American Journal of Medical Genetics Part A最新文献

Outcomes from a Novel Approach to Studying Consumer Genetic Testing for Germline Cancer and Cardiovascular Risk. 一种研究生殖系癌症和心血管风险的消费者基因检测新方法的结果。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-29 DOI: 10.1002/ajmg.a.64169

Madison K Kilbride, Daniel Chavez-Yenter, Bob Wong, J Scott Roberts, Jacqueline Park, Jason Iuliano, Angela R Bradbury

{"title":"Outcomes from a Novel Approach to Studying Consumer Genetic Testing for Germline Cancer and Cardiovascular Risk.","authors":"Madison K Kilbride, Daniel Chavez-Yenter, Bob Wong, J Scott Roberts, Jacqueline Park, Jason Iuliano, Angela R Bradbury","doi":"10.1002/ajmg.a.64169","DOIUrl":"https://doi.org/10.1002/ajmg.a.64169","url":null,"abstract":"Despite the growing availability of consumer genetic testing for serious disease risks, outcomes data remain limited for individuals undergoing testing for high- and moderate-penetrance genes. To address this gap, we evaluated the feasibility of the Consumer Genetic Testing Outcomes Evaluation Paradigm (CGT-OEP), a novel approach for studying cognitive, affective, and behavioral outcomes in individuals pursuing physician-mediated genetic testing. We recruited participants to purchase Color Health's genetic test for cancer and cardiovascular disease risk. Participants completed Baseline (T0), Pre-Disclosure (T1), and Two-Week Post-Disclosure (T2) surveys and shared results with the study team. Of 185 consented participants, 105 (56.8%) purchased tests, with 103 (98.1%) completing all requirements. Purchasers were predominantly white (89%), female (73%), and college-educated (80%). Participants reported high satisfaction and minimal negative emotions, uncertainty, or decisional regret; most (n = 67, 65%) planned to share results with providers. Although genetic knowledge increased and anxiety decreased post-disclosure, many participants misinterpreted negative and VUS results as indicating lower-than-average risk for cancer (n = 41, 42%) and cardiovascular disease (n = 45, 46%). Our findings demonstrate that the CGT-OEP is a feasible, effective approach for studying consumer genetic testing. While participants reported positive experiences, findings highlight concerns about result comprehension and potential false reassurance, particularly for negative/VUS results.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64169"},"PeriodicalIF":1.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Variable Intrafamilial Cardiac Phenotype Segregating With a TBX20 Missense Variant in the Putative Transcriptional Activation Domain. 在假定的转录激活域中，TBX20错义变异的可变家族内心脏表型分离。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-28 DOI: 10.1002/ajmg.a.64200

Gioia Mastromoro, Alice Traversa, Daniele Guadagnolo, Carolina Putotto, Viviana Caputo, Maria Gnazzo, Antonio Novelli, Flavia Ventriglia, Bruno Marino, Antonio Pizzuti

引用次数: 0

Possible Founder Effect of Glycine Encephalopathy: Evidence of a GLDC c.2714T>G (p.Val905Gly) Common Variant in the Paisa Community Based in Cali, Colombia. 甘氨酸脑病可能的创始效应：哥伦比亚卡利Paisa社区GLDC c.2714T>G （p.Val905Gly）共同变异的证据

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-27 DOI: 10.1002/ajmg.a.64173

Stiven Ernesto Sinisterra-Diaz, Carlos E Prada, Harry Pachajoa

{"title":"Possible Founder Effect of Glycine Encephalopathy: Evidence of a GLDC c.2714T>G (p.Val905Gly) Common Variant in the Paisa Community Based in Cali, Colombia.","authors":"Stiven Ernesto Sinisterra-Diaz, Carlos E Prada, Harry Pachajoa","doi":"10.1002/ajmg.a.64173","DOIUrl":"https://doi.org/10.1002/ajmg.a.64173","url":null,"abstract":"Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by defects in the mitochondrial glycine cleavage system, most commonly involving variants in GLDC. Clinical presentation is heterogeneous, ranging from severe neonatal encephalopathy with intractable epilepsy to attenuated forms with variable neurodevelopmental outcomes. We conducted a comprehensive clinical, biochemical, molecular, and genealogical analysis of eight Colombian patients with NKH, all of whom shared ancestry from the Paisa population. All patients were born at term after uncomplicated pregnancies and presented in the neonatal period with hypotonia, lethargy, feeding difficulties, and treatment-resistant seizures. Elevated glycine levels were detected in plasma for all patients and cerebrospinal fluid in three cases. Molecular testing identified the same homozygous GLDC variant (NM_000170.3:c.2714 T>G; p.Val905Gly) in all individuals. Although no consanguinity was reported, shared surname and regional ancestry suggested intra- and interfamilial isonymy, raising the possibility of a founder effect. Clinical outcomes varied despite the implementation of early supportive interventions. This is the first report of a recurrent GLDC variant in Colombian patients, supporting a potential founder effect in the Paisa population. These findings highlight the importance of regional genetic studies in enhancing diagnostic precision and guiding population-specific strategies for rare disease management.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64173"},"PeriodicalIF":1.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Speech and Language Disorders Associated With 7q31 Deletions Implicating FOXP2. 与FOXP2相关的7q31缺失相关的言语和语言障碍

