美国医学遗传学杂志 - A 部分 (AJMG) 为您提供遗传疾病和出生缺陷的所有生物学和医学方面的持续报道，以及在当前基因型/表型相关性的背景下深入记录表型分析。除了 A 部分，AJMG 还出版了另外两个部分： B 部分：神经精神遗传学，涵盖了对神经和精神疾病遗传机制的实验和临床研究。 C 部分：医学遗传学研讨会，客座编辑的主题评论合集AJMG 读者的热门话题。

The American Journal of Medical Genetics, Part A focuses on the biological and medical aspects of genetic disorders and birth defects, providing ongoing research and in-depth analysis of phenotype in the context of current genotype/phenotype correlations. In addition to Part A, AJMG publishes two other parts: Part B, which covers experimental and clinical studies on the genetic mechanisms of neuropsychiatric disorders; and Part C, which is a collection of themed reviews edited by guest editors on topics of interest to AJMG readers.

《American Journal of Medical Genetics, Part A》（美国医学遗传学杂志 - A 部分）专注于遗传疾病和出生缺陷的生物学与医学各个方面的持续研究，深入探讨基因型与表型之间的关系。除了 A 部分外，AJMG 还出版了两个其他部分：B 部分专注于神经精神遗传学，涵盖神经和精神疾病的遗传机制的实验与临床研究；C 部分则是医学遗传学研讨会，汇集了客座编辑对AJMG读者感兴趣的热门话题的评论合集。

American Journal of Medical Genetics, Part A

Abstract Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease‐causing PUF60 SNVs have been reported in peer‐reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients ( n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.

Andrew Paul Fennell

Anne Elizabeth Baxter

Samuel Frank Berkovic

Carolyn Jane Ellaway

Caitlin Forwood

Michael Stephen Hildebrand

Smitha Kumble

Colina McKeown

David Mowat

Gemma Poke

Sulekha Rajagopalan

Brigid M. Regan

Ingrid Eileen Scheffer

Zornitza Stark

Chloe Alice Stutterd

Tiong Yang Tan

Ella Jane Wilkins

Alison Yeung

Matthew Frank Hunter

American Journal of Medical Genetics Part A

The diverse pleiotropic effects of spliceosomal protein <scp>PUF60</scp>: A case series of Verheij syndrome

剪接体蛋白<scp>PUF60</scp>的多效性影响：Verheij综合征病例系列

The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.

Anita Rauch

Juliane Hoyer

Sabine Guth

Christiane Zweier

Cornelia Kraus

Christian Becker

Martin Zenker

Ulrike Hüffmeier

Christian Thiel

Franz Rüschendorf

Peter Nürnberg

André Reis

Udo Trautmann

Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation

各种遗传学方法在不明原因发育迟缓或智力障碍患者中的诊断率

American Journal of Medical Genetics Part AVolume 149A, Issue 7 p. 1578-1580 Research Letter A case of Asian Indian OCA3 patient† Pei-Wen Chiang, Corresponding Author Pei-Wen Chiang pei-wen.chiang@ucdenver.edu UC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UC Denver School of Medicine, Aurora, ColoradoUC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UCDHSC, Aurora, Colorado.Search for more papers by this authorElaine Spector, Elaine Spector UC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UC Denver School of Medicine, Aurora, ColoradoSearch for more papers by this authorAngela Scheuerle, Angela Scheuerle Tesserae Genetics, Dallas, TexasSearch for more papers by this author Pei-Wen Chiang, Corresponding Author Pei-Wen Chiang pei-wen.chiang@ucdenver.edu UC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UC Denver School of Medicine, Aurora, ColoradoUC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UCDHSC, Aurora, Colorado.Search for more papers by this authorElaine Spector, Elaine Spector UC Denver DNA Diagnostic Laboratory, Department of Pediatrics, UC Denver School of Medicine, Aurora, ColoradoSearch for more papers by this authorAngela Scheuerle, Angela Scheuerle Tesserae Genetics, Dallas, TexasSearch for more papers by this author First published: 16 June 2009 https://doi.org/10.1002/ajmg.a.32930Citations: 13 † How to cite this article: Chiang P-W, Spector E, Scheuerle A. 2009. A case of Asian Indian OCA3 patient. Am J Med Genet Part A 149A:1578–1580. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume149A, Issue7July 2009Pages 1578-1580 RelatedInformation

