American Journal of Medical Genetics Part A最新文献

Cohesins: Crossroad Between Cornelia de Lange Spectrum and Cancer Predisposition.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-05 DOI: 10.1002/ajmg.a.64076

Laura Rigotti, Stefano Rebellato, Antonella Lettieri, Silvia Castiglioni, Milena Mariani, Simona Totaro, Claudia Saitta, Cristina Gervasini, Grazia Fazio, Valentina Massa, Giovanni Cazzaniga, Angelo Selicorni

{"title":"Cohesins: Crossroad Between Cornelia de Lange Spectrum and Cancer Predisposition.","authors":"Laura Rigotti, Stefano Rebellato, Antonella Lettieri, Silvia Castiglioni, Milena Mariani, Simona Totaro, Claudia Saitta, Cristina Gervasini, Grazia Fazio, Valentina Massa, Giovanni Cazzaniga, Angelo Selicorni","doi":"10.1002/ajmg.a.64076","DOIUrl":"https://doi.org/10.1002/ajmg.a.64076","url":null,"abstract":"The cohesin complex plays crucial roles in DNA repair, chromatid separation, and gene transcription regulation. Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next-generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on N = 120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total-10 germline and 1 somatic-variants in cohesin genes. Data of N = 205 brain tumors were extracted by bioinformatic analysis of data from open-source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13 years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline NIPBL variants in CdLSp, whereas RAD21 and STAG1/2 are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64076"},"PeriodicalIF":1.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787605","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

Growth Charts for Children With Beckwith-Wiedemann Spectrum.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-04 DOI: 10.1002/ajmg.a.64073

Saskia M Maas, Peter Lauffer, Guido Cocchi, Madison DeMarchis, Andrew M George, Alessandro Mussa, Francesco Pellegrino, Alexander M J Spaans, Emma C van den Brink, Jan M Wit, Leonie A Menke, Jennifer M Kalish

{"title":"Growth Charts for Children With Beckwith-Wiedemann Spectrum.","authors":"Saskia M Maas, Peter Lauffer, Guido Cocchi, Madison DeMarchis, Andrew M George, Alessandro Mussa, Francesco Pellegrino, Alexander M J Spaans, Emma C van den Brink, Jan M Wit, Leonie A Menke, Jennifer M Kalish","doi":"10.1002/ajmg.a.64073","DOIUrl":"https://doi.org/10.1002/ajmg.a.64073","url":null,"abstract":"Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder caused by (epi)genetic alterations in chromosome 11p15. This study aimed to develop BWSp-specific growth charts and explore genotype/phenotype correlations with respect to growth. Heights, weights, and head circumferences were retrospectively collected from 581 individuals with BWSp from the Netherlands, Italy, and the United States. The Generalized Additive Models for Location, Scale, and Shape (GAMLSS) method was employed to develop the following charts: height-for-age, weight-for-age, BMI-for-age, and head circumference-for-age for males and females. Mean height, weight, and head circumference were compared with those of the growth charts generated by the World Health Organization (WHO). Individuals with BWSp show enhanced growth rate during puberty and adolescence, and all growth parameters were increased compared to WHO charts. Mean modeled height at 18 years of age was 180.6 cm for males and 166.3 cm for females (+0.6 SDS and +0.5 SDS, respectively, compared to WHO charts). In conclusion, these growth charts offer valuable insights into the growth patterns in BWSp individuals and provide a key tool for personalized medical care for individuals with BWSp.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64073"},"PeriodicalIF":1.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778814","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

Gut Microbiome Pilot Study of Patients With CHARGE Syndrome and Sibling Controls.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.64053

Emily R Chedrawe, Jessica Connors, Angela Arra, Katherine Dunn, Kim Blake, Johan van Limbergen

{"title":"Gut Microbiome Pilot Study of Patients With CHARGE Syndrome and Sibling Controls.","authors":"Emily R Chedrawe, Jessica Connors, Angela Arra, Katherine Dunn, Kim Blake, Johan van Limbergen","doi":"10.1002/ajmg.a.64053","DOIUrl":"https://doi.org/10.1002/ajmg.a.64053","url":null,"abstract":"Difficulties with feeding and digestion are common in individuals with CHARGE syndrome. Animal models with CHD7 gene variants demonstrate abnormal gut innovation and dysmotility. Our pilot study evaluated whether individuals with CHARGE syndrome have differences in their gut microbiome compared to unaffected siblings. Participants between the ages of 2-18 were recruited from Atlantic Canada with a confirmed genetic diagnosis of CHARGE syndrome. Gut Microbiome DNA analysis was performed on stool samples using 16S ribosomal RNA (rRNA) gene sequences. The PASSFP and PEDSQL served as GI symptom questionnaires. Eleven participants completed this study with one twin pair (CHARGE syndrome = 7, sibling controls = 4). The mean percent abundance for the four most common phyla in individuals with CHARGE versus Controls showed a trend towards increased Bacteroidetes, Proteobacteria, and a decrease in Firmicutes and Actinobacteria but was not significant. Microbiome comparisons based on abnormal (< 77) and normal ( <math> <semantics><mrow><mo>≥</mo></mrow> <annotation>$$ ge $$</annotation></semantics> </math> 77) GI scores, found significantly elevated Bacteroidetes (p = 0.042, 59.5% ± 15.1% vs. 33.1% ± 14.6%) and decreased Firmicutes (p = 0.042, 37.5% ± 15.9% vs. 62.4% ± 14.0%) with abnormal scores. Alpha diversity did not differ with either disease or GI symptom scores. Our data showed that, although there was a trend in changes in the gut microbiome in individuals with CHARGE compared to unaffected siblings, this change appears to be related to the severity of GI symptoms and not necessarily CHARGE itself, as differences were more pronounced in individuals with more difficulties with feeding and GI symptoms.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64053"},"PeriodicalIF":1.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771061","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 5, May 2025

