American Journal of Medical Genetics Part A最新文献

{"title":"De Novo Chromosomes 3q and 5q Chromothripsis Leads to a 5q14.3 Microdeletion Syndrome Presentation: Case Report and Review of the Literature.","authors":"Melina L Corriveau, Joshua C Korb, Sydney L Michener, Nichole M Owen, Erica L Wilson, Jamie Kubala, Alicia Turner, Danielle S Takacs, Lorraine Potocki, John W Swann, Mingshan Xue, Hongzheng Dai, Hsiao-Tuan Chao","doi":"10.1002/ajmg.a.63975","DOIUrl":"https://doi.org/10.1002/ajmg.a.63975","url":null,"abstract":"<p><p>5q14.3 microdeletion syndrome (MIM#613443) is a neurodevelopmental disorder (NDD) involving copy number loss of multiple genes including Myocyte enhancer factor 2C (MEF2C) gene in the q14.3 region of chromosome 5. Chromosomes 5 and 15 chromothripsis involving 5q14.3 was previously reported in one individual with developmental epileptic encephalopathy (DEE). A complex chromothripsis between chromosomes 3, 5, 7, 9, and 18 that involved 5q14.3 was also reported in a pregnancy complicated by brain and kidney anomalies on fetal ultrasound. Here, we report chromothripsis of chromosomes 3q and 5q involving 5q14.3 in a three-year-old female with Lennox-Gastaut syndrome. The chromosomes 3q and 5q chromothripsis was found by trio genome sequencing (GS) and confirmed by fluorescent in situ hybridization (FISH). Notable clinical findings include medically refractory seizures, global developmental delay, increased fluid-attenuated inversion recovery (FLAIR) signal in the left inferior temporal gyrus, and dysmorphic features. Chromothripsis of chromosomes 3 and 5 was previously recognized in renal cell carcinomas. To the best of our knowledge, this is the first reported case of chromosomes 3q and 5q chromothripsis leading to a developmental epileptic encephalopathy (DEE) due to disruption of 5q14.3. These findings expand chromosomes 3 and 5 chromothripsis as a genomic mechanism underlying 5q14.3 microdeletion syndrome.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63975"},"PeriodicalIF":1.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063243","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}

{"title":"Functional Analyses of SATB2 Variants Reveal Pathogenicity Mechanisms Linked With SATB2-Associated Syndrome.","authors":"Nao Ukita, Takuya Ogawa, Mamiko Yamada, Chisen Takeuchi, Kenjiro Kosaki, Keiji Moriyama","doi":"10.1002/ajmg.a.64005","DOIUrl":"https://doi.org/10.1002/ajmg.a.64005","url":null,"abstract":"<p><p>SATB2-associated syndrome (SAS) is characterized by intellectual disability, neurodevelopmental disorders, cleft palate, and dental abnormalities. SAS is caused by variants in the special AT-rich sequence-binding protein 2 (SATB2), which encodes a transcription factor containing two CUT domains and a homeobox (HOX) domain. Here, we report the case of a 16-year-old male diagnosed with SAS using exome sequencing and investigate the functional consequences of previously reported SATB2 variants, including those in this case. The patient carried a heterozygous missense variant (c.1147G>C, p.A383P) in SATB2, which was predicted to be pathogenic in silico but was absent from public databases. Immunofluorescence assays demonstrated that SATB2 proteins with variants in the CUT2 domain predominantly localized to the cytoplasm. Functional analysis further revealed that wild-type SATB2 increased the activity of the Msx1 promoter, which is involved in palatogenesis and tooth development, whereas variants in the CUT1 domain disrupted this transcriptional activation. These findings suggest that the nuclear localization signal of SATB2 resides in the CUT2 domain and that Msx1 promoter impairment owing to SATB2 variants may contribute to the pathogenesis of cleft palate and tooth agenesis in SAS. This research highlights a novel pathogenic variant and the functional implications for understanding SAS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64005"},"PeriodicalIF":1.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063247","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}

