American Journal of Medical Genetics Part A最新文献_第8页

Puberty With Microcephalic Osteodysplastic Primordial Dwarfism Type II. 青春期伴有小头畸形、骨发育异常、原始侏儒症II型。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-07 DOI: 10.1002/ajmg.a.64208

Sarah M Little, Emily D Longenecker, Angela L Duker

引用次数: 0

Intestinal Atresia in PPP1R12A-Related Urogenital and Brain Malformation Syndrome. ppp1r12a相关泌尿生殖和脑畸形综合征的肠闭锁。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-06 DOI: 10.1002/ajmg.a.64217

Adriana Gomes, Sanjana Karamcheti, Álvaro Martín Rodriguez, Anna-Kaisa Niemi, Lynne M Bird

{"title":"Intestinal Atresia in PPP1R12A-Related Urogenital and Brain Malformation Syndrome.","authors":"Adriana Gomes, Sanjana Karamcheti, Álvaro Martín Rodriguez, Anna-Kaisa Niemi, Lynne M Bird","doi":"10.1002/ajmg.a.64217","DOIUrl":"https://doi.org/10.1002/ajmg.a.64217","url":null,"abstract":"PPP1R12A-related urogenital and brain malformation syndrome (UBMS) is a newly described disorder characterized by congenital anomalies primarily involving the urogenital system and the brain. We describe a preterm female neonate with multiple congenital anomalies, including type IIIb jejunal atresia, incomplete intestinal rotation, imperforate anus without rectal fistula, and vaginal atresia. Brain imaging revealed bilateral periventricular white matter echogenicity, and echocardiography identified a muscular ventricular septal defect. Genetic testing revealed a stop-loss PPP1R12A variant c.3092A>T (p.Ter1031LeuextTer71), identical to the variant reported in a previous case by Harris et al., which also presented with jejunal atresia. This case represents an additional case of UBMS with gastrointestinal anomalies and the second documented instance of small intestinal atresia associated with the c.3092A>T variant in PPP1R12A, suggesting an expansion of the phenotype with gastrointestinal atresia. While brain and urogenital malformations are the hallmark features of UBMS, this case highlights gastrointestinal anomalies as an important part of the phenotypic spectrum.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64217"},"PeriodicalIF":1.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793261","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

Prolonged Follow-Up in a 30-Year-Old Male With a Novel Pathogenic Variant in MSL3: A Case Report and a Brief Review of the Literature. 1例30岁男性MSL3新型致病变异的长期随访：1例报告及文献综述。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-06 DOI: 10.1002/ajmg.a.64196

Giulia Pisanò, Carlo Alberto Cesaroni, Susanna Rizzi, Agnese Pantani, Anna Cavalli, Stefano Giuseppe Caraffi, Simonetta Rosato, Camilla Stefanini, Martina Gnazzo, Livia Garavelli, Daniele Frattini, Carlo Fusco

{"title":"Prolonged Follow-Up in a 30-Year-Old Male With a Novel Pathogenic Variant in MSL3: A Case Report and a Brief Review of the Literature.","authors":"Giulia Pisanò, Carlo Alberto Cesaroni, Susanna Rizzi, Agnese Pantani, Anna Cavalli, Stefano Giuseppe Caraffi, Simonetta Rosato, Camilla Stefanini, Martina Gnazzo, Livia Garavelli, Daniele Frattini, Carlo Fusco","doi":"10.1002/ajmg.a.64196","DOIUrl":"https://doi.org/10.1002/ajmg.a.64196","url":null,"abstract":"Basilicata-Akhtar syndrome (BAS) is an ultra-rare X-linked neurodevelopmental disorder caused by pathogenic variants in the MSL3 gene, critical for histone H4 acetylation and chromatin regulation. To date, only 42 cases have been documented, affecting both males and females, with most variants being de novo and loss-of-function. We present a case of a 30-year-old male with BAS, exhibiting developmental delay, intellectual disability, hypotonia, motor disturbances, and dysmorphic features. Genetic testing revealed a novel de novo hemizygous variant in the MSL3 gene (NM_078629:c.1293G > A, NP_523353.2:p.(Trp431*)), leading to loss of function. Neuroimaging showed multifocal leukoencephalopathy, and the individual is receiving treatment with carbidopa-levodopa with improvement in bradykinesia and camptocormia. This case expands our understanding of BAS and highlights the importance of genetic testing, especially Exome Sequencing (ES), in diagnosing rare conditions. Early diagnosis and multidisciplinary care are crucial for managing BAS and improving outcomes.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64196"},"PeriodicalIF":1.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788005","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