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.63747

引用次数: 0

A Novel Deep Intronic Variant in NSD1 Causing Sotos Syndrome.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.64074

Alejandro Parra, Mario Cazalla, Juan A Jimenez-Estrada, Cristina Silván, Lucía Miranda-Alcaraz, Natalia Gallego-Zazo, Mónica Mora-Gómez, Manuel Rodríguez-Canó, Pedro Arias, Carlos Rodríguez-Antolín, Julián Nevado, Víctor Luis Ruiz Pérez, Jair Tenorio-Castano, Pablo Lapunzina

引用次数: 0

Human Phenotype Ontology Annotations for Rare Congenital Conditions: Application to Arthrogryposis Multiplex Congenita.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.64067

Shahrzad Nematollahi, Reggie C Hamdy, Harold van Bosse, Joyce Li, Daniel Blanshay-Goldberg, Johanna I P de Vries, Klaus Dieterich, Isabel Filges, Tanya Bedard, Melissa Haendel, Monica Munoz Torres, Peter N Robinson, Noémi Dahan-Oliel

{"title":"Human Phenotype Ontology Annotations for Rare Congenital Conditions: Application to Arthrogryposis Multiplex Congenita.","authors":"Shahrzad Nematollahi, Reggie C Hamdy, Harold van Bosse, Joyce Li, Daniel Blanshay-Goldberg, Johanna I P de Vries, Klaus Dieterich, Isabel Filges, Tanya Bedard, Melissa Haendel, Monica Munoz Torres, Peter N Robinson, Noémi Dahan-Oliel","doi":"10.1002/ajmg.a.64067","DOIUrl":"https://doi.org/10.1002/ajmg.a.64067","url":null,"abstract":"Arthrogryposis multiplex congenita (AMC) represents a large, rare group of congenital conditions. This study addressed major challenges in AMC research posed by the lack of systematic frameworks for data collection and the use of inconsistent terminologies and text descriptions. We aimed to systematically review the Human Phenotype Ontology (HPO) terms, encode AMC phenotypic traits as HPO terms, and pilot test the encoding process in a cohort of children with AMC. An international consensus-based dataset for AMC was used to extract phenotypic traits from the fetal period to adulthood. The encoding process was developed by an international expert panel to expand and revise HPO ontology for joint contractures, as the main characterizing traits in AMC. Using a pre-tested mapping algorithm, the HPO mapping process resulted in a 62% complete match, a 12% incomplete match, and a 26% no match. The encoding process included 37 new terms and annotations and 13 re-structures across 10 different joints. The implemented annotations significantly increased the number of available HPO terms for joint contractures in a cohort of children with AMC (p-value = 0.04). Our encoding and annotation approach may be used as a blueprint for systematic HPO (re)annotations for musculoskeletal and non-musculoskeletal phenotypic traits of AMC.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64067"},"PeriodicalIF":1.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771062","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

Re-Analysis Yields Diagnosis in Over 500 Patients with Rare Diseases

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.63744

引用次数: 0

Long Somatic DNA-Repeat Expansion Responsible for Clinical Findings in Huntington’s Disease

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-03 DOI: 10.1002/ajmg.a.63742

引用次数: 0

Tall Stature and Scoliosis Associated With a Novel Homozygous Loss-of-Function Missense Variant in NPR3.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-02 DOI: 10.1002/ajmg.a.64080

Pierre Moffatt, Chantal Janelle, Valancy Miranda, Ghalib Bardai, Frank Rauch

{"title":"Tall Stature and Scoliosis Associated With a Novel Homozygous Loss-of-Function Missense Variant in NPR3.","authors":"Pierre Moffatt, Chantal Janelle, Valancy Miranda, Ghalib Bardai, Frank Rauch","doi":"10.1002/ajmg.a.64080","DOIUrl":"https://doi.org/10.1002/ajmg.a.64080","url":null,"abstract":"NPR3-related tall stature is characterized by tall stature, elongated big toes, and additional epiphyses in hand and foot bones. The condition is caused by biallelic loss-of-function variants affecting natriuretic peptide receptor 3 (NPR3). Five individuals from four different families have been reported. Here we describe three siblings with NPR3-related tall stature who were tall (height z-scores between +2.9 and + 4.9) and had markedly elongated proximal and middle phalanges. Two siblings had additional epiphyses in phalangeal and metacarpal bones. All three siblings developed scoliosis, requiring spinal fusion surgery in one individual. Lumbar spine bone mineral density appeared low considering the tall stature. Sequencing of a skeletal disorders gene panel in one sibling revealed a homozygous missense variant in NPR3 (NM_001204375.2; c.382C>T; p.Pro128Ser). Sanger sequencing demonstrated the same homozygous variant in the other siblings. In vitro functional testing in MC3T3-E1 preosteoblastic cells showed that NPR3 carrying the p.Pro128Ser variant was expressed but was retained in the endoplasmic reticulum, leading to loss of NPR3 function. In conclusion, the novel homozygous p.Pro128Ser loss-of-function variant in NPR3 led to the typical features of NPR3-related tall stature and, in addition, was associated with scoliosis. These observations expand the genotypic and phenotypic spectrum of NPR3-related tall stature.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64080"},"PeriodicalIF":1.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762794","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

Biallelic Variant in LYSET Associated With Mucolipidosis II-Like Phenotype.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-02 DOI: 10.1002/ajmg.a.64063

Ariana Kariminejad, Farzaneh Pouya, Fatemeh Ahangari, Saeed Talebi, Fariba Afroozan, Frans W Verheijen, Hossein Najmabadi, Edwin H Jacobs

引用次数: 0