American Journal of Medical Genetics Part A最新文献_第4页

Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review. 扩大线粒体磷酸载体缺乏症的临床谱：一例报告并文献复习。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-13 DOI: 10.1002/ajmg.a.64259

Arzu Selamioglu, Mazlum Akif Altun, Kimberly Bliven, Gökçen Ünverengil, Dilek Güneş, Meryem Karaca, Mehmet Cihan Balcı, Asuman Gedikbaşı, Fatmahan Atalar, Gülden Gökçay

{"title":"Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review.","authors":"Arzu Selamioglu, Mazlum Akif Altun, Kimberly Bliven, Gökçen Ünverengil, Dilek Güneş, Meryem Karaca, Mehmet Cihan Balcı, Asuman Gedikbaşı, Fatmahan Atalar, Gülden Gökçay","doi":"10.1002/ajmg.a.64259","DOIUrl":"https://doi.org/10.1002/ajmg.a.64259","url":null,"abstract":"Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure. This report presents a case of a 32-year-old female manifesting with HCMP and myopathy beyond the neonatal period. The patient's neuromotor development was initially normal, but from 1.5 years of age, she exhibited fatigue and muscle weakness, particularly after walking. Muscle biopsy revealed normal muscle fiber size with a predominance of type 1 fibers. The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy. The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated. Genetic analysis identified a homozygous splicing variant in the SLC25A3 gene [NM_005888.4:c.158-9A>G (IVS2-9A>G)], consistent with mitochondrial PiC deficiency. At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels. This case supports the expansion of the clinical spectrum of mitochondrial PiC deficiency by presenting a patient with a later-onset phenotype compared to previously reported cases.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64259"},"PeriodicalIF":1.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051396","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 Non-Coding Causative Variant Underlying Warsaw Breakage Syndrome Using Long-Read Based Genomic Sequencing and Transcriptome Analysis. 使用基于长读的基因组测序和转录组分析鉴定华沙断裂综合征的非编码致病变异。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-12 DOI: 10.1002/ajmg.a.64252

Makenna DuBois, Katherine Dixon, Charlotte Sherlaw-Sturrock, Yaoqing Shen, Frank Probst, Lorne Clarke, Dmitry Lyalin, Cheryl Shuman, Steven Jones, Cornelius Boerkoel, Grant S Stewart, Phillip Richmond, Angela Myers

{"title":"Identification of a Non-Coding Causative Variant Underlying Warsaw Breakage Syndrome Using Long-Read Based Genomic Sequencing and Transcriptome Analysis.","authors":"Makenna DuBois, Katherine Dixon, Charlotte Sherlaw-Sturrock, Yaoqing Shen, Frank Probst, Lorne Clarke, Dmitry Lyalin, Cheryl Shuman, Steven Jones, Cornelius Boerkoel, Grant S Stewart, Phillip Richmond, Angela Myers","doi":"10.1002/ajmg.a.64252","DOIUrl":"https://doi.org/10.1002/ajmg.a.64252","url":null,"abstract":"Currently, exome and genome sequencing achieve a diagnostic rate of 30%-50% for rare genetic diseases. With multi-modal technologies profiling the genome, transcriptome, and epigenome, interrogation of genomic elements outside of protein-coding regions shows potential to improve this as demonstrated herein. Siblings with sensorineural hearing loss, microcephaly, intellectual impairment, and growth restriction were seen in consultation. Following extensive clinical testing, long-read whole genome and cDNA-based transcriptome sequencing on the Oxford Nanopore platform identified a homozygous 1.6 kb deletion of the 5' UTR and promoter region of DDX11, a gene associated with Warsaw breakage syndrome. The deletion included the hypomethylated CpG island regulating DDX11, led to a loss of expression of DDX11 mRNA and protein, and resulted in the characteristic \"railroad chromosome.\" Identifying a causal variant for this family required expanding the search space for genomic variants beyond protein-coding regions, and multi-modal data integration enabled a more holistic approach to variant prioritization and classification prior to pursuing targeted protein and functional assays. This multi-modal genome-wide approach heralds promise for patients on the diagnostic odyssey and who have exhausted standard of care testing.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64252"},"PeriodicalIF":1.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039018","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

Caregiver Interviews Regarding Health in Down Syndrome. 关于唐氏综合症患者健康状况的护理人员访谈。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-12 DOI: 10.1002/ajmg.a.64253