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-26 DOI: 10.1002/ajmg.a.64190

Lottie D Morison, Ruth Braden, David J Amor, Angela T Morgan

{"title":"Speech and Language Disorders Associated With 7q31 Deletions Implicating FOXP2.","authors":"Lottie D Morison, Ruth Braden, David J Amor, Angela T Morgan","doi":"10.1002/ajmg.a.64190","DOIUrl":"https://doi.org/10.1002/ajmg.a.64190","url":null,"abstract":"Some 7q31 deletions encompass FOXP2, a gene long associated with speech and language disorders. Intragenic pathogenic FOXP2 variants cause FOXP2-related speech and language disorder, which has been well characterized in the literature. Conversely, the phenotype associated with 7q31 deletions is neglected. Here we characterize the phenotype of eight individuals (4 males) with 7q31 deletions (median age 4 years, 3 months, range 1-32 years). Deletion size ranged from 6.8 to 15.2 Mb. All had protracted speech and language milestones, and those with larger deletions had little to no speech. All verbal individuals had childhood apraxia of speech (5/5, 100%). Participants used augmentative and alternative communication (AAC) including key word sign (5/8, 63%), and low-tech (6/8, 75%) and high-tech (4/8, 50%) systems. Oral and written language impairment was universal. The larger the deletion size, the poorer an individual's language skills (p = 0.03, p < 0.05). Daily living, socialization, and motor skills were also impaired. Cognition ranged from average to severely impaired. Childhood feeding impairment (50%), sleep disturbance (38%), structural brain abnormalities (38%), and autism (25%) were noted. All individuals received one or more allied health therapies. Speech and language impairments emphasize the need for early, tailored speech therapy, including literacy and AAC interventions, for individuals with 7q31 deletions.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64190"},"PeriodicalIF":1.7,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Poland Anomaly and Atretic Cephalocele in the Same Child: Coincidence or Association? 波兰畸形和闭锁性头膨出在同一个孩子：巧合还是关联？

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-26 DOI: 10.1002/ajmg.a.64197

Alessandra Greta Grassi, Silvia Pontesilli, Laura Demelas, Francesca Vigliani, Massimo Agosti, Angelo Selicorni

引用次数: 0

Challenges in Genomic Variant Interpretation Within Pakistani Populations due to Genomic Healthcare Inequalities. 由于基因组保健不平等，在巴基斯坦人群中基因组变异解释的挑战。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-26 DOI: 10.1002/ajmg.a.64191

Zantasha Khalid, Matthew Adams, Anees Muhammad, Raeesa Tehreen, Arfa Azeem, Asif Ahmed, Nishanka Ubeyratna, Claire G Salter, Joseph S Leslie, Nikol Voutsina, Emma L Baple, Andrew H Crosby, Sabika Firasat, Muhammad Tahir Sarwar, Shamim Saleha, Asma Gul, Lettie E Rawlins

