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

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

Paroxysmal Kinesigenic Dyskinesia in Two Siblings With Novel Heterozygous TMEM151A Frameshift Variant: The First Case Report in Japan.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-01 DOI: 10.1002/ajmg.a.64079

Hirokazu Kurahashi, Yoshiteru Azuma, Tomoya Takeuchi, Mayuko Shimada, Shingo Numoto, Mizuki Nishida, Yoshinori Ito, Tomoo Ogi, Akihisa Okumura

{"title":"Paroxysmal Kinesigenic Dyskinesia in Two Siblings With Novel Heterozygous TMEM151A Frameshift Variant: The First Case Report in Japan.","authors":"Hirokazu Kurahashi, Yoshiteru Azuma, Tomoya Takeuchi, Mayuko Shimada, Shingo Numoto, Mizuki Nishida, Yoshinori Ito, Tomoo Ogi, Akihisa Okumura","doi":"10.1002/ajmg.a.64079","DOIUrl":"https://doi.org/10.1002/ajmg.a.64079","url":null,"abstract":"Paroxysmal kinesigenic dyskinesia is a rare movement disorder that typically has a genetic basis, with PRRT2 being the primary causative gene. However, TMEM151A mutations have recently emerged as causative factors. Here, we report the cases of two Japanese siblings diagnosed with paroxysmal kinesigenic dyskinesia caused by a novel heterozygous TMEM151A frameshift variant (c.760_761insT). Case 1 was a 17-year-old male who had experienced involuntary movements triggered by sudden actions since the age of 12 years. Carbamazepine alleviated the symptoms but caused side effects, leading to a switch to lacosamide, which was effective. Case 2 was a 14-year-old female who experienced subtle discomfort at the onset of physical activity. Genetic analysis confirmed the presence of the same TMEM151A variant in both siblings. Lacosamide effectively managed the patients' symptoms. TMEM151A-positive paroxysmal kinesigenic dyskinesia differs phenotypically from PRRT2-positive paroxysmal kinesigenic dyskinesia, presenting later onset and shorter-duration dystonia. Case 1 presented with dystonia with a relatively long duration of 15 s. We also found differences in involuntary movements among siblings. This report emphasizes the clinical and genetic diversity of paroxysmal kinesigenic dyskinesia, which may lead to challenges in diagnosing sporadic cases, and finally, reports on the efficacy of lacosamide as a treatment.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64079"},"PeriodicalIF":1.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750656","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 New EP300-Related Syndrome With Prominent Developmental and Immune Phenotypes.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-04-01 DOI: 10.1002/ajmg.a.64050

Devi Priyanka Maripuri, Jessica Gold, Nina Gold, Alanna Strong

{"title":"A New EP300-Related Syndrome With Prominent Developmental and Immune Phenotypes.","authors":"Devi Priyanka Maripuri, Jessica Gold, Nina Gold, Alanna Strong","doi":"10.1002/ajmg.a.64050","DOIUrl":"https://doi.org/10.1002/ajmg.a.64050","url":null,"abstract":"Rubinstein Taybi syndrome (RTS) is a disorder of chromatin remodeling and transcriptional regulation caused by heterozygous pathogenic variants in CREBBP and EP300. RTS is characterized by a distinct facial gestalt, intellectual disability, structural kidney and heart differences, feeding difficulties, and broad thumbs and great toes. Individuals with EP300 variants tend to have milder disease, but overall disease features are similar. Recently, a cohort of individuals with heterozygous variants in exons 30-31 of CREBBP and homologous regions in EP300 was described. Affected individuals presented with global developmental delay, autism, feeding difficulties, vision and hearing impairment, and microcephaly, but did not share the typical RTS facial gestalt or organ malformations, suggesting an allelic disorder. Here we present a family with mild dysmorphisms, recurrent respiratory infections, and speech delay found by exome sequencing to have a missense variant in exon 8 of EP300 in the KIX CBP coactivator domain. Follow-up methylation testing revealed an abnormal methylation pattern overlapping with both RTS and Cornelia de Lange syndromes. We propose that missense variants in EP300 may cause a distinct neurodevelopmental syndrome with a milder phenotype.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64050"},"PeriodicalIF":1.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750654","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 SIAH1-Associated Phenotypic Spectrum: Insights From Loss-of-Function Variants.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-03-29 DOI: 10.1002/ajmg.a.64048

Liza Douiev, Paula Fernandez Alvarez, Marika Frank, Lucy Hanington, Trevor L Hoffman, Mira B Irons, Jenny Kim, Akash Kumar, Amaia Lasa-Aranzasti, Diana Le Duc, Helen Livesey, Oliver Murch, Deborah Shears, Brandon K Walther, Tamar Harel

