

Si Li

Jiyu Guo

Luan Wen

Chongwen Lv

Feng Leng

Zefeng Chen

Mengqian Zeng

Juan Xu

Yongsheng Li

Xia Li

Pan-cancer analysis reveals age-associated genetic alterations in protein domains

泛癌分析揭示蛋白质结构域中与年龄相关的遗传变异

EP400 encodes a core catalytic ATPase subunit of ATP-dependent chromatin remodeling complexes. The gene-disease association of EP400 is undetermined. In this study, we performed trio-based whole-exome sequencing in a cohort of 402 families with epilepsy and neurodevelopmental disorders (NDDs) and identified compound heterozygous EP400 variants in six unrelated individuals. Six additional EP400 individuals were recruited via the match platform of China, including two de novo heterozygous and four compound heterozygous variants. The individual with a heterozygous de novo frameshift variant presented with NDDs, while the others exhibited epilepsy and NDDs, explained by the damaged genetic dependence quantity. EP400 presented significantly higher excesses of variants in the individuals. Clustering analysis revealed that the majority paralogs of EP400 were associated with NDDs/epilepsy and co-expressed highly with EP400. Analysis of the spatiotemporal expression indicated that EP400 is highly expressed in the developing brain and cells during differentiation, indicating its vital role in neurodevelopment; EP400 is predominantly expressed in inhibitory neurons in the early stage but in excitatory neurons in the mature stage. The development-dependent expression pattern of neuron specificity explained the favorable outcome of epilepsy. Knockdown of EP400 ortholog in Drosophila caused significantly increased susceptibility to seizures and abnormal neuronal firing. The ep400 crispant zebrafish exhibited brain developmental abnormalities, poorer adaptability, lower response to stimulation, epileptic discharges, abnormal cellular apoptosis, and increased susceptibility to seizures. Transcriptome analysis showed that ep400 deficiency caused expressional dysregulation of 84 epilepsy/NDD-associated genes, including 11 highly dose-sensitive genes. This study identified EP400 as a causative gene of epilepsy/NDDs.

Sheng Luo

Peng-Yu Wang

Peng Zhou

Wen-Jun Zhang

Yu-Jie Gu

Xiao-Yu Liang

Jing-Wen Zhang

Jun-Xia Luo

Hong-Wei Zhang

Song Lan

Ting-Ting Zhang

Jie-Hua Yang

Su-Zhen Sun

Xiang-Yang Guo

Ju-Li Wang

Lin-Fan Deng

Ze-Hai Xu

Liang Jin

Yun-Yan He

Zi-Long Ye

Wei-Yue Gu

Bing-Mei Li

Yi-Wu Shi

Xiao-Rong Liu

Hong-Jun Yan

Yong-Hong Yi

Yu-Wu Jiang

Xiao Mao

Wen-Ling Li

Heng Meng

Wei-Ping Liao

Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders

编码染色质重塑因子的EP400基因变异导致癫痫伴神经发育障碍

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.

Marcello Scala

Clarrisa A Bradley

Jennifer L Howe

Brett Trost

Nelson Bautista Salazar

Carole Shum

Marla Mendes

Miriam S Reuter

Evdokia Anagnostou

Jeffrey R MacDonald

Sangyoon Y Ko

Paul W Frankland

Jessica Charlebois

Mayada Elsabbagh

Leslie Granger

George Anadiotis

Verdiana Pullano

Alfredo Brusco

Roberto Keller

Sarah Parisotto

Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus

DDX53基因变异与Xp22.11位点相关的自闭症谱系障碍有关

Abbreviation	Am. J. Hum. Genet.
Journal Impact	8.18
Quartiles(Global)	GENETICS & HEREDITY(Q1)

ISSN	0002-9297, 1537-6605
h-index	330
Top Journals	Yes

Publication Information	Publisher: Cell Press，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1950，Proportion of original research papers: 96.18%，Self Citation Rate:3.70%， Gold OA Rate: 82.67%
Average review cycle	网友分享经验：一般,3-6周
Average recruitment ratio	网友分享经验：很难

American Journal of Human Genetics

Journal Citation Format

A journal article with 1 author

A journal article with 2 authors

A journal article with 3 authors

A journal article with 5 or more authors

Books Citation Format

Thesis Citation Format

Web sites Citation Format

Patent Citation Format

Staying up late manually editing references? ivySCI automatically matches journals and helps you generate references with a single click.

Share Submission Experience