American Journal of Medical Genetics Part A最新文献_第2页

An OGT Missense Variant With Impaired Enzyme Activity in a Child With Severe Developmental Delay and Hepatoblastoma. 严重发育迟缓和肝母细胞瘤儿童的OGT错义变异与酶活性受损。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-10-01 DOI: 10.1002/ajmg.a.64275

Alfonso Manuel D'Alessio, Huijie Yuan, Leandro Raul Soria, Sara Basse Hansen, Iolanda Boffa, Paola Arena, Benedetta Attianese, Maureen O'Sullivan, Noelle Cullinan, Lewis Pang, Daan Marinus Ferdinand van Aalten, Nicola Brunetti-Pierri, Sally Ann Lynch

{"title":"An OGT Missense Variant With Impaired Enzyme Activity in a Child With Severe Developmental Delay and Hepatoblastoma.","authors":"Alfonso Manuel D'Alessio, Huijie Yuan, Leandro Raul Soria, Sara Basse Hansen, Iolanda Boffa, Paola Arena, Benedetta Attianese, Maureen O'Sullivan, Noelle Cullinan, Lewis Pang, Daan Marinus Ferdinand van Aalten, Nicola Brunetti-Pierri, Sally Ann Lynch","doi":"10.1002/ajmg.a.64275","DOIUrl":"https://doi.org/10.1002/ajmg.a.64275","url":null,"abstract":"O-GlcNAc transferase (OGT) and its antagonist O-GlcNAcase (OGA) regulate protein O-GlcNAcylation, a highly conserved post-translational modification involved in metabolic sensing. Pathogenic variants in the OGT gene cause an X-linked congenital disorder of glycosylation (OGT-CDG) presenting developmental delay, hypotonia, intellectual disability, and dysmorphic features. Here, we report on a child with developmental delay, hypotonia, and dysmorphic features who was found to carry a hemizygous novel OGT variant. This child also developed hepatoblastoma by the age of 17 months. OGT-CDG was diagnosed by exome sequencing that identified a de novo missense variant in the OGT gene. Functional validation by Western blot on patient-derived fibroblasts showed reduced O-GlcNAcylation and OGA expression, while significantly reduced enzyme activity in vitro confirmed the pathogenicity of the variant. To date, no patients with OGT-CDGs have been reported with hepatoblastoma or other malignancies. Although the occurrence of hepatoblastoma in the proband might be coincidental, the role of O-GlcNAcylation in cancer suggests that the deficiency of OGT activity might be associated with increased cancer risk.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64275"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197468","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

Response to: An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations. 回应：一项国际ASXL3自然历史研究：深度表型分析，包括温和表型的详细报告，新的关联和临床建议。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-29 DOI: 10.1002/ajmg.a.64272

Shemonti Hasan, David Melville, Mohammad K Chaaban, Ehab Y Harahsheh, Bukola A Olarewaju, Linnea M Baudhuin, Wei Shen, Fadi Shamoun, Mayowa A Osundiji

引用次数: 0

A Confirmatory Case of Severe Spondylocostal Dysostosis Caused by Biallelic Loss-of-Function of DMRT2. 由双等位基因DMRT2功能丧失引起的严重脊柱侧凸不全的确诊病例。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-27 DOI: 10.1002/ajmg.a.64270

Jonathan Rips, Hagar Mor-Shaked, Oded Shamriz, Raz Somech, Rawan Abu Omar, Smadar Eventov-Friedman, Noa Ofek-Shlomai, Dvorah Zaguer, Tamar Harel