{"title":"Phenotypic Expansion of Knobloch Syndrome Type 2 in an Individual With a De Novo PAK2 Variant.","authors":"Elizabeth A Werren, Louisa Kalsner, Jessica M Ewald, Michael Peracchio, Cameron King, Purva Vats, Peter A Audano, Peter N Robinson, Mark D Adams, Melissa A Kelly, Adam P Matson","doi":"10.1002/ajmg.a.64006","DOIUrl":"https://doi.org/10.1002/ajmg.a.64006","url":null,"abstract":"<p><p>P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelic PAK2 variants cause Knobloch syndrome type 2 (KNO2)-a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novel de novo heterozygous missense variant in PAK2, NM_002577.4:c.1273G>A, p.(D425N), by genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes observed in this individual were global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging by in silico analysis. Previous clinical genetic testing did not report this variant due to unknown relevance of PAK2 variants at the time of testing, highlighting the importance of reanalysis. Our findings substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical phenotypic spectrum.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64006"},"PeriodicalIF":1.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057770","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}

{"title":"Genetic Services in Appalachia Conference Series.","authors":"Kimberly M Kelly, Trupti Dhumal, Virginia G Scott, Nadia Falah, Rebecca Kronk, Alissa Bovee Terry, Kristi Graves, Justine Pickarski, Margaret Au","doi":"10.1002/ajmg.a.63990","DOIUrl":"https://doi.org/10.1002/ajmg.a.63990","url":null,"abstract":"<p><p>This study examined the data generated as part of a seven-session webinar series that focused on genetics care provision in the medically underserved, rural Appalachian region and examined how these services have adapted to challenging practice environments. Barriers and facilitators to care in our region were considered. Data included a baseline survey of registrants, transcripts of sessions, and feedback about sessions. We analyzed data with a sequential and concurrent mixed methods approach. Registrants (n = 137) were disproportionately healthcare providers with genetic services expertise (37.2%). Approximately half (43.8%) of registrants were from KY, WV, and TN in the central Appalachian region. Our baseline survey found that the most noted barriers were the cost of services, lack of providers, and access to care. The most common facilitator was telehealth. Analysis of transcripts identified barriers that were consistent with those noted in the baseline survey, but additional support and network opportunities were discussed to allow for learning across services. Numerous barriers to service delivery were noted; however, despite challenges, participants identified opportunities and resources in the community. These insights will inform a research agenda aimed at advancing genetics services in rural Appalachia, addressing challenges, and leveraging assets for improved healthcare access and outcomes.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63990"},"PeriodicalIF":1.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045250","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}

{"title":"MYRF Variants in Patients With 46,XY Differences/Disorders of Sex Development and Literature Review.","authors":"Wei Zhang, Xi Wang, Jiangfeng Mao, Yaqing Cao, Xiaoxia Zhang, Min Nie, Xueyan Wu","doi":"10.1002/ajmg.a.64002","DOIUrl":"https://doi.org/10.1002/ajmg.a.64002","url":null,"abstract":"<p><p>46,XY differences/disorders of sex development (DSD) are genetically heterogeneous conditions characterized by atypical development of the reproductive system. MYRF, a gene encoding a transcription factor, has been identified as a potential causative gene for DSD and cardiac urogenital syndrome (CUGS). This study aims to delineate the clinical manifestations of patients with 46,XY DSD and MYRF mutations, encompassing both from our cohort and cases reported in the literature. Patients with 46,XY DSD were recruited from Peking Union Medical College Hospital and identified through a comprehensive review of published literature. Whole-exome sequencing was conducted to elucidate the genetic etiology. Comprehensive clinical data, including physical examination findings, hormonal profiles, and imaging results, were retrospectively gathered from medical records and published sources. Three of our patients with 46,XY DSD were found to harbor heterozygous loss-of-function mutations in the MYRF gene, including the recurrent variant c.789dup and two novel variants c.1915C>T and c.2154del. The patients exhibited underdeveloped testicular tissue, inadequate masculinization, and the persistence of Müllerian ducts. A review of the literature indentified 31 MYRF-linked 46,XY DSD patients and two 46,XX DSD patients. Among these, 11 cases presented with isolated testicular dysgenesis, 20 cases exhibited severe cardiopulmonary issues, and the majority of patients had congenital diaphragmatic hernia. Genetic analysis revealed 26 distinct MYRF variants among these patients, including 10 missense, 8 frameshift, 5 nonsense, and 3 splice site alterations, affecting critical domains of the MYRF gene. Our study broadens the spectrum of MYRF mutations in 46,XY DSD patients and highlighting the gene's indispensable role in gonadal development. However, a clear genotype-phenotype correlation in MYRF-related DSD remain elusive.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64002"},"PeriodicalIF":1.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045273","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}

