American Journal of Medical Genetics Part A最新文献

A New Case Linking a Somatic NRAS Variant to Encephalocraniocutaneous Lipomatosis. 一个将体细胞NRAS变异与脑颅皮脂肪病联系起来的新病例。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64202

Omar Azrak, Sheng-Che Hung, Nathaniel G Wooten, Clara C Hildebrandt

引用次数: 0

Medical Multimorbidity in Patients With Treatment-Resistant Psychosis and Rare Copy Number Variants: A Retrospective Case Series of 24 Patients. 难治性精神病和罕见拷贝数变异患者的医学多病：24例回顾性病例系列

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64215

Tyler E Dietterich, Rose Mary Xavier, Maya L Lichtenstein, Matthew K Harner, Lisa Bruno, Robert Stowe, Martilias Farrell, Rita A Shaughnessy, Jonathan S Berg, Patrick F Sullivan, Richard C Josiassen

{"title":"Medical Multimorbidity in Patients With Treatment-Resistant Psychosis and Rare Copy Number Variants: A Retrospective Case Series of 24 Patients.","authors":"Tyler E Dietterich, Rose Mary Xavier, Maya L Lichtenstein, Matthew K Harner, Lisa Bruno, Robert Stowe, Martilias Farrell, Rita A Shaughnessy, Jonathan S Berg, Patrick F Sullivan, Richard C Josiassen","doi":"10.1002/ajmg.a.64215","DOIUrl":"https://doi.org/10.1002/ajmg.a.64215","url":null,"abstract":"Neurodevelopmental disorder-risk copy number variations (NDD CNVs) are associated with complex neuropsychiatric phenotypes. These CNVs also confer risk for a host of medical outcomes in adults; yet, the long-term health consequences in the context of comorbid psychiatric illness have not been well documented. Twenty-four psychiatric inpatients with treatment-resistant psychosis were identified as carriers of NDD CNVs as part of a larger Pennsylvania State Hospital genomics study. Comprehensive life course phenotyping was performed through review of medical records, specialized neurobehavioral evaluation, and synthesis of data using the Human Phenotype Ontology. Phenotypes examined across the cohort indicated comorbid medical manifestations across multiple organ systems. Cardiovascular disorders were present in 96% of patients and motor disorders in 92%. All patients had multiple organ system involvement, and most organ systems (12/17 systems) were affected in 50% or more of patients, culminating in a high degree of individual-level multimorbidity. Comparing our observations to previously known CNV-associated phenotypes indicated several potentially novel health outcomes for individual CNV loci. Our descriptive case series supports a complex and multidimensional course of illness. Thorough reporting on the long-term implications of these variants is the first step toward advancing clinical care for these complex psychiatric patients carrying NDD CNVs.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64215"},"PeriodicalIF":1.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764302","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

Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact. 儿童Joubert综合征——生活质量、功能独立性和家庭影响的综合分析。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-01 DOI: 10.1002/ajmg.a.64213

Erhan Elmaoğlu, Adnan Batuhan Coşkun, Serkan Usgu, Zerrin Çiğdem, Selda Yüzer Alsaç

{"title":"Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact.","authors":"Erhan Elmaoğlu, Adnan Batuhan Coşkun, Serkan Usgu, Zerrin Çiğdem, Selda Yüzer Alsaç","doi":"10.1002/ajmg.a.64213","DOIUrl":"https://doi.org/10.1002/ajmg.a.64213","url":null,"abstract":"This study examines the quality of life, functional independence, and family impact of children diagnosed with Joubert Syndrome (JS) to address gaps in the literature on its developmental and psychosocial challenges. A descriptive, cross-sectional study was conducted with 49 parents of children with JS in Turkey. Data were collected using the Pediatric Quality of Life Inventory, Pediatric Functional Independence Measure, and Impact on Family Scale. Statistical analyses included descriptive and reliability assessments. Children with JS exhibited significant motor and cognitive delays, reduced functional independence, and lower quality of life. Feeding difficulties affected 38.8% of participants, highlighting the need for early nutritional interventions. Consanguineous marriage was reported by 61.2% of families, yet only 8.2% underwent genetic screening, emphasizing the importance of genetic counseling. Parents faced high psychosocial and economic burdens, underscoring the need for structured family support programs. The findings highlight the need for early, multidisciplinary interventions, including physical and speech therapy, nutritional support, and psychosocial care, to enhance functional independence and overall well-being. A comprehensive care model integrating neurology, pulmonology, rehabilitation, and genetic counseling is essential for improving outcomes in JS. A family-centered, multidisciplinary approach should be prioritized to improve patient care and caregiver support. Expanding rehabilitation services, genetic counseling, and structured family education can enhance long-term quality of life and independence in children with JS.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64213"},"PeriodicalIF":1.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764301","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