{"title":"A Confirmatory Case of Severe Spondylocostal Dysostosis Caused by Biallelic Loss-of-Function of DMRT2.","authors":"Jonathan Rips, Hagar Mor-Shaked, Oded Shamriz, Raz Somech, Rawan Abu Omar, Smadar Eventov-Friedman, Noa Ofek-Shlomai, Dvorah Zaguer, Tamar Harel","doi":"10.1002/ajmg.a.64270","DOIUrl":"https://doi.org/10.1002/ajmg.a.64270","url":null,"abstract":"Spondylocostal dysostosis (SCDO) is a rare genetic disorder characterized by abnormal development of the axial skeleton, resulting in malformations of the vertebrae and ribs that often impair lung development and lead to significant respiratory morbidity. SCDO is thought to arise from defects in the paraxial presomitic mesoderm, an embryonic tissue that forms the vertebral column and ribs. Pathogenic variants in DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2 have been identified in various SCDO subtypes. In addition, a single case of a lethal SCDO-like phenotype caused by a homozygous start-loss variant in DMRT2 has been reported. DMRT2 encodes a transcription factor expressed in the dermomyotome during early somite formation in mice. Here, we describe a newborn with severe costovertebral malformations and dysmorphic features, in whom exome sequencing identified a homozygous loss-of-function variant in DMRT2. The phenotype strikingly overlaps the previous report, further supporting the role of biallelic pathogenic DMRT2 variants in a severe SCDO-like disorder. Notably, our patient also exhibited thymic aplasia and immunodeficiency. A review of the exome sequencing data did not reveal any variant that could account for the immunodeficiency. These features have not been previously associated with SCDO, suggesting a potential phenotypic expansion.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64270"},"PeriodicalIF":1.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172263","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 Rare Craniosynostosis Phenotype Associated With a Homozygous CYP26B1 Pathogenic Variant in the Absence of Extremity Synostosis. 一种罕见的与纯合子CYP26B1致病变异相关的颅缝闭锁表型在四肢关节闭锁缺失中。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-26 DOI: 10.1002/ajmg.a.64257

Busra Ozguc Caliskan, Mikail Demir, Suat Oktem, Selcan Ozturk, Mehmet Canpolat, Munis Dundar

{"title":"A Rare Craniosynostosis Phenotype Associated With a Homozygous CYP26B1 Pathogenic Variant in the Absence of Extremity Synostosis.","authors":"Busra Ozguc Caliskan, Mikail Demir, Suat Oktem, Selcan Ozturk, Mehmet Canpolat, Munis Dundar","doi":"10.1002/ajmg.a.64257","DOIUrl":"https://doi.org/10.1002/ajmg.a.64257","url":null,"abstract":"CYP26B1, a member of the cytochrome P450 enzyme family, is one of the enzymes responsible for the inactivation of retinoic acid. Pathogenic variants in genes involved in endogenous retinoic acid production and control can result in craniofacial disorders and extremity abnormalities. The patient was referred due to craniosynostosis and dysmorphic appearance at the age of 3 years. Clinical exome sequencing showed a likely pathogenic homozygous missense variant, c.1190G>A (p.Arg397Gln), in exon 5 of the CYP26B1 gene. Nine cases with craniosynostosis, various skeletal deformities, arachnodactyly, and encephalocele have been reported in the literature so far, caused by biallelic pathogenic variants in the CYP26B1. All patients had a fusion of various bones in the upper extremity, in addition to premature closure of the skull sutures. Although our patient had craniosynostosis, there was no additional obvious joint synostosis. Herein, we describe a case of an extremely rare skeletal disorder caused by a pathogenic variant in CYP26B1. We broaden the phenotypic spectrum and underscore that extremity joint fusions are not a universal finding of the disease.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64257"},"PeriodicalIF":1.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147507","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

TBX3- Related Disorder. TBX3-相关疾病。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-25 DOI: 10.1002/ajmg.a.64260

Ziv Halperin, Karin Weiss

引用次数: 0

FLNA Variants Related to Melnick-Needles Syndrome: Two Mexican Case Reports and a Comprehensive Variant Review. 与Melnick-Needles综合征相关的FLNA变异：两个墨西哥病例报告和一个全面的变异回顾。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-25 DOI: 10.1002/ajmg.a.64246

Thania Ordaz-Robles, Jessica Vanesa Sánchez-Aguilar, Carlos Alfonso Guzmán-Martín, Sergio Saldaña-Pimentel, Ilan Vinitzky Brener, Fernando Ramírez-Jiménez, María Hortensia Valdez-de la Torre, Ghalib Bardai, Frank Rauch