Pei‐Wen Chiang

Elaine Spector

Angela Scheuerle

A case of Asian Indian OCA3 patient

一例亚洲印度OCA3患者病例

Abstract The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1 . However, there have been reports of SMA‐like disorders that are independent of SMN1 , including those due to pathogenic variants in the glycyl‐tRNA synthetase gene ( GARS1 ) . We report three unrelated patients with de novo variants in GARS1 that are associated with infantile‐onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease‐associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss‐of‐function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot–Marie–Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS ‐associated disease and support that severe early‐onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.

Rebecca Markovitz

Rajarshi Ghosh

Molly E. Kuo

William Hong

Jaehyung Lim

Saunder Bernes

Stephanie Manberg

Kathleen Crosby

Pranoot Tanpaiboon

Diana Bharucha‐Goebel

Carsten Bonnemann

Carrie A. Mohila

Elizabeth Mizerik

Suzanne Woodbury

Weimin Bi

Timothy Lotze

Anthony Antonellis

Rui Xiao

Lorraine Potocki

Am J Med Genet

GARS‐related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

婴儿脊髓性肌萎缩症中的GARS相关疾病：对诊断和治疗的启示

Abstract Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The absence of the SMN1 gene has been shown to occur in all types of SMA, childhood and adult forms. In rare cases, asymptomatic family members have also been found with homozygous mutations in the SMN1 gene, suggesting a role for phenotypic modifiers. We describe three unrelated asymptomatic individuals, with family histories of SMA, who were shown to have the homozygous SMN1 deletion. Quantitative studies indicated that the three individuals all had increased SMN2 copy numbers. These cases not only support the role of SMN2 in modifying the phenotype, but our data also demonstrate that expression levels consistent with five copies of the SMN2 genes maybe enough to compensate for the absence of the SMN1 gene. Lastly, in cases similar to the ones described, the measurement of the SMN2 gene copy number may provide valuable prognostic information. © 2004 Wiley‐Liss, Inc.

Thomas W. Prior

Kathryn J. Swoboda

H. Denman Scott

Ashley Q. Hejmanowski

Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2

无症状家族成员中的纯合SMN1缺失及SMN2对表型的修饰

ABSTRACT Niemann‐Pick disease, type C1 (NPC1) is an ultra rare, autosomal recessive disorder characterized by impaired intracellular cholesterol trafficking. This study assessed neuron‐specific enolase (NSE) as a biomarker for disease status and treatment response in individuals with NPC1. We also evaluated the concordance between serum and cerebrospinal fluid (CSF) NSE measurements. A total of 34 individuals with NPC1 were included in this analysis. Overall, 10 participants were used to compare concurrent samples of CSF and serum NSE. NSE levels were correlated with indexes of disease severity (Annual Severity Increment Score [ASIS] and age of neurological onset) and disease burden (NPC Neurological Severity Score [NSS]). NSE was elevated in CSF, but paired CSF/serum samples were not correlated ( r s = −0.16, p = 0.64). Additionally, no significant correlations were observed between serum NSE levels and clinical measures of either disease burden or severity. CSF NSE values showed a significant positive association with the ASIS ( r s = 0.37, p = 0.0291) but no association with age of neurological onset or NPC NSSs. Longitudinal analysis of nine participants showed a significant ( p = 0.0317) decrease in CSF NSE levels after initiation of intrathecal 2‐hydroxypropyl‐β‐cyclodextrin (IT HPβCD) therapy. This study suggests that CSF NSE may have some utility as a biomarker in NPC1 therapeutic trials.