{"title":"Challenges in Genomic Variant Interpretation Within Pakistani Populations due to Genomic Healthcare Inequalities.","authors":"Zantasha Khalid, Matthew Adams, Anees Muhammad, Raeesa Tehreen, Arfa Azeem, Asif Ahmed, Nishanka Ubeyratna, Claire G Salter, Joseph S Leslie, Nikol Voutsina, Emma L Baple, Andrew H Crosby, Sabika Firasat, Muhammad Tahir Sarwar, Shamim Saleha, Asma Gul, Lettie E Rawlins","doi":"10.1002/ajmg.a.64191","DOIUrl":"https://doi.org/10.1002/ajmg.a.64191","url":null,"abstract":"Accurate classification of genomic variants is crucial to ensure correct diagnosis, genetic counseling, and clinical management of monogenic inherited disorders. Variant interpretation can be hindered in populations that are significantly underrepresented in large reference genomic databases, leading to genomic healthcare inequalities. Despite a relatively high prevalence of inherited autosomal recessive diseases within Pakistan, this population remains significantly underrepresented in reference genomic databases. This genomic data disparity, alongside other population characteristics, including limited access to genomic healthcare, high rates of consanguineous unions, tribal, ethnic, and geographical isolation leading to increased autozygosity, can result in frequent challenges in rare variant interpretation. Here, we describe four Pakistani families with rare monogenic disorders in which whole-exome sequencing identified previously unpublished candidate biallelic variants of uncertain significance (VUS) in four genes: INTS1, PPFIBP1, HSPG2, and ACOX3. Our studies highlight the challenges of rare variant interpretation within the Pakistani community, leading to an increased proportion of variants being classified as VUS. Collectively, our findings highlight the need for increased diversity within genomic research to effectively tackle healthcare inequities faced by underrepresented communities.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64191"},"PeriodicalIF":1.7,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Waardenburg Syndrome: Review of Genotype-Phenotype Relationships in 30 Patients in Hong Kong. Waardenburg综合征：香港30例患者基因型-表型关系的回顾

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-24 DOI: 10.1002/ajmg.a.64193

Jennifer Y Y Poon, W C Yiu, Stephanie K L Ho, Shirley Sze Wing Cheng, Ho-Ming Luk, Ivan F M Lo

引用次数: 0

Childhood-Onset Neurodegeneration With Progressive Microcephaly (CONPM) due to a DTYMK Homozygous Pathogenic Variant: Outlining the Phenotype of an Ultra-Rare Disease. 由DTYMK纯合致病变异引起的儿童期神经退行性变伴进行性小头畸形（CONPM）：概述一种超罕见疾病的表型

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-22 DOI: 10.1002/ajmg.a.64187

Hernández-Carreto Raúl, Acosta-Rodríguez-Bueno Carlos Patricio, Barragán-Arevalo Tania, Ruiz-Robles Osiris, Valdés-Ortega Esteban Alberto, Cerón-Rodríguez Magdalena, Viveros-Rodríguez Romina Tamara, Moreno-Salgado Rodrigo

{"title":"Childhood-Onset Neurodegeneration With Progressive Microcephaly (CONPM) due to a DTYMK Homozygous Pathogenic Variant: Outlining the Phenotype of an Ultra-Rare Disease.","authors":"Hernández-Carreto Raúl, Acosta-Rodríguez-Bueno Carlos Patricio, Barragán-Arevalo Tania, Ruiz-Robles Osiris, Valdés-Ortega Esteban Alberto, Cerón-Rodríguez Magdalena, Viveros-Rodríguez Romina Tamara, Moreno-Salgado Rodrigo","doi":"10.1002/ajmg.a.64187","DOIUrl":"https://doi.org/10.1002/ajmg.a.64187","url":null,"abstract":"Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is a rare autosomal recessive disorder caused by pathogenic variants in the DTYMK gene. This ultra-rare condition is characterized by progressive neurological regression, epilepsy, severe microcephaly, and global cerebral atrophy. Only four cases have been reported in the literature to date. This paper's objective is to describe the fifth globally reported case of CONPM and the first documented in a Mexican patient, confirmed through whole-exome sequencing (WES), and to compare findings with previously reported cases. Clinical evaluation, neuroimaging studies, and genetic analysis using WES followed by Sanger sequencing were performed. Clinical and genetic data were analyzed in the context of existing literature on CONPM. A 2-year-old male with progressive neurodevelopmental regression presented with severe microcephaly, epilepsy, hypertonia, and cortical and cerebellar atrophy. Genetic analysis identified a homozygous missense variant in DTYMK (NM_012145.4:c.242C>T; p.Pro81Leu). This variant is predicted to disrupt dTMP phosphorylation, a key step in the maintenance of dTTP pools required for genomic stability and neural function. This case expands the known phenotypic and genotypic spectrum of CONPM and underscores the importance of considering DTYMK variants in cases of childhood neurodegeneration with microcephaly. Further functional studies are needed to elucidate the mechanisms linking DTYMK dysfunction to neurodegeneration.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64187"},"PeriodicalIF":1.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Undiagnosed Hackathon Ends Diagnostic Odyssey in a Patient With DNA2-Related Rothmund-Thomson Syndrome. 未确诊的黑客马拉松结束了与dna相关的罗斯蒙-汤姆森综合征患者的诊断过程。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-22 DOI: 10.1002/ajmg.a.64179