{"title":"Phenotypical Characterization of Gastroenterological and Metabolic Manifestations in Patients With Williams-Beuren Syndrome.","authors":"Maria Francesca Bedeschi, Annarita Baldassarri, Roberta Villa, Federico Tanzi, Simona Salera, Vincenza Lombardo, Alessandro Draghi, Nicole Piazza O'Sed, Giovanni Casazza, Maurizio Vecchi, Mirella Fraquelli","doi":"10.1002/ajmg.a.63993","DOIUrl":"https://doi.org/10.1002/ajmg.a.63993","url":null,"abstract":"<p><p>Gastrointestinal (GI) symptoms are common in patients with Williams-Beuren syndrome (WBS), but their prevalence and possible causes are not yet fully known. This study assessed GI symptoms' prevalence and their possible origin by performing a predefined set of tests in adult WBS patients. Laboratory tests and a questionnaire were administered to assess GI symptoms and dietary habits. All the patients underwent the urea breath test, H₂-lactose and H₂-glucose breath tests, and intestinal ultrasound (IUS) and vibration-controlled transient elastography for liver stiffness measurement (LSM) and controlled attenuation parameter (CAP, dB/m). Thirty-one patients were enrolled (72% of the whole cohort, 17 males, median age 32 years). Gastroesophageal reflux disease (GERD) symptoms were reported in 29% of the patients, abdominal pain in 26%, and altered bowel habits in 48%. Pathologic signs at (IUS) were present in 60% of the cases. Prevalence was 0.26 (95% CI 0.12-0.44) for Helicobacter pylori infection and 0.61 (95% CI 0.42-0.78) for lactose intolerance. LSM was > 6 kPa (in the range of a fibrosis score > F1) in three patients, and CAP values were > 268 dB/m (corresponding to a steatosis score > S2, e.g., moderate steatosis) in nine. The presence of altered bowel habits was significantly related to chronic abdominal pain (OR 13.1, p = 0.03). Increased BMI (> 28 kg/m²) (OR 10.8, p = 0.04) was associated with the presence of moderate-severe hepatic steatosis. After specific treatment and dietary counseling, most patients reported resolution/improvement of symptoms, whereas a few retained/developed symptoms during follow-up. Chronic abdominal pain, GERD symptoms, and unbalanced metabolic parameters were common in our WBS patients, together with an increased prevalence of lactose intolerance/colonic diverticula. Specific counseling and treatment improved symptoms for most patients.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63993"},"PeriodicalIF":1.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045285","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}

{"title":"Cardiac Involvement and TBCK-Related Neurodevelopmental Disorder: Is It a New Feature of This Condition?","authors":"Gioia Mastromoro, Daniele Guadagnolo, Francesca Gianno, Nader Khaleghi Hashemian, Alessandra Terracciano, Laura Bernardini, Antonella Giancotti, Antonio Novelli, Gerardo Piacentini, Cira Di Gioia, Antonio Pizzuti","doi":"10.1002/ajmg.a.64001","DOIUrl":"https://doi.org/10.1002/ajmg.a.64001","url":null,"abstract":"<p><p>TBCK (TBC1 Domain-Containing Kinase) encodes a protein playing a role in actin organization and cell growth/proliferation via the mTOR signaling pathway. Deleterious biallelic TBCK variants cause Hypotonia, infantile, with psychomotor retardation and characteristic facies 3. We report on three affected sibs, also displaying cardiac malformations. The parents, a consanguineous couple of first cousins, were referred to schedule invasive diagnosis for their sixth pregnancy. They were known to carry the pathogenic c.1532G>A TBCK variant. The variant was originally identified in homozygosity in the first and second children of the couple, both affected. One also presented a right-sided aortic arch. The other had Tetralogy of Fallot. Present pregnancy ultrasound revealed cystic hygroma and hypoplastic nasal bone, not previously reported in this condition. Chromosomal microarray analysis found no imbalance and identified 8.6% runs of homozygosity. Whole exome sequencing confirmed the TBCK variant without additional pathogenic or candidate variants. Fetal echocardiography revealed left ventricle and aortic arch hypoplasia. The couple opted for pregnancy termination. Fetopsy confirmed sonographic findings and revealed a hypoplastic aorta arising from right ventricle and corpus callosum agenesis. Interestingly, the cardiac phenotype segregates with variants and cardiac involvement might be considered a new feature of this variant causing Hypotonia, infantile, with psychomotor retardation and characteristic facies 3.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64001"},"PeriodicalIF":1.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045245","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}