Novel Intragenic Duplication of GATAD2B in a Patient With GAND. GAND患者中新的基因内复制GATAD2B。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-06 DOI: 10.1002/ajmg.a.64205

Mari Mori, Steven Estes, Swetha Ramadesikan, Betsy Schmalz, Shayne Plourde, Maria E Hernandez Gonzalez, Anthony R Miller, Bimal P Chaudhari, Richard K Wilson, Daniel C Koboldt

{"title":"Novel Intragenic Duplication of GATAD2B in a Patient With GAND.","authors":"Mari Mori, Steven Estes, Swetha Ramadesikan, Betsy Schmalz, Shayne Plourde, Maria E Hernandez Gonzalez, Anthony R Miller, Bimal P Chaudhari, Richard K Wilson, Daniel C Koboldt","doi":"10.1002/ajmg.a.64205","DOIUrl":"https://doi.org/10.1002/ajmg.a.64205","url":null,"abstract":"The nucleosome remodeling and deacetylation (NuRD) complex is a major chromatin regulator and plays a critical role in regulating gene transcription, genome integrity, and cell cycle progression. Heterozygous variants in GATAD2B, a core NuRD component, have been reported to cause GATAD2B-Associated Neurodevelopmental Disorder (GAND), an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, hypotonia, and distinctive craniofacial features. The vast majority of disease-causing variants in GATAD2B reported to date are loss-of-function (nonsense, frameshift, or splice site) variants. Here, we report a 6-year-old male patient with profound global developmental delay and dysmorphic features, who was found to have a de novo ~97 kbp partial duplication of the GATAD2B gene. Using long-read transcriptome and genome sequencing on the Pacific BioSciences (PacBio) platform, we show that the duplication is a tandem event whose breakpoint in the 3' UTR of the gene causes skipping of the last exon and transcriptional read-through. The resulting transcript contains two incomplete copies of GATAD2B, one with exons 1-10 and the other with exons 2-7, likely representing a loss-of-function allele. Follow-up clinical evaluations confirmed the patient's diagnosis of GAND, ending a years-long diagnostic odyssey for the family and highlighting an unusual mechanism of gene disruption in GATAD2B.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64205"},"PeriodicalIF":1.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793262","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

Trisomy 5p: Long Recognized, Rarely Published- Three New Cases and Review of the Literature. 5p三体：长期被认识，很少发表——三个新病例和文献综述。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-06 DOI: 10.1002/ajmg.a.64198

Gabriela J Kim, Kristen N Lee, Amanda B Pritchard

引用次数: 0

Exonic Variation and Its Clinical Impact in 7221 Old Order Amish. 7221名旧秩序阿米什人的外显子变异及其临床影响。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-06 DOI: 10.1002/ajmg.a.64212

Braxton D Mitchell, Ebuka Onyenobi, Joshua P Lewis, Brady Gaynor, James A Perry, Kristin Maloney, Jeffrey R O'Connell, Jessica Tiner, Amber L Beitelshees, Cristopher V Van Hout, Patrick F McArdle, Huichun Xu, Erik G Puffenberger, Karlla W Brigatti, Melanie Daue, Hilary B Whitlatch, Anna Alkelai, Alejandro A Schäffer, John Overton, Elizabeth A Streeten, Toni I Pollin, Alan R Shuldiner

{"title":"Exonic Variation and Its Clinical Impact in 7221 Old Order Amish.","authors":"Braxton D Mitchell, Ebuka Onyenobi, Joshua P Lewis, Brady Gaynor, James A Perry, Kristin Maloney, Jeffrey R O'Connell, Jessica Tiner, Amber L Beitelshees, Cristopher V Van Hout, Patrick F McArdle, Huichun Xu, Erik G Puffenberger, Karlla W Brigatti, Melanie Daue, Hilary B Whitlatch, Anna Alkelai, Alejandro A Schäffer, John Overton, Elizabeth A Streeten, Toni I Pollin, Alan R Shuldiner","doi":"10.1002/ajmg.a.64212","DOIUrl":"https://doi.org/10.1002/ajmg.a.64212","url":null,"abstract":"The Amish of Lancaster County, PA has been the focus of genetic studies for many years due to its demographic history and unique genetic makeup that includes a historical bottleneck event and subsequent genetic drift, resulting in a marked decrease in genetic diversity and increased frequency of some variants that have substantially shaped the health of the community. To characterize the coding variation in the Amish genome, we sequenced the exomes of 7221 adult community members, and in this report, we contrast genetic diversity between the Amish and Europeans from the UK Biobank. Exome sequences of 7221 Amish contained only 14% as many variants as the same number of UKB participants. This reduced genetic diversity has substantial clinical implications. We identified pathogenic (P) and likely pathogenic (LP) variants from ClinVar and a population-specific genetic screening panel and found that most of the variants present in the Amish were highly enriched, resulting in 5.2% of Amish individuals being homozygous for a recessive P/LP variant and 25.6% being heterozygous for at least one dominant P/LP variant. In 43.6% of the 2141 Amish spouse-pairs in our sample, at least one spouse was heterozygous for a P/LP dominant variant, and 24.3% of couples were autosomal recessive disease carrier couples, meaning that each of their children was at ~25% risk of inheriting two copies of that variant. Gene discovery efforts in other founder communities will likely uncover distinct P (and beneficial) variants impacting the health of these communities, with implications for all of human health.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64212"},"PeriodicalIF":1.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788004","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

A Cross-Sectional Study Survey to Develop a Clinical Screen for Down Syndrome Regression Disorder in the United Kingdom. 在英国开展唐氏综合症退行性障碍临床筛查的横断面研究调查

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64207

Abinaya Seenivasan, Ella Rachamim, Jonathan D Santoro

{"title":"A Cross-Sectional Study Survey to Develop a Clinical Screen for Down Syndrome Regression Disorder in the United Kingdom.","authors":"Abinaya Seenivasan, Ella Rachamim, Jonathan D Santoro","doi":"10.1002/ajmg.a.64207","DOIUrl":"https://doi.org/10.1002/ajmg.a.64207","url":null,"abstract":"Down syndrome regression disorder (DSRD) is marked by a sudden loss of previously acquired skills or behavior without a clear cause in individuals with Down syndrome (DS). Awareness of this condition has increased recently, with new therapeutic options under trial. The precise incidence is unknown due to confounding factors and gaps in capturing symptoms within the broader community. The application of narrower guidelines presents challenges in accurately reporting symptoms across the wider DS community. We conducted a survey across the UK based on 2022 DSRD consensus guidelines among parents and carers of children and young adults with DS, with 158 detailed responses about demographics, symptoms, and triggers. The survey revealed critical insights into the challenges faced by parents and carers. Results indicate a significant diagnostic threshold for DSRD within a symptom score range of 20.2-25.6, capturing about 80% of cases. Patients scoring above 20.2 are at high risk for DSRD from a statistical perspective. This threshold is vital for early detection and intervention, potentially improving patient outcomes. While it may overestimate diagnoses, the questionnaire serves as a screening tool for identifying those at risk.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64207"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783255","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

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64192

Alexandra Garrett, Vera M Kalscheuer, Rebeca Ridings Figueroa, Elizabeth E Palmer, Angela T Morgan

{"title":"CLCN4-Related Neurodevelopmental Condition: Characterization of Speech and Language Abilities.","authors":"Alexandra Garrett, Vera M Kalscheuer, Rebeca Ridings Figueroa, Elizabeth E Palmer, Angela T Morgan","doi":"10.1002/ajmg.a.64192","DOIUrl":"https://doi.org/10.1002/ajmg.a.64192","url":null,"abstract":"Speech and language difficulties are a core feature of the CLCN4-related neurodevelopmental condition, but these have not been well described. Here we systematically phenotype speech and language in 13 participants (10 female, aged 1 year 10 months-41 years 10 months) with pathogenic CLCN4 variants (12 missense de novo, 1 premature stop codon maternal inheritance). Speech, language, and augmentative and alternative communication (AAC) methods were examined. Expressive and receptive language conditions were highly penetrant (12/13, 92%). Eight participants were minimally verbal but used a range of low (e.g., gesture) and high-tech (e.g., device) methods to communicate. Verbal participants had both apraxia and dysarthria, characterized by inconsistent productions, sound distortions, resonance changes, and persistent voice quality and prosodic errors. Participants were all intentional communicators, being motivated to get their message across. A discrepancy was present, however, between the ability to express basic needs versus demonstrate social skills or social exchanges. Data highlight the potential for the implementation of tailored AAC to enhance functional social participation and extend language abilities. Communication difficulties are pervasive in CLCN4-related neurodevelopmental condition. Data emphasize the importance of individualized and timely speech therapy, and particularly the introduction of AAC to optimize language growth.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64192"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783257","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

Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series. 罕见疾病患者的混合表型：巴西病例系列。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64209

Caroline Brandão Piai, Gabriela Yumi Goto Salti, Marcella Cardoso Allegro, Priscila Barbosa Betty, Fernanda de Souza Valente, Isabela Dorneles Pasa, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Rachel Sayuri Honjo, Debora Romeo Bertola, Masamune Sakamoto, Yuta Inoue, Ken Saida, Naomi Tsuchida, Noriko Miyake, Naomichi Matsumoto, Chong Ae Kim

{"title":"Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series.","authors":"Caroline Brandão Piai, Gabriela Yumi Goto Salti, Marcella Cardoso Allegro, Priscila Barbosa Betty, Fernanda de Souza Valente, Isabela Dorneles Pasa, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Rachel Sayuri Honjo, Debora Romeo Bertola, Masamune Sakamoto, Yuta Inoue, Ken Saida, Naomi Tsuchida, Noriko Miyake, Naomichi Matsumoto, Chong Ae Kim","doi":"10.1002/ajmg.a.64209","DOIUrl":"https://doi.org/10.1002/ajmg.a.64209","url":null,"abstract":"The growing use of whole exome sequencing and whole genome sequencing in clinical practice has revealed the existence of a group of individuals that do not fit into only one molecular diagnosis. These subjects are those in whom pathogenic or likely pathogenic variants occur in more than one gene, creating \"blended phenotypes\" There are also genes that warrant reporting, even if they are not associated with the primary phenotype, referred to as 'secondary findings'. In this report, we analyze the prevalence of blended phenotypes in a cohort of 447 individuals who underwent broad genomic sequencing and also present a case series of eight probands who presented multiple diagnoses, generating a mixed phenotype and creating a peculiar clinical situation. In total, 3.86% (8/207) were found to have blended phenotypes, which would have been missed had those individuals not undergone comprehensive genetic testing. We reflect upon the clinical complexity of such cases and explore the consequences of the use of broad sequencing strategies in clinical practice, particularly focusing on the potential to provide a more complete diagnostic scenario. By acknowledging and understanding the complexities of blended phenotypes, clinicians can adopt a more nuanced and tailored approach to patient care.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64209"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783256","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

Secondary Findings in a Research Cohort: Spectrum and the Indian Perspective. 研究队列的次要发现：光谱和印度人的观点。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-08-05 DOI: 10.1002/ajmg.a.64199

Pooja Motwani, Rajesh K Maurya, Dhwoni, Shubha R Phadke, Amita Moirangthem

{"title":"Secondary Findings in a Research Cohort: Spectrum and the Indian Perspective.","authors":"Pooja Motwani, Rajesh K Maurya, Dhwoni, Shubha R Phadke, Amita Moirangthem","doi":"10.1002/ajmg.a.64199","DOIUrl":"https://doi.org/10.1002/ajmg.a.64199","url":null,"abstract":"Genomic sequencing identifies both primary findings related to a patient's phenotype and secondary findings (SFs) which are actionable with early intervention. In the Indian population, there is limited data about types and frequencies of SFs as well as on the understanding of patients' perspectives on receiving these findings. We identified P/LP variants in SF genes (ACMG v3.2) from 500 families who underwent research-based exome sequencing at our center. Families were recontacted, and phenotypic diagnostic tests were done for at-risk individuals. In a separate group of families undergoing diagnostic exome sequencing, a questionnaire-based survey assessed parents' perspectives of these findings for themselves and their extended family members. Frequency of SF is 2.2% with 12 P/LP variants identified in 11 families predominantly in genes of the cardiovascular group (6) and cancer group (5). One family had a positive family history compatible with the associated disease. In response to the questionnaire survey of families undergoing diagnostic exome sequencing, the majority of parents supported SF inclusion in proband tests (97.2%) and in themselves (84.7%). While thorough knowledge of all SFs was favored, financial constraints reduced willingness to pay for additional tests. A comprehensive study from Medical Genetics Center in India reporting 2.2% frequency of SF in 81 SF genes. Clinicians should ensure thorough pretest counseling and clear communication on long-term follow-up for phenotype-negative individuals, variable penetrance, expressivity, and differential severity of SFs and stringent variant interpretation. With the surge in genomic diagnostic tests, it is imperative to assess preparedness of the healthcare systems to ensure equitable and sustainable care for all patients.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64199"},"PeriodicalIF":1.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783258","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