Mary Witt, Kavita Krell, Stephanie L Santoro

{"title":"Caregiver Interviews Regarding Health in Down Syndrome.","authors":"Mary Witt, Kavita Krell, Stephanie L Santoro","doi":"10.1002/ajmg.a.64253","DOIUrl":"https://doi.org/10.1002/ajmg.a.64253","url":null,"abstract":"Individuals with Down syndrome (DS) have co-occurring medical conditions. Research on how caregivers understand, interpret, and answer questions about the health of their son or daughter with DS is needed to guide the development of a measure of the health status of children and adolescents with DS. We conducted 1-h virtual cognitive interviews of caregivers of individuals aged 0 to 21 with DS about our drafted survey items on physical, mental, and social health using a modified \"think-aloud\" approach with probes. In addition to using their feedback to iteratively refine our survey, in this manuscript we describe the themes of feedback from caregivers and summarize survey item changes. Four rounds of cognitive interviews for a total of 40 interviews of 42 caregivers of individuals with DS were completed. Cognitive interview themes included: using the easiest phrase possible, focusing on the present, being conversational in terminology, and specifying who items refer to or who comparison groups are, among others. Caregiver interviews were informative and led us to make modifications to our survey items. Themes emerged which hold use to other researchers conducting surveys in populations with genetic syndromes. Trial Registration:NCT04631237.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64253"},"PeriodicalIF":1.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038955","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

Expansion of Phenotyping and Genotypic Spectra of KIF7-Related Intellectual Disability: Case Report and Review of Literature. kif7相关智力残疾表型和基因型谱的扩展：病例报告和文献综述。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-11 DOI: 10.1002/ajmg.a.64244

Rutairat Wongong, Phichittra Od-Ek, Wuttichart Kamolvisit, Vorasuk Shotelersuk

{"title":"Expansion of Phenotyping and Genotypic Spectra of KIF7-Related Intellectual Disability: Case Report and Review of Literature.","authors":"Rutairat Wongong, Phichittra Od-Ek, Wuttichart Kamolvisit, Vorasuk Shotelersuk","doi":"10.1002/ajmg.a.64244","DOIUrl":"https://doi.org/10.1002/ajmg.a.64244","url":null,"abstract":"Neurodevelopmental disorders (NDDs), which typically emerge in childhood, affect nervous system development. Recent studies have linked KIF7 mutations, which disrupt the Hedgehog signaling pathway essential for embryonic development, to certain features of NDDs. Here, we report two male siblings with intellectual disability, short stature, macrocephaly, epilepsy, Dandy-Walker malformation, dysmorphic facial features, cryptorchidism, and skeletal anomalies. Both siblings exhibited absence of fifth distal and middle phalanges bilaterally, which has never been previously reported. Whole-genome sequencing of both siblings and their parents demonstrated that the siblings were homozygous for a novel frameshift mutation, c.2975_2988del (p.Leu992ArgfsTer51) in KIF7, while their parents were heterozygous for the variant. These findings expand the phenotypic and mutational spectra of KIF7-associated intellectual disability. Additionally, we analyzed all previously reported cases of KIF7 mutations to investigate genotype-phenotype correlations, but no specific mutation type or functional domain was definitively associated with a particular phenotype.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64244"},"PeriodicalIF":1.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038967","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

Basal Metabolic Requirements, Biomarkers of Cardiometabolic Health, and Anthropometric Measures of Obesity in Women and Men With Restricted Growth Conditions. 基础代谢需求，心脏代谢健康的生物标志物，以及生长受限的女性和男性肥胖的人体测量测量。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-11 DOI: 10.1002/ajmg.a.64235

Lucy H Merrell, Harry A Smith, Harriet A Carroll, Yung-Chih Chen, Dylan Thompson, Javier T Gonzalez, Greg Atkinson, James A Betts