{"title":"A Case Study of a Female Infant With Primary Hypertrophic Osteoarthropathy Demonstrates That Early Initiation of Celecoxib Slows but Does Not Prevent Symptom Progression.","authors":"Kara Zehr, Morgan Buckley, Joshua W Owens, Tomas Vanagunas, Patricia Vega Fernandez, Robert J Hopkin, Amelle Shillington","doi":"10.1002/ajmg.a.64000","DOIUrl":"https://doi.org/10.1002/ajmg.a.64000","url":null,"abstract":"<p><p>Primary Hypertrophic Osteoarthropathy (PHOAR1) is characterized by autosomal recessive loss of function variants in 15-hydroxyprostaglandin dehydrogenase (HPGD) leading to digital clubbing, periostosis, pachydermia, and severe hyperhidrosis. HPGD catalyzes the first step of prostaglandin E2 (PGE2) degradation. Selective COX-2 inhibitors have proved beneficial in adults, though it is unknown if early initiation of COX-2 inhibitors can alter the natural history of PHOAR1. This individual was diagnosed with PHOAR1 at 3.5 months of age due to homozygous HPGD c.218-1G>A variants. At presentation, she had a diffuse erythematous rash secondary to hyperhidrosis, mild symmetric clubbing of her fingertips, and mildly decreased mobility of her knees and wrists. By 20 months of age, she had more significant clubbing, mild flexion contractures, joint pain, and fatigue. She started celecoxib at 26 months of age. ResultsAfter 7 months of celecoxib, she had stable digital clubbing, improved hyperhidrosis and contractures, and resolution of her joint pain and fatigue. COX-2 inhibition appears to be a safe and effective intervention in young children with PHOAR1. More investigation is needed to assess safety and long-term impact on the natural history of PHOAR1 after COX-2 inhibition is initiated in early childhood.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64000"},"PeriodicalIF":1.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998675","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}

{"title":"Diverse Clinical Presentation of RAC1-Related Intellectual Developmental Disorder.","authors":"Jariya Upadia, Jiao Liu, Caide Bier, Madeline Chenevert, Yuwen Li","doi":"10.1002/ajmg.a.63991","DOIUrl":"https://doi.org/10.1002/ajmg.a.63991","url":null,"abstract":"<p><p>RAC1 encodes the protein RAS-related C3 Botulinum Toxin Substrate 1 (RAC1), which plays a pivotal role in various cellular functions. Pathogenic variants in RAC1 are linked to the rare intellectual developmental disorder, autosomal-dominant 48 (MRD48). We present one case with typical phenotype and two cases with a mild phenotype. This report expands the phenotypic spectrum of MRD48.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63991"},"PeriodicalIF":1.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998044","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}

{"title":"Adult-Onset Hypomagnesemia With Secondary Hypocalcemia Caused by a Novel Variant in TRPM6 Gene: A Case Report.","authors":"Yan Chen, Jian Liang, Yuhua Hu, Yunyun Hong, Qiang Liu","doi":"10.1002/ajmg.a.63982","DOIUrl":"https://doi.org/10.1002/ajmg.a.63982","url":null,"abstract":"<p><p>Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder caused by biallelic variants in the transient receptor potential melastatin 6 (TRPM6) gene, typically presenting in infancy. Currently, there is a lack of reports in the literature on adult-onset cases. This case report describes a 51-year-old male with adult-onset HSH, presenting with limb weakness, muscle spasms, and electrolyte imbalances, including severe hypomagnesemia (0.28 mmol/L). Genetic testing revealed a novel heterozygous variant in the TRPM6 gene (c.4914del, p.E1638Dfs*8), classified as likely pathogenic. The patient's symptoms significantly improved following magnesium supplementation, and his electrolyte levels gradually normalized. This case highlights the importance of considering HSH in patients with unexplained hypomagnesemia and emphasizes the role of genetic testing in confirming the diagnosis. The findings also suggest that magnesium supplementation can effectively alleviate symptoms and improve the quality of life in patients with adult-onset HSH. Early recognition and treatment are crucial to prevent potential complications, such as neurological damage.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63982"},"PeriodicalIF":1.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997706","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}