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

With only a small number of cases in the medical literature, mosaic trisomy 15 in liveborn infants is very rare. Despite its rarity, similar features among individuals have been described, including intrauterine growth retardation, craniofacial abnormalities and facial dysmorphisms, cardiac disease, and other organ anomalies. Very few liveborns have survived the first year of life. We report here on a term infant with growth restriction and multiple congenital anomalies who was found to have mosaic trisomy 15. The proband presented with some frequently reported findings such as dysmorphic facies and overlapping fingers, and the uncommon finding of whorled hypopigmentation. Previously unreported findings include abnormal cerebral vasculature and dysplastic kidneys. We add this new phenotypic information to widen the spectrum previously reported and provide a review of the literature to date.

Jacob McPadden

Benjamin M. Helm

Brooke B. Spangler

Leslie P. Ross

Debra B. Boles

Samantha A. Schrier Vergano

American Journal of Medical Genetics Part A

Mosaic trisomy 15 in a liveborn infant

活产婴儿中的15号染色体嵌合三体

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

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 Triplications involving 5q21.3q23.3 are rare, and a phenotype has not been established. Here, we present a 4‐month‐old male with dysmorphic facial features and congenital cardiac malformation. Chromosomal microarray identified a pathogenic triplication of 5q21.3q23.3 with chromosome analysis showing the extra 5q material inserted into 16q. Optical genome mapping (OGM) was performed to further characterize the triplication. We compared the clinical features of our proband with previous case reports of individuals with duplications or triplications in the region to identify a phenotype. Common features appear to include short stature, developmental delays, learning difficulties, and cardiac malformations. We discuss genes in the region with a reported role in cardiac development, hypothesize that the triplication may have resulted from microhomology‐mediated break‐induced replication, and discuss the utility and limitations of OGM in this case. To our knowledge, this is the first reported case of a de novo triplication of 5q21.3q23.3.

Jacob A. Ginter

Sarah Beaudry

Natalya Guseva

Jaime Nagy

Aaron A. Stence

Alpa Sidhu

Nonrecurrent Triplication of 5q21.3q23.3: A Case Report and Review of the Literature

5q21.3q23.3非重复性三体：一例病例报告及文献综述

ABSTRACT Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.82G &gt;C p.(Ala28Pro)] in GLDN . Two pregnancies presented with significant obstetrical complications including placental abruption and hemorrhage. Four infants died shortly after birth, while one survived past the neonatal period. This individual, while apparently asymptomatic during infancy, then presented with progressive neuromuscular and respiratory compromise that became more evident in adolescence. Data from a Nunavik Inuit cohort demonstrated a minor allele frequency (MAF) of 0.03571 for this variant compared to 0.00001341 in the general population, suggesting a founder effect in the Nunavik Inuit population. Our findings support the presence of a founder variant associated with LCCS11 in Nunavik Inuit populations. Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long‐term survivors are at risk of progressive neuromuscular compromise. We also highlight in this report the significant obstetrical complications associated with this fetal‐onset condition.

Alexa McAdam

Yoko A. Ito

Marilyn Richard

Dan Spiegelman

Daniel Rochefort

Lan Xiong

Maryam Oskoui

David Zielinski

Guy A. Rouleau

Sirui Zhou

Kym M. Boykott

Isabelle De Bie

Identification of a Founder <scp>GLDN</scp> Variant Associated With “Lethal” Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long‐Term Survivors' Management

与努纳维克因纽特人中“致死性”关节弯曲相关的创始人GLDN变异的鉴定：对产科和长期幸存者管理的意义

ABSTRACT Osteogenesis imperfecta (OI) is a rare disease, hallmarked by bone fragility, multiple fractures, and deformities, and is commonly caused by pathogenic variants in the genes encoding type I collagen. Type II OI is the most severe form and is lethal in the perinatal period. Here, we report recurrence of perinatal lethal OI in two fetuses due to parental mosaicism for a deep intronic pathogenic variant at c.2451 + 77C &gt; T in intron 35 of COL1A1 , which resulted in aberrant splicing and the in‐frame addition of 75 nucleotides into the mRNA. These patients highlight the importance of considering deep intronic variants in type 1 collagen genes in patients with high suspicion of OI, which may be missed with conventional genetic analysis.