{"title":"FLNA Variants Related to Melnick-Needles Syndrome: Two Mexican Case Reports and a Comprehensive Variant Review.","authors":"Thania Ordaz-Robles, Jessica Vanesa Sánchez-Aguilar, Carlos Alfonso Guzmán-Martín, Sergio Saldaña-Pimentel, Ilan Vinitzky Brener, Fernando Ramírez-Jiménez, María Hortensia Valdez-de la Torre, Ghalib Bardai, Frank Rauch","doi":"10.1002/ajmg.a.64246","DOIUrl":"https://doi.org/10.1002/ajmg.a.64246","url":null,"abstract":"Melnick-Needles Syndrome (MNS; OMIM #309350) is a rare X-linked dominant osteochondrodysplasia caused by FLNA gain-of-function variants. It is characterized by short stature, facial dysmorphism, skeletal anomalies, and systemic complications. FLNA encodes Filamin A, a cytoskeletal protein with over 90 binding partners. Variants in FLNA cause a broad spectrum of disorders, among which MNS represents one of the most severe phenotypes. Despite increasing research on MNS, many aspects of its genetic and phenotypic spectrum remain unknown. In this work, we presented two Mexican cases with a diagnosis of MNS with different FLNA missense variants p.(Leu1193Pro) and p.(Ser1199Leu). In addition, we performed a comprehensive review of the literature about FLNA variants related to MNS. This study reinforced the genetic and phenotypic complexity of MNS, emphasizing the critical role of exon 22 variants in the pathogenesis of the disease.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64246"},"PeriodicalIF":1.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136245","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

Clinically Irrelevant Terminal 16q21 Deletion Detected by NIPT Is Attributable to Inherited Fragility at FRA16B. NIPT检测到的临床无关末端16q21缺失可归因于FRA16B的遗传性易碎性。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-24 DOI: 10.1002/ajmg.a.64271

Servi J C Stevens, Wanwisa van Dijk, Nicole Y Souren, Merryn V E Macville, Guillaume van de Zande, Brigitte H W Faas, Bart de Koning, Arthur van den Wijngaard, Sonja de Munnik, Masoud Zamani Esteki

{"title":"Clinically Irrelevant Terminal 16q21 Deletion Detected by NIPT Is Attributable to Inherited Fragility at FRA16B.","authors":"Servi J C Stevens, Wanwisa van Dijk, Nicole Y Souren, Merryn V E Macville, Guillaume van de Zande, Brigitte H W Faas, Bart de Koning, Arthur van den Wijngaard, Sonja de Munnik, Masoud Zamani Esteki","doi":"10.1002/ajmg.a.64271","DOIUrl":"https://doi.org/10.1002/ajmg.a.64271","url":null,"abstract":"Genome-wide non-invasive prenatal testing (NIPT) is a powerful tool for prenatal detection of the common aneuploidies causing Down-, Edwards-, and Patau syndrome. Its genome-wide reach also enables the detection of unbalanced structural chromosomal abnormalities. We report a case where NIPT indicated a ~25 Mb terminal deletion of the long arm of chromosome 16, later confirmed to be mosaic in maternal blood and buccal cells (in 35%-45% of cells). Remarkably, the same mosaic deletion was seen in the child, who was born healthy at term after an uneventful pregnancy. Further analysis using bromodeoxyuridine (BrdU)-induced cultures revealed that the deletion originated from the expression of a rare autosomal fragile site (RFS), FRA16B, resulting in enhanced chromosomal fragility at 16q21. Rather than inheriting the maternal deletion, the child had inherited the maternal RFS, causing increased fragility at 16q21 in both mother and child. Employing long-read sequencing (LRS), we characterized the molecular structure of this RFS. FRA16B is an expanded repeat region of > 20 kb in size, comprising over 700 AT-rich minisatellite repeats. We resolved both distal (35-mer) and proximal (28-mer) repeat motifs at nucleotide precision. This uncovered striking molecular parallels between FRA16B and FRA10B, an RFS that is also associated with clinically irrelevant deletions found occasionally in NIPT. Our case underscores the importance of cautious interpretation of 16q21 terminal deletions in NIPT in order to avoid unnecessary invasive prenatal testing, as their presence reflects maternal and/or fetal fragile site instability rather than a pathogenic chromosome abnormality.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64271"},"PeriodicalIF":1.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129828","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 Noncanonical Splice Variant in RTEL1 Responsible for Familial Pulmonary Fibrosis. 家族性肺纤维化与RTEL1基因的非典型剪接变异有关。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-23 DOI: 10.1002/ajmg.a.64267