Cameron J. Padilla

Derek M. Alexander

Desiree A. Labor

Orsolya K. Albert

Kendall P. Robbins

Elizabeth Berry‐Kravis

Forbes D. Porter

Cerebrospinal Fluid and Serum Neuron‐Specific Enolase in Niemann‐Pick Disease Type <scp>C1</scp>

脑脊液和血清神经元特异性烯醇化酶在尼曼-皮克病C1型中的研究

ABSTRACT Epidermolysis Bullosa (EB) is a group of genetic skin disorders characterized by extreme skin fragility and blistering. In North African countries, including Tunisia, complex genetic and phenotypic diversity is entangled with a scarcity of scientific research on EB. This lack of knowledge presents a distinct challenge in terms of diagnostic accuracy and patient care. Our study cohort includes 10 Tunisian patients with EB whose genetic profiles were investigated by exome sequencing. In silico analysis was conducted to determine the functional impact of three novel variants. We revealed ten genetic variants, including three novel ones within the COL7A1 and DST genes. The in silico analysis shed light on the potential structural and functional implications of these novel variants. By establishing the correlation between clinical features and genetic alterations, we have expanded the existing database of disease‐causing variants associated with EB in Northern Africa. Our study fills a critical knowledge gap in the North African context, where the scarcity of clinical database and genetic testing in addition to the genetic diversity necessitates comprehensive research. Our findings have the potential to improve diagnosis and management strategies for EB patients in low and middle‐income countries across the region, especially through the integration of exome sequencing and in silico analysis.

Haifa El Mabrouk

Houcemeddine Othman

Lobna Boussofarra

Moez Gribaa

Ali Saad

Mohamed Denguezli

Cristina Has

Dorra H'mida

Genetic Insights Into Epidermolysis Bullosa: Identification of Novel Variants in Tunisian Patients

遗传性大疱性表皮松解症的遗传学洞察：在突尼斯患者中鉴定出新型变异

ABSTRACT Angelman syndrome (AS) is a severe genetic neurodevelopmental disorder with an estimated prevalence of 1:20,000. Life expectancy appears to be normal, however, data regarding lifespan in AS are scarce. Until 2018, there was no unique diagnosis code for AS, thus true incidence, prevalence, mortality and morbidity rates are unknown. A social media effort was launched by caregivers of people with AS to gather community‐sourced data to understand AS mortality risks. Information on 220 deaths was verified with obituaries and public postings. Respiratory illness was the primary cause of death among people with AS overall, followed by accidents and seizures. Surprisingly, sudden unexpected death in sleep (SUDS) was the fourth most common cause, which has not been reported previously. Approximately 91% of people with AS have epilepsy, thus some SUDS cases may represent sudden unexpected deaths in epilepsy (SUDEP). Causes of death vary by age, and differ from the general population. Though there are obvious limitations to data collected through social media, grass roots science is a starting point to amass preliminary data and inform future epidemiological research on AS.

Adriana T. Gomes

Amanda Moore

Meagan Cross

Cristy Hardesty

Kelly David

Maria Galan Sampedro

Sophie Dube

Sharon Weil‐Chalker

Adela Gentil Montepagano

Ursula Christel

Rachel Martin

Anne Wheeler

Wen‐Hann Tan

Lynne M. Bird

Terry Jo Bichell

Community‐Sourced Reporting of Mortalities in Angelman Syndrome (1979–2022)