{"title":"Basal Metabolic Requirements, Biomarkers of Cardiometabolic Health, and Anthropometric Measures of Obesity in Women and Men With Restricted Growth Conditions.","authors":"Lucy H Merrell, Harry A Smith, Harriet A Carroll, Yung-Chih Chen, Dylan Thompson, Javier T Gonzalez, Greg Atkinson, James A Betts","doi":"10.1002/ajmg.a.64235","DOIUrl":"https://doi.org/10.1002/ajmg.a.64235","url":null,"abstract":"Population-specific thresholds have not been defined for the levels of adiposity and systemic biomarkers that predict chronic health risks in people with restricted growth conditions. Here, anthropometric measures of adiposity, basal metabolic requirements, and fasted blood samples were obtained from adults with restricted growth (age 41 ± 14 years, height 1.30 ± 0.10 m, body mass 60.5 ± 18.3 kg, female: male n = 24:13, achondroplasia n = 26; mean ± SD). Basal metabolic rate was 6529 ± 1703 kJ·d-1 and total mass-normalized energy requirements were higher for females versus males. Plasma concentrations of glucose (5.55 ± 0.73 mmol·L-1), insulin (36.4 ± 19.9 pmol·L-1) and lipids (triacylglycerol 0.84 ± 0.37 mmol·L-1; total cholesterol 4.54 ± 0.85 mmol·L-1; high-density lipoprotein cholesterol 1.41 ± 0.31 mmol·L-1; low-density lipoprotein cholesterol 2.73 ± 0.69 mmol·L-1) were mostly within healthy clinical reference ranges. Sagittal abdominal diameter was positively correlated with plasma glucose and leptin concentrations (r = 0.85; 95% CI: 0.61, 0.95; p < 0.0001, and r = 0.85; 95% CI: 0.61, 0.95; p < 0.0001, respectively). Mean ± SD body mass index (BMI) was 36.1 ± 11.0 kg·m-2. However, we found that body mass scaled to height by the power of 1.4 (95% CI: 0.2, 2.6) rather than 2 associated with conventional BMI. Conventional biomarkers of cardiometabolic health are not substantially elevated in these individuals with restricted growth despite the classification of obesity using height-dependent references (e.g., traditional BMI).","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64235"},"PeriodicalIF":1.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038997","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

De Novo Truncating Variants in ZNF865 Cause a Novel Neurodevelopmental Disorder. ZNF865的从头截断变异导致一种新的神经发育障碍。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-11 DOI: 10.1002/ajmg.a.64242

Samuel M Bradbrook, Gail Graham, Melissa T Carter, Maria Kibaek, Christina Fagerberg, Martin J Larsen, Katherine Dawson, Cheryl Meuter, Alexander Pepler, Thomas Besnard, Marie Vincent, Bertrand Isidor, Stephane Bezieau, Benjamin Cogne, Kathrine Bjørgo, Silja Svanstrøm Amundsen, Thomas Courtin, Lisa Emrick, Jill A Rosenfeld, Monika Weisz-Hubshman, Bryan C Mak, Julian Martinez-Agosto, Mathilde Heulin, Gilles Morin, Boris Keren, Sacha Schutz, Pauline Monin, Mathilde Pujalte, Louis Januel, Gaetan Lesca, Marie-Noëlle Bonnet-Dupeyron Valence, Henri Margot, Jonathan Levy, Emmanuela Iovino, Federica Isidori, Tommaso Pippucci, Francesca Montanari, Lauren Bell, Jennifer Burton, Erin Torti, Ingrid M Wentzensen, Julien Marcadier

{"title":"De Novo Truncating Variants in ZNF865 Cause a Novel Neurodevelopmental Disorder.","authors":"Samuel M Bradbrook, Gail Graham, Melissa T Carter, Maria Kibaek, Christina Fagerberg, Martin J Larsen, Katherine Dawson, Cheryl Meuter, Alexander Pepler, Thomas Besnard, Marie Vincent, Bertrand Isidor, Stephane Bezieau, Benjamin Cogne, Kathrine Bjørgo, Silja Svanstrøm Amundsen, Thomas Courtin, Lisa Emrick, Jill A Rosenfeld, Monika Weisz-Hubshman, Bryan C Mak, Julian Martinez-Agosto, Mathilde Heulin, Gilles Morin, Boris Keren, Sacha Schutz, Pauline Monin, Mathilde Pujalte, Louis Januel, Gaetan Lesca, Marie-Noëlle Bonnet-Dupeyron Valence, Henri Margot, Jonathan Levy, Emmanuela Iovino, Federica Isidori, Tommaso Pippucci, Francesca Montanari, Lauren Bell, Jennifer Burton, Erin Torti, Ingrid M Wentzensen, Julien Marcadier","doi":"10.1002/ajmg.a.64242","DOIUrl":"https://doi.org/10.1002/ajmg.a.64242","url":null,"abstract":"Despite significant knowledge advances in recent decades, the role of most protein-coding genes in human disease remains incompletely understood. Exome sequencing continues to improve our understanding by elucidating novel genotype-phenotype associations. Across multiple healthcare centers, either exome or genome sequencing was performed in 18 patients with shared features of global developmental delay, hypotonia, and dysmorphisms. De novo, truncating variants in ZNF865 were identified in all 18 patients, with all but one clustered toward the C-terminus. Four variants were seen more than once in unrelated patients. No disease-causing variants were identified in other genes that would explain the patients' phenotypes. Little is known of the function of ZNF865, which belongs to the poly-zinc finger family of proteins that contain a large array of tandem C2H2 zinc finger DNA binding domains. Our findings suggest that protein-truncating variants in this gene lead to intellectual disability with a recognizable phenotypic pattern.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64242"},"PeriodicalIF":1.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038983","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

Long-Read Sequencing of a Neurodevelopmental Disorder Patient Reveals Complex Rearrangement Involving the ARID1B Gene. 神经发育障碍患者的长读测序揭示了涉及ARID1B基因的复杂重排。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-11 DOI: 10.1002/ajmg.a.64249

Tam P Sneddon, Scott A Melville, Mai Xiong, Kimberly Foss, Emma B Cardwell, Kelly Rafferty, Karen E Weck, Ana Berglind, Erin L Heinzen, Matt L Tedder, Muge Gucsavas-Calikoglu, Yael Shiloh-Malawsky, Zheng Jane Fan, Bradford C Powell, Senyene E Hunter

{"title":"Long-Read Sequencing of a Neurodevelopmental Disorder Patient Reveals Complex Rearrangement Involving the ARID1B Gene.","authors":"Tam P Sneddon, Scott A Melville, Mai Xiong, Kimberly Foss, Emma B Cardwell, Kelly Rafferty, Karen E Weck, Ana Berglind, Erin L Heinzen, Matt L Tedder, Muge Gucsavas-Calikoglu, Yael Shiloh-Malawsky, Zheng Jane Fan, Bradford C Powell, Senyene E Hunter","doi":"10.1002/ajmg.a.64249","DOIUrl":"https://doi.org/10.1002/ajmg.a.64249","url":null,"abstract":"Long-read sequencing can identify disease-causing variants that are missed by short-read sequencing. Here, we report the use of Oxford Nanopore Technology long-read sequencing to resolve a complex translocation-inversion involving the ARID1B gene in a 5-year-old male with a history of febrile seizures, intractable epilepsy, epileptic encephalopathy, and speech delay. Prior clinical genetic testing included a karyotype with a t(6;11)(q25.3;q22.3) apparently balanced translocation and a chromosomal microarray with a 1.48 Mb interstitial deletion within 4p13 that were both deemed not clinically significant, normal fragile X and Prader-Willi/Angelman DNA assays, and no significant findings on epilepsy or neurotransmitter disorders gene panels. Extensive metabolic testing was also negative. The patient was enrolled in the University of North Carolina (UNC) Genetic Determinants of Neurological and Developmental Disorders (GDNDD) study. Research short-read genome single nucleotide and structural variant analysis was negative. Subsequent identification by long-read sequencing that the translocation interrupted the ARID1B gene highlights the use of long-read sequencing to identify and resolve complex rearrangements underlying genetic disorders and may be valuable in determining the pathogenicity of unexplained balanced translocations for other genetic disorders.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64249"},"PeriodicalIF":1.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032595","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

Table of Contents, Volume 197A, Number 10, October 2025 目录，197A卷，第10期，2025年10月

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-09 DOI: 10.1002/ajmg.a.63767

引用次数: 0

Gene Therapy for Duchenne Muscular Dystrophy in Limbo 杜氏肌营养不良症的基因治疗

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-09 DOI: 10.1002/ajmg.a.63762

引用次数: 0

Device Streamlines Approach to Genetic Testing for Rare Mutations 设备简化了罕见突变的基因检测方法

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-09 DOI: 10.1002/ajmg.a.63764

引用次数: 0