{"title":"Expanding the SIAH1-Associated Phenotypic Spectrum: Insights From Loss-of-Function Variants.","authors":"Liza Douiev, Paula Fernandez Alvarez, Marika Frank, Lucy Hanington, Trevor L Hoffman, Mira B Irons, Jenny Kim, Akash Kumar, Amaia Lasa-Aranzasti, Diana Le Duc, Helen Livesey, Oliver Murch, Deborah Shears, Brandon K Walther, Tamar Harel","doi":"10.1002/ajmg.a.64048","DOIUrl":"https://doi.org/10.1002/ajmg.a.64048","url":null,"abstract":"SIAH1 encodes for a RING-type E3 ubiquitin ligase involved in protein ubiquitination. More specifically, it positively regulates Wnt signaling through promoting the accumulation of β-catenin and mediates ubiquitination and degradation of Akt3 in neural development. Heterozygous de novo missense pathogenic variants in SIAH1 have been described in five unrelated individuals and are associated with developmental delay, hypotonia, and dysmorphic features. In this report, we present additional individuals from eight unrelated families and their clinical and genetic findings. We identified two missense and six predicted loss-of-function variants. Motor and speech delay and intellectual disabilities of varying severity were observed in all individuals. Neurodevelopmental issues, as well as infantile hypotonia and facial dysmorphism, were observed in the majority of individuals. Hearing loss, gastroesophageal reflux disease or other gastrointestinal issues, endocrinology abnormalities, and recurrent infections were observed in over 50% of individuals. This study expands the phenotypic spectrum of this syndrome and emphasizes the diverse impact of SIAH1 variation on multi-system clinical manifestations.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64048"},"PeriodicalIF":1.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741731","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

Extended Growth Curves for the Wolf-Hirschhorn Syndrome (4p-).

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-03-29 DOI: 10.1002/ajmg.a.64075

Amy R U L Calhoun, Amanda Lortz, T Charles Casper, John C Carey

{"title":"Extended Growth Curves for the Wolf-Hirschhorn Syndrome (4p-).","authors":"Amy R U L Calhoun, Amanda Lortz, T Charles Casper, John C Carey","doi":"10.1002/ajmg.a.64075","DOIUrl":"https://doi.org/10.1002/ajmg.a.64075","url":null,"abstract":"Wolf-Hirschhorn syndrome (WHS) is a rare, highly variable contiguous gene deletion syndrome caused by deletions of the distal portion of the short arm of chromosome 4. Individuals with this disorder have prenatal onset of poor growth of all dimensions, along with neurological manifestations, developmental disability, and distinctive facial appearance. There are two previously published growth charts for individuals with WHS. Antonius and colleagues included 101 children aged 0-4 years, and Shimojima and Yamamoto included 34 individuals ranging from 15 months to 24 years of age. We present detailed length/height and weight curves on an additional 65 patients from birth to 18 years of age and occipitofrontal circumference curves from birth to 2 years of age. Our data provide additional insight into growth patterns for individuals with WHS. As expected, these individuals are generally smaller than typically growing individuals for all parameters. Unexpected findings included near absence of the pubertal growth spurt and a higher-than-expected number of individuals overlapping the typical growing range. Growth charts are a critical part of pediatric healthcare, and syndrome-specific growth charts are particularly important in conditions where abnormal growth is a major feature. These additional growth charts serve as a useful addition to the literature on WHS, particularly providing additional information on growth through puberty and final adult height.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64075"},"PeriodicalIF":1.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741735","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

Distal 1q Duplication and Distal 9p Deletion: A Follow-Up Case Report and Literature Review on Candidate Genes for 9p Deletion Syndrome.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-03-28 DOI: 10.1002/ajmg.a.64066

Jonas Helbig, Jürgen Kunz, Anca Mannhardt, Ellen Gandaputra, Christiane Kling

引用次数: 0

Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and TBX4-FGF10 Signaling Pathways.

IF 1.7 4区生物学

American Journal of Medical Genetics Part A Pub Date : 2025-03-27 DOI: 10.1002/ajmg.a.64071

Katarzyna Bzdęga, Gail H Deutsch, Małgorzata Rydzanicz, Witold Błaż, Elżbieta Rafińska-Ważny, Anna P Terpin, Dariia Klepach, Valentyna Zakharova, Rafał Płoski, Tomasz Szczapa, Justyna A Karolak

{"title":"Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and TBX4-FGF10 Signaling Pathways.","authors":"Katarzyna Bzdęga, Gail H Deutsch, Małgorzata Rydzanicz, Witold Błaż, Elżbieta Rafińska-Ważny, Anna P Terpin, Dariia Klepach, Valentyna Zakharova, Rafał Płoski, Tomasz Szczapa, Justyna A Karolak","doi":"10.1002/ajmg.a.64071","DOIUrl":"https://doi.org/10.1002/ajmg.a.64071","url":null,"abstract":"Lethal lung developmental disorders (LLDDs), histologically classified as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), congenital alveolar dysplasia (CAD), acinar dysplasia (AcDys), and primary pulmonary hypoplasia (PH), are rare diseases associated with high neonatal mortality due to refractory respiratory failure. Although ACDMPV mostly results from single nucleotide variants (SNVs) or copy-number variants (CNVs) involving FOXF1, AcDys, CAD, and PH are often associated with abnormalities within TBX4 or FGF10. These genes interact in the SHH-FOXF1 and TBX4-FGF10 signaling network and are known regulators of lung development. Recent studies conducted in TBX4-, FGF10-, or FOXF1-deficient LLDD lungs revealed decreased expression of TMEM100 at the transcriptomic and immunohistochemical levels. Here, we present four new patients with genetically and histopathologically confirmed LLDD, including ACDMPV (n = 2), AcDys (n = 1), and PH (n = 1), in whom we detected a heterozygous variants involving FOXF1 (n = 2) or TBX4 (n = 2). Additional immunohistochemical (TMEM100) and qPCR analyses (TMEM100, TBX4, FOXF1) performed in lung tissues of these newborns revealed a significant reduction in TMEM100, TBX4, and FOXF1 expression. Our results confirm previous findings indicating the possible involvement of TMEM100 in FOXF1-TBX4-FGF10 molecular signaling that, when disrupted, may lead to LLDD.","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64071"},"PeriodicalIF":1.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717616","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