社区来源的安格曼综合征死亡报告（1979-2022年）

ABSTRACT Monozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins. We analyzed 42,663 RNA transcripts in 1453 MZ twins and 1294 DZ twins from the Netherlands Twin Register (NTR), followed by sex‐stratified analyses. The top 5% transcripts with lowest p ‐values were analyzed for replication in 217 MZ and 158 DZ twins from the older Finnish Twin cohort (FTC). In the NTR, one transcript ( PURG) was significantly differentially expressed between MZ and DZ twins; but this did not replicate in FTC. Pathway analyses highlighted the WNT‐pathway, previously associated with MZ twinning, and the TGF‐B and SMAD pathway, previously associated with DZ twinning. Meta‐analysis of 169 serum metabolites in 2797 MZ and 2040 DZ twins from the NTR, FTC and FinnTwin12, showed no metabolomic differences. Overall, we did not find replicable transcript‐level expression differences in blood between MZ and DZ twins, but highlighted the TGF‐B/SMAD pathway as a potential transcriptional biomarker for DZ twinning.

Nikki Hubers

Gabin Drouard

Rick Jansen

René Pool

Jouke Jan Hottenga

Miina Ollikainen

Xiaoling Wang

Gonneke Willemsen

Jaakko Kaprio

Dorret I. Boomsma

Jenny van Dongen

Transcriptomic and Metabolomic Analyses in Monozygotic and Dizygotic Twins

单卵双生和双卵双生双胞胎的转录组和代谢组分析

ABSTRACT The alpha 1 and 2 chains of type IV collagen, encoded by the COL4A1 (MIM 120130) and COL4A2 (MIM 120090) respectively, play essential roles in the vascular basement membranes. Pathogenic variants in COL4A1 / COL4A2 are associated with autosomal dominant cerebral angiopathies. The clinical manifestations of COL4A1 / COL4A2 ‐related disorders include: aneurysms, intracerebral hemorrhage, polymicrogyria, porencephaly, heterotopia, periventricular leukomalacia, epilepsy, and neurodevelopmental disorders. COL4A1 pathogenic variants that are in exons 24 and 25 have been associated with hereditary angiopathy, nephropathy, aneurysms, and cramps. The multisystemic phenotypes of COL4A1 / COL4A2 ‐related disorders are increasingly being studied. Animal models have suggested that COL4A2 ‐related disorders may also manifest with a variable combination of multisystemic abnormalities affecting the eyes, muscles, and kidneys. Okano and colleagues recently reported a case of recurrent episodes of rhabdomyolysis in a 2‐year‐old with COL4A1 ‐related disorder raising fundamental questions on mechanisms of COL4A1 / COL4A2 variants in muscle homeostasis. To date, rhabdomyolysis has not been associated with COL4A2 ‐related disorder in humans. Rhabdomyolysis is a medical emergency, where there is elevated creatine kinase (CK) level in the blood and increased excretion of myoglobin in urine, due to skeletal muscle damage and release of intracytoplasmic proteins into systemic circulation. Rhabdomyolysis is a serious medical condition. It require intensive care management due to an increased risk of some life‐threatening complications [including disseminated intravascular coagulation, renal failure, and severe hyperkalemia]. Herein, we report a case of rhabdomyolysis in an adult with COL4A2 ‐related structural brain malformations (including polymicrogyria and heterotopia).

Bukola A. Olarewaju

Judy Tejon

Shaymaa Shurrab

Alicia Chen

Fadi Shamoun

Benn E. Smith

Mayowa A. Osundiji

<scp>COL4A2</scp>‐Related Disorder Presenting in Adulthood With Rhabdomyolysis

<scp>COL4A2</scp>相关疾病在成年期表现为横纹肌溶解

Abbreviation	Am. J. Med. Genet.
Journal Impact	1.75
Quartiles(Global)	GENETICS & HEREDITY(Q3)

ISSN	1552-4825, 1552-4833
h-index	131

Publication Information	Publisher: John Wiley and Sons Inc，Publishing cycle: Semimonthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2003，Proportion of original research papers: 92.08%，Self Citation Rate:5.90%， Gold OA Rate: 17.04%
Average review cycle	网友分享经验：较快,2-4周
Average recruitment ratio	网友分享经验：容易

American Journal of Medical Genetics, Part A

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The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome