American Journal of Medical Genetics Part A最新文献

Expanding the Phenotype of STAMBP-Related Microcephaly-Capillary Malformation Syndrome. 扩展stambp相关小头-毛细血管畸形综合征的表型。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-01-28 DOI: 10.1002/ajmga.70067

Vykuntaraju K Gowda, Amaresh Roy, B Disha, Periyasamy Govindaraj, Varunvenkat M Srinivasan

引用次数: 0

Identification of a Novel TBCK Variation in an Azari Consanguineous Family With Psychomotor Developmental Disorder. 精神运动发育障碍阿扎里家族一种新的TBCK变异的鉴定。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-01-28 DOI: 10.1002/ajmga.70061

Sara Arish, Ramiz Nobakht, Haleh Mokabber, Somayeh Takrim Nojedeh, Sana Davarnia, Shirin Hasanzadeh, Hourieh Kalhor, Behzad Davarnia

{"title":"Identification of a Novel TBCK Variation in an Azari Consanguineous Family With Psychomotor Developmental Disorder.","authors":"Sara Arish, Ramiz Nobakht, Haleh Mokabber, Somayeh Takrim Nojedeh, Sana Davarnia, Shirin Hasanzadeh, Hourieh Kalhor, Behzad Davarnia","doi":"10.1002/ajmga.70061","DOIUrl":"10.1002/ajmga.70061","url":null,"abstract":"TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracellular trafficking, but the full spectrum of pathogenic variants remains poorly understood. We investigated a consanguineous Iranian family with psychomotor delay. Whole exome sequencing (WES) identified a candidate TBCK variant, confirmed by Sanger sequencing. Functional studies were performed using amniotic fluid-derived cell culture, Western blotting, protein structural modeling, and molecular docking analyses. A novel homozygous frameshift variant, TBCK (NM_001163435.3): c.1969dupT (p.Cys657Leufs*17), was detected and absent from population databases. Clinically, the proband presented with severe developmental delay, hypotonia, seizures, and facial dysmorphism, and died at 9 months. Western blotting showed a significant decrease in TBCK expression (p < 0.007). Structural analysis of a theoretically modeled truncated protein indicated C-terminal truncation with loss of critical domains, while in silico docking demonstrated reduced binding affinity between mutant TBCK and Rab1B, suggesting impaired Rab-mediated trafficking. This study reports a novel pathogenic TBCK variant associated with severe neurodevelopmental delay, contributing to the clinical and molecular spectrum of TBCK syndrome. Our findings underscore the importance of genetic testing in rare neurodevelopmental disorders and provide insight into the molecular mechanisms underlying TBCK dysfunction.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1231-1238"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058580","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

The Infant and Toddler Developmental Profile of Kleefstra Syndrome. 婴幼儿Kleefstra综合征的发展概况。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-06 DOI: 10.1002/ajmga.70071

Shanna L Yue, Rajapillai L I Pillai, Zoë Frazier, Hailey Osika, Meg Quinn, Jillian O'Toole, Brynn Heslin, Bo Zhang, Kira A Dies, Lynn Pais, Anne O'Donnell-Luria, Max A Horlbeck, Joe Kossowsky, Jonathan Lipton, Siddharth Srivastava

{"title":"The Infant and Toddler Developmental Profile of Kleefstra Syndrome.","authors":"Shanna L Yue, Rajapillai L I Pillai, Zoë Frazier, Hailey Osika, Meg Quinn, Jillian O'Toole, Brynn Heslin, Bo Zhang, Kira A Dies, Lynn Pais, Anne O'Donnell-Luria, Max A Horlbeck, Joe Kossowsky, Jonathan Lipton, Siddharth Srivastava","doi":"10.1002/ajmga.70071","DOIUrl":"10.1002/ajmga.70071","url":null,"abstract":"The early developmental profile of Kleefstra syndrome remains undercharacterized. To address this gap, this study investigated a large clinical cohort of patients with Kleefstra syndrome, characterizing age of achievement of infant/toddler developmental milestones and quantifying language and visual motor developmental quotients (DQs) using the Capute Scales developmental screening tool. We conducted a retrospective chart review on individuals with molecularly confirmed Kleefstra syndrome. We reported age of achievement of motor and language milestones. In a subset of this cohort, we evaluated DQs for language and visual motor skills based on the Capute Scales. Among 100 individuals (43 males, 57 females; median age 9 years), rolling occurred at a median of 6 months, sitting at 10 months, independent walking at 1.96 years, and first words at 24 months. Capute Scales testing (n = 24) showed median DQs as follows: visual motor skills (53, IQR = 42-71), overall language (56, IQR = 42-67), expressive language (52, IQR = 35-60), and receptive language (50, IQR = 42-61). This work quantifies the early developmental profile of Kleefstra syndrome and suggests that developmental delay can be significant from an early age, making early initiation of services such as physical therapy, occupational therapy, and speech therapy crucial to ensuring optimal skills development. This cross-sectional analysis highlights the need for incorporating longitudinal developmental assessments into the clinical care of patients with Kleefstra syndrome-particularly during infancy and early childhood-to ensure that appropriate educational supports are in place.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1267-1272"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130978","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

Case Reviews for Two Families With Unique Variants in TBX22 Causing Abruzzo-Erickson Syndrome. 引起Abruzzo-Erickson综合征的两个TBX22独特变异家族的病例回顾

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-02 DOI: 10.1002/ajmga.70066

Kamerin Smith, Michael A Abruzzo, Robert P Erickson, Amy Thomas, Mary Kukolich

{"title":"Case Reviews for Two Families With Unique Variants in TBX22 Causing Abruzzo-Erickson Syndrome.","authors":"Kamerin Smith, Michael A Abruzzo, Robert P Erickson, Amy Thomas, Mary Kukolich","doi":"10.1002/ajmga.70066","DOIUrl":"10.1002/ajmga.70066","url":null,"abstract":"The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have been identified in individuals with classic X-linked cleft palate (CPX) and also in Abruzzo-Erickson Syndrome (ABERS). We compare the phenotypic features of a newly suspected family with ABERS to those of the original family with ABERS to help determine if family-specific pathogenic variants in TBX22 are the cause of ABERS. Furthermore, we discuss possible mechanisms of action of the identified TBX22 variants. We conducted an observational case series in a new family (Family B) suspected of having ABERS, and a retrospective review of participants in the original family with ABERS (Family A), as described by Abruzzo and Erickson (1977). Thirteen individuals from two different families were included in this case series. As previously reported in 2013, DNA samples from four individuals in Family A were screened for variants in TBX22, and each was found to carry the same unique pathogenic variant. Five individuals from Family B were screened for variants in TBX22, and the four with abnormal features were found to be positive for a new pathogenic variant; however, the variant segregating in this family differed from the one present in Family A. Despite this, there was considerable overlap between Family A and Family B in phenotypic features. Thus, we hypothesize that gain-of-function pathogenic variants in TBX22 are the probable cause of ABERS in both Family A and Family B.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1396-1402"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103539","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

Homozygous Achondroplasia With Long-Term Survival: Growth Patterns, Medical Interventions, and Practice Implications. 纯合子软骨发育不全与长期生存：生长模式，医疗干预和实践意义。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-01-16 DOI: 10.1002/ajmga.70057

Hannah Singerline, Jason Laufman, Kimberly Wallis, Michelle Merrill

引用次数: 0

Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients. 胞质磷酸烯酰丙酮酸羧激酶缺乏症：五名非芬兰患者的临床、生化和遗传特征。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-01-19 DOI: 10.1002/ajmga.70063

Isaac Bernhardt, Polona Le Quesne Stabej, Claire Hart, Mark De Hora, Sarah Hulley, Mark Anderson, Harry G Leitch, Hugh Lemonde, Bryony Ryder, James Davison

{"title":"Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients.","authors":"Isaac Bernhardt, Polona Le Quesne Stabej, Claire Hart, Mark De Hora, Sarah Hulley, Mark Anderson, Harry G Leitch, Hugh Lemonde, Bryony Ryder, James Davison","doi":"10.1002/ajmga.70063","DOIUrl":"10.1002/ajmga.70063","url":null,"abstract":"Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1192-1203"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997106","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

Facilitating Genetic Testing for Perinatal Demise: Development of a Multidisciplinary Workflow. 促进围产期死亡的基因检测：多学科工作流程的发展。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-08 DOI: 10.1002/ajmga.70075

Mackenzie Mosera, Samantha Stover, Elise Boos, Molly Casey, Joseph Fanning, Chelsea Fechter, Matthew Grace, L Dupree Hatch, Michaela Ibach, Carla Jackson, Jiancong Liang, Caitlin Mann, Emily A Morris, Jessica Turnbull, Marie Williams, Bryce A Schuler

{"title":"Facilitating Genetic Testing for Perinatal Demise: Development of a Multidisciplinary Workflow.","authors":"Mackenzie Mosera, Samantha Stover, Elise Boos, Molly Casey, Joseph Fanning, Chelsea Fechter, Matthew Grace, L Dupree Hatch, Michaela Ibach, Carla Jackson, Jiancong Liang, Caitlin Mann, Emily A Morris, Jessica Turnbull, Marie Williams, Bryce A Schuler","doi":"10.1002/ajmga.70075","DOIUrl":"10.1002/ajmga.70075","url":null,"abstract":"Genetic contributors to perinatal demise are common but frequently undiagnosed due to clinical and logistical barriers. We aimed to improve access to genetic for intrauterine fetal demise (IUFD), stillbirth, and early neonatal death by developing a multidisciplinary workflow. A working group representing clinical genetics, maternal-fetal medicine, neonatology, pathology, obstetrics, palliative care, laboratories, and health information technology identified barriers and designed solutions for genetic testing in perinatal demise. Tools developed included testing algorithms, specimen collection and handling guides, documentation templates, and electronic health record integration. Case reviews and stakeholder feedback informed iterative refinement. The workflow clarified team roles, timing, and coordination across specialties. Scenario-specific algorithms for stillbirth, neonatal demise, and pediatric genetics consultations guided testing decisions. A specimen-testing matrix linked sample types with available tests and laboratories. Implementation was supported by education and centralized resources. Representative cases demonstrated improved sample collection, diagnostic yield, and family counseling through early communication and defined responsibilities. A multidisciplinary workflow improved the feasibility and consistency of genetic evaluation in perinatal demise. This model may guide other institutions seeking to implement or enhance genetic testing processes for families affected by pregnancy loss or neonatal death.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1273-1285"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140722","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 Phenotype of TAB2-Related Syndrome: The First Case With Cleft Palate and Insights Into Palatal Development. 扩展tab2相关综合征的表型：第一例腭裂和对腭发育的见解。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-18 DOI: 10.1002/ajmg.a.70092

Alberto De Rosa, Silvia Kalantari, Marta Carboni, Antonella Casella, Elisa Giorgio, Antonia Apicella, Alessia Claudia Codazzi, Fabio Sirchia

引用次数: 0

Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2. 本月综合征：尺桡关节闭锁伴2型无核细胞性血小板减少症。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-04 DOI: 10.1002/ajmga.70077

Daniel R Schecter, Danielle Zamalin, V Peter Abdow, Brenton Francisco, Matthew Drago, Veniamin Ratner, Rory J Tinker

{"title":"Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2.","authors":"Daniel R Schecter, Danielle Zamalin, V Peter Abdow, Brenton Francisco, Matthew Drago, Veniamin Ratner, Rory J Tinker","doi":"10.1002/ajmga.70077","DOIUrl":"10.1002/ajmga.70077","url":null,"abstract":"Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement. It is caused by heterozygous germline pathogenic variants in the MDS1 and EVI1 Complex Locus (MECOM) gene, which encodes transcription factors essential for hematopoietic stem cell regulation and embryonic development. Disruption of highly conserved zinc finger domains within MECOM impairs long-term hematopoietic stem cell maintenance, leading to amegakaryocytic thrombocytopenia and, in many cases, progression to pancytopenia. Although MECOM is also implicated in leukemogenesis through somatic dysregulation, germline variants associated with RUSAT-2 result in a distinct developmental and hematologic phenotype with highly variable penetrance and age of onset. As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation. This review summarizes the current understanding of the genetic basis, clinical manifestations, differential diagnosis, clinical course, management considerations, and outstanding mechanistic questions surrounding RUSAT-2.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"1239-1244"},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111948","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

Correction to "Multiple Genomic Technologies Validate Rare Novel Variant and Direct Medical Care in Vascular Anomalies". 更正“多种基因组技术验证罕见的新变异和血管异常的直接医疗护理”。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2026-06-01 Epub Date: 2026-02-17 DOI: 10.1002/ajmga.70056

引用次数: 0