Beril Ay, Ozlem Akgun-Dogan, Fulya Taylan, Carlo Marcelis, Saygin Abali, Jiin Ying Lim, May Christine Malicdan, Helene Cederroth, Mikk Cederroth, Lorenzo D Botto, Yasemin Alanay

{"title":"Undiagnosed Hackathon Ends Diagnostic Odyssey in a Patient With DNA2-Related Rothmund-Thomson Syndrome.","authors":"Beril Ay, Ozlem Akgun-Dogan, Fulya Taylan, Carlo Marcelis, Saygin Abali, Jiin Ying Lim, May Christine Malicdan, Helene Cederroth, Mikk Cederroth, Lorenzo D Botto, Yasemin Alanay","doi":"10.1002/ajmg.a.64179","DOIUrl":"https://doi.org/10.1002/ajmg.a.64179","url":null,"abstract":"Rothmund-Thomson syndrome (RTS) is an ultra-rare, genetically heterogeneous autosomal recessive genodermatosis characterized by poikiloderma, sparse hair and eyebrows, photosensitivity, and short stature. The recently described RTS type 4 (RTS-4), caused by biallelic variants in the DNA2 gene, is associated with additional distinctive features such as microphthalmia, corneal opacity, congenital cataracts (rather than juvenile), and hypothyroidism. To date, eight individuals with RTS-4 have been reported, all carrying a deep intronic variant in DNA2 (ENST00000358410.8:c.588-2214A>G) and originating from Brazilian or Portuguese ethnic backgrounds. We present the first patient with RTS-4 outside these ethnic backgrounds, harboring the same deep intronic DNA2 variant (ENST00000358410.8:c.588-2214A>G) in combination with a novel pathogenic variant (ENST00000358410.8:c.2519 T>C, Leu840Pro). This patient expands the molecular spectrum of RTS-4 and underscores the critical role of genome sequencing in identifying pathogenic deep intronic variants. Additionally, the patient's response to recombinant human growth hormone treatment is described. Finally, this patient, undiagnosed for several years, was solved through an international effort at the 2024 Undiagnosed Hackathon, highlighting the value of international cooperation and resource sharing toward ensuring that no patient remains undiagnosed.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64179"},"PeriodicalIF":1.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expanding the Clinical Spectrum of Cousin Syndrome: A Novel Biallelic Missense Variant in TBX15 Causing a Milder Phenotype. 扩展表亲综合征的临床谱：TBX15中一种新的双等位基因错义变异导致较温和的表型。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-22 DOI: 10.1002/ajmg.a.64195

Suzanne E L Detiger, Martijn V Verhagen, Tuula Rinne, Hermine E Veenstra-Knol

{"title":"Expanding the Clinical Spectrum of Cousin Syndrome: A Novel Biallelic Missense Variant in TBX15 Causing a Milder Phenotype.","authors":"Suzanne E L Detiger, Martijn V Verhagen, Tuula Rinne, Hermine E Veenstra-Knol","doi":"10.1002/ajmg.a.64195","DOIUrl":"https://doi.org/10.1002/ajmg.a.64195","url":null,"abstract":"Cousin syndrome is a rare skeletal dysplasia characterized by distinctive facial features, humeroradial synostosis, and hypoplasia of the ilia and scapula. Since the original description of the phenotype in two cases by Cousin in 1982, only three additional cases have been published. A molecular origin was found in homozygous truncating mutations in TBX15, a member of the T-box gene family that encodes transcription factors regulating the developing limb buds. Here we present a sixth patient with a biallelic novel missense variant in TBX15 that causes a milder form of Cousin syndrome. Our patient presented with mild iliac and scapula hypoplasia, bilateral humeroradial dislocation, and a milder version of the distinctive facial appearance. We speculate that the biallelic missense variant in our patient either allows for some residual activity or affects some functions of the protein more than others. This finding expands the clinical spectrum of TBX15-related conditions by adding a milder phenotype caused by a homozygous missense variant.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64195"},"PeriodicalIF":1.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0