Identification of a Second-Hit Brain Somatic DEPDC5 Variant Supports Causality of a DEPDC5 Germline Variant of Uncertain Significance. Time for a Classification Update? 二击脑体细胞DEPDC5变异的鉴定支持了不确定意义的DEPDC5种系变异的因果关系。是时候更新分类了？

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-31 DOI: 10.1002/ajmg.a.64204

Ala'a Alsayed, Zainab Hakim, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Walter Hader, Tyler Soule, Setareh Ashtiani, Grace Polanco-Tovar, Morris Scantlebury, Hamed Rahi, Yang Cao, Jennifer A Chan, Juan P Appendino, Gerald Pfeffer, Ping Yee Billie Au, Karl Martin Klein

{"title":"Identification of a Second-Hit Brain Somatic DEPDC5 Variant Supports Causality of a DEPDC5 Germline Variant of Uncertain Significance. Time for a Classification Update?","authors":"Ala'a Alsayed, Zainab Hakim, Daria Merrikh, Maryam Khanbabaei, Navprabhjot Kaur, Walter Hader, Tyler Soule, Setareh Ashtiani, Grace Polanco-Tovar, Morris Scantlebury, Hamed Rahi, Yang Cao, Jennifer A Chan, Juan P Appendino, Gerald Pfeffer, Ping Yee Billie Au, Karl Martin Klein","doi":"10.1002/ajmg.a.64204","DOIUrl":"https://doi.org/10.1002/ajmg.a.64204","url":null,"abstract":"Germline variants in DEPDC5 are a cause of familial focal epilepsy with variable foci. Affected individuals may have focal cortical dysplasia if a second brain somatic variant occurs. As access to brain tissue is limited, the second somatic hit in the brain is usually presumed if a clear pathogenic germline variant is present. Here, we present a patient with structural focal epilepsy due to focal cortical dysplasia. He underwent epilepsy surgery at age 2 months. Clinical genetic testing revealed a germline variant of uncertain significance (VUS) DEPDC5 c.920T>G, p. (Leu307Arg). We hypothesized that if the proband's germline DEPDC5 variant was disease-causal, a second somatic variant may be identifiable in affected cortical tissue. DNA was extracted from archived brain formalin-fixed paraffin-embedded tissue and subjected to deep gene panel analysis. This revealed an additional somatic pathogenic variant in DEPDC5, which was confirmed using droplet digital PCR. Identification of the second somatic hit in brain tissue (DEPDC5 c.982C>T, p.(Arg328*)) confirmed the two-hit situation in this patient and supported disease causality of the germline variant. In conclusion, testing tissue for somatic variants may be clinically relevant at a patient-specific level if a germline VUS affects a gene where a two-hit mechanism is known.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64204"},"PeriodicalIF":1.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752083","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

ARSK-Related Mucopolysaccharidosis Type 10. arsk相关粘多糖病10型。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-31 DOI: 10.1002/ajmg.a.64210

Intisar Al Fahdi, Swati Singh, Krishnaveni Yadavalli, Kiranam Chatti, Gandham SriLakshmi Bhavani, Katta M Girisha

引用次数: 0

Further Evidence That Chondrocalcinosis 1 (CCAL1) is a Confirmed Mendelian Phenotype With a Known Molecular Basis. 软骨钙化1 （CCAL1）是一种已知分子基础的孟德尔表型的进一步证据。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-30 DOI: 10.1002/ajmg.a.64185

Anna-Christina Pansa, Mareike Selig, Markus Wingendorf, Matthew A Brown, Oliver Bartsch

{"title":"Further Evidence That Chondrocalcinosis 1 (CCAL1) is a Confirmed Mendelian Phenotype With a Known Molecular Basis.","authors":"Anna-Christina Pansa, Mareike Selig, Markus Wingendorf, Matthew A Brown, Oliver Bartsch","doi":"10.1002/ajmg.a.64185","DOIUrl":"https://doi.org/10.1002/ajmg.a.64185","url":null,"abstract":"Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop-loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in TNFRSB11B on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic TNFRSF11B loss-of-function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5-associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop-lost variant, likely a gain-of-function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64185"},"PeriodicalIF":1.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740907","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

45th Annual David Smith Workshop on Malformations and Morphogenesis. 第45届大卫·史密斯畸形和形态发生研讨会。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-07-30 DOI: 10.1002/ajmg.a.64194

Alison M Elliott, A Micheil Innes

引用次数: 0

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