Mackenna E. Schouw

Claudia A. L. Ruivenkamp

Tamara T. Koopmann

Gijs W. E. Santen

Peter G. J. Nikkels

Karin van der Tuin

A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type <scp>II</scp>

COL1A1基因深内含子剪接变异导致II型成骨不全症

ABSTRACT Diamond Blackfan anemia (DBA) is an autosomal dominant disorder with a heterogeneous clinical presentation which may include macrocytic anemia typically presenting in the first year of life, growth retardation, and congenital malformations in 30%–50% of patients. This phenotypic variability is partially explained by genotype–phenotype correlations, with several ribosomal protein genes implicated in this disorder. Most cases are due to de novo variants, but familial occurrences highlight variable expressivity and reduced penetrance. To date, one case has been previously reported with a pathogenic variant in the RPL26 gene: a 3.5‐year‐old female with multiple congenital anomalies and typical hematological features of DBA. Here, we report a novel frameshift variant in RPL26 identified in a proband and his brother with limb malformations without anemia. Decreased RPL26 protein levels were detected in the proband's lymphoblasts. Subsequent clinical workup revealed high erythrocyte adenosine deaminase activity (eADA) in the proband, without anemia. This family represents the second report of RPL26 ‐associated congenital anomalies in the DBA spectrum and further illustrates the non‐hematological presentation of Diamond Blackfan “anemia”.

Lisa M. Karger

Bryn D. Webb

Lisa Edelmann

Jun Liao

Lakshmi Mehta

Familial RPL26 Variant Causing Congenital Anomalies Without Hematological Features of Diamond Blackfan Anemia

家族性RPL26变异导致先天性异常而无Diamond Blackfan贫血的血液学特征

Myoclonus-dystonia syndrome (MDS, OMIM #159900) is an autosomal-dominant movement disorder caused by heterozygous variants in the epsilon sarcoglycan gene (SGCE) and characterized by a combination of myoclonic jerks, dystonia, and psychiatric comorbidities. Patients with MDS have a normal life expectancy with markedly reduced quality of life. Here, we report four family members diagnosed with MDS of variable severity due to a novel heterozygous splicing variant in SGCE (c.341-2A>G), including a 13-year-old female who presented with disabling dystonic spasms, myoclonic jerks, and psychiatric symptoms. She had shown little or no response to several conventional MDS treatments. However, disabling axial dystonia was significantly improved by sodium oxybate (1 g, twice daily). Although there was less effect on myoclonus, sodium oxybate treatment significantly improved the overall quality of life at the 3-years follow-up. Clinical trials are warranted to assess the clinical efficacy and safety of sodium oxybate for MDS-associated dystonia.

Malak Ali Alghamdi

Muddathir H. Hamad

Isra Alghamdi

Ghiada Alghamdi

Muneera Al‐Jelaify

Sohaila Alshimemeri

Hebattalah Hamed

Nouran Adly

Mustafa A. Salih

Naif A. Almontashiri

Fahad A. Bashiri

Sodium Oxybate‐Treated Familial Myoclonus‐Dystonia Syndrome Due to Novel <scp>SGCE</scp> Variant

新型<scp>SGCE</scp>变异导致的羟丁酸钠治疗家族性肌阵挛-肌张力障碍综合征

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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Mosaic trisomy 15 in a liveborn infant

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

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

A case of Asian Indian OCA3 patient

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

Nonrecurrent Triplication of 5q21.3q23.3: A Case Report and Review of the Literature

Identification of a Founder GLDN Variant Associated With “Lethal” Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long‐Term Survivors' Management

A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II

Familial RPL26 Variant Causing Congenital Anomalies Without Hematological Features of Diamond Blackfan Anemia

Sodium Oxybate‐Treated Familial Myoclonus‐Dystonia Syndrome Due to Novel SGCE Variant