Alexandre White-Brown, Aren Marshall, Xueqi Wang, Minh Tran, Tara Keays, David A Dyment

引用次数: 0

The De Novo p.(Ser802Phe) Variant Causes Helsmoortel-Van der Aa/ADNP Syndrome in a 24-Year-Old Woman and Is Predicted to Perturb ADNP-DNA Affinity. De Novo p.（Ser802Phe）变异导致24岁女性Helsmoortel-Van der Aa/ADNP综合征，并预计会扰乱ADNP- dna亲和力。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-22 DOI: 10.1002/ajmg.a.64264

Mario Benvenuto, Marilena Carmela Di Giacomo, Ada Piepoli, Massimo Carella, Paola D'Addetta, Orazio Palumbo, Marco Castori, Pietro Palumbo

{"title":"The De Novo p.(Ser802Phe) Variant Causes Helsmoortel-Van der Aa/ADNP Syndrome in a 24-Year-Old Woman and Is Predicted to Perturb ADNP-DNA Affinity.","authors":"Mario Benvenuto, Marilena Carmela Di Giacomo, Ada Piepoli, Massimo Carella, Paola D'Addetta, Orazio Palumbo, Marco Castori, Pietro Palumbo","doi":"10.1002/ajmg.a.64264","DOIUrl":"https://doi.org/10.1002/ajmg.a.64264","url":null,"abstract":"The ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and/or HP1 domains of ADNP. Rare missense changes in the ADNP gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24-year-old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self- and hetero-aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next-generation sequencing showed the novel de novo missense variant c.2405C>T, p.(Ser802Phe) affecting the DNA-binding homeodomain of ADNP. In silico analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for ADNP syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP-DNA interaction, thus opening the path to the hypothesis of a gain-of-function effect. This clinical report expands genotype-phenotype variability and correlations in ADNP syndrome.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64264"},"PeriodicalIF":1.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111789","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

Detection of Isodisomy Utilizing SNP Microarray: Frequency, Ascertainment, and Implications. 利用SNP微阵列检测同位体：频率、确定和意义。

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-09-22 DOI: 10.1002/ajmg.a.64265

Sharon Molinari, Niecy Williams, Gloria Haskell, Andrea Penton, Alexandra Arreola, Inder Gadi, Karen Phillips, Jim Tepperberg, Stuart Schwartz

{"title":"Detection of Isodisomy Utilizing SNP Microarray: Frequency, Ascertainment, and Implications.","authors":"Sharon Molinari, Niecy Williams, Gloria Haskell, Andrea Penton, Alexandra Arreola, Inder Gadi, Karen Phillips, Jim Tepperberg, Stuart Schwartz","doi":"10.1002/ajmg.a.64265","DOIUrl":"https://doi.org/10.1002/ajmg.a.64265","url":null,"abstract":"This study investigates the frequency, ascertainment, and clinical implications of whole chromosomal isodisomy using a database of over 415,000 chromosomal microarray (CMA) tests conducted since 2008 across prenatal, postnatal, and products of conception specimens. In this cohort, 0.04% of cases exhibited the rare chromosomal phenomenon of isodisomy. Analysis of these cases revealed distinct patterns in frequency, chromosome involvement, and parent of origin related to specimen type. Isodisomy 14 was most frequent in prenatal samples, while chromosomes 6, 7, and 15 were more common in postnatal cases. The involvement of imprinted and non-imprinted chromosomes was equivalent for prenatal cases, while imprinted chromosomes consisted of two-thirds of postnatal cases, with paternal uniparental isodisomy more prevalent than maternal across all specimen types. Several cases demonstrated unmasking of pathogenic variants in recessive genes, and findings support prior studies of associations between isodisomy 11 and prenatal or neonatal lethality. These results underscore the diagnostic value of CMA and contribute to an extended understanding of isodisomy's clinical relevance.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64265"},"PeriodicalIF":1.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111645","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