American Journal of Medical Genetics Part A最新文献

{"title":"SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype.","authors":"Saima Kayani, Victor Daescu, Hamza Dahshi, Souad Messahel, Kasey Woleban, Berge A Minassian, Qinglan Ling, Steven J Gray","doi":"10.1002/ajmg.a.63947","DOIUrl":"https://doi.org/10.1002/ajmg.a.63947","url":null,"abstract":"<p><p>Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi-allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age-matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% (p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi-allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes (p = 0.008) and more MRI abnormalities (p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63947"},"PeriodicalIF":1.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779136","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":"Exploring the Clinical Spectrum of HUWE1-Related Neurodevelopmental Disorder: Five New Patients and Literature Review.","authors":"Alessandro De Falco, Elia Marco Paolo Minale, Camilla Meossi, Stefano Pagano, Rosanna Trovato, Emanuele Agolini, Mafalda Mucciolo, Antonio Novelli, Emanuele Bartolini, Filippo Maria Santorelli, Carmelo Piscopo","doi":"10.1002/ajmg.a.63959","DOIUrl":"https://doi.org/10.1002/ajmg.a.63959","url":null,"abstract":"<p><p>Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder associated with variants in the HUWE1 gene on chromosome Xp11. The condition is characterized by variable phenotypes, including global developmental delay, intellectual disability, and distinctive facial dysmorphisms, with inheritance patterns ranging from X-linked recessive to de novo mutations in females. Here, we describe five probands in two families, highlighting their clinical features and genetic findings. Trio whole-exome sequencing identified a de novo variant in HUWE1 in the proband in one family and a maternally inherited hemizygous variant in three boys in a second family. A comprehensive review of HUWE1-associated cases from the literature assisted genotype-phenotype correlations, revealing consistent features such as intellectual disability, skeletal anomalies, and facial dysmorphisms as well as instances of intrafamilial variability. Our findings confirm the phenotypic variability of MRXST and underscore the significance of the HUWE1 gene product in neurodevelopment. We propose a baseline monitoring protocol to aid in diagnosis and management, contributing to the development of specific guidelines for patient follow-up.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63959"},"PeriodicalIF":1.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765267","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":"Immune Dysregulation in a Child With SOD1-Related Neurological Disease.","authors":"Rozlyn Claire Thomas Boutin, Farzaneh Shobeirian, Shelin Adam, Anna Lehman, Ramona Salvarinova, Jan M Friedman","doi":"10.1002/ajmg.a.63949","DOIUrl":"https://doi.org/10.1002/ajmg.a.63949","url":null,"abstract":"<p><p>Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63949"},"PeriodicalIF":1.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765291","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":"Telehealth Is Effective in the Evaluation of Individuals With Undiagnosed Rare Disorders: An Undiagnosed Diseases Network Study.","authors":"Queenie K-G Tan, Allyn McConkie-Rosell, Rachel Mahoney, Rebecca C Spillmann, Kelly Schoch, Sirisak Chanprasert, Maria T Acosta, Camilo Toro, Jill A Rosenfeld, James P Orengo, Daryl A Scott, Jorge L Granadillo, Kathleen Sisco, Daniel J Wegner, Mustafa Tekin, Stephanie Bivona, LéShon Peart, Lance Rodan, Devon Bonner, Matthew T Wheeler, Jonathan A Bernstein, Maura Ruzhnikov, David R Adams, Fuki M Hisama, Vandana Shashi","doi":"10.1002/ajmg.a.63956","DOIUrl":"10.1002/ajmg.a.63956","url":null,"abstract":"<p><p>Patients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassisted virtual physical examination (PE) with an in-person PE in undiagnosed individuals and also assessed participant telehealth satisfaction. Twenty-six individuals enrolled in the Undiagnosed Diseases Network study underwent an in-home synchronous virtual PE, and a subsequent in-person PE, by the same clinician. The participants completed surveys on telehealth usability and provider empathy. On PE, general appearance and craniofacial features showed near perfect agreement (κ = 0.81-1.00) between the telehealth and in-person evaluations. Specific components of the neurological examination demonstrated substantial agreement (speech, gait, coordination; κ > 0.61), whereas others had moderate agreement (muscle tone, strength; κ = 0.41-0.60), and a few had none to slight agreement (skin; κ < 0.20). Some systems could not be examined in the virtual PE. Importantly, features relevant to diagnosis or management were missed on the virtual PE in only 2/26 individuals. The participants were satisfied with the quality of the telehealth interaction, as well as empathy demonstrated by providers in the virtual interface. Telehealth is effective for PEs in undiagnosed diseases and is acceptable to affected individuals.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63956"},"PeriodicalIF":1.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765311","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":"Alu-Mediated Deletion of FANCA in Turkish Families With Fanconi Anemia: Evidence of a Founder Effect.","authors":"Ceren Damla Durmaz, Fatma Gümrük, Tiraje Celkan, Sule Unal, Arda Çetinkaya","doi":"10.1002/ajmg.a.63945","DOIUrl":"https://doi.org/10.1002/ajmg.a.63945","url":null,"abstract":"<p><p>Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome characterized by pancytopenia, increased susceptibility to malignancies, and a spectrum of congenital anomalies. Here, we report on eight affected individuals from six unrelated families with a large Alu-mediated intragenic deletion encompassing exons 6-31 in the FANCA gene, identified as a founder mutation in the Turkish population through haplotype analysis. This deletion, mediated by Alu repeat sequences, underscores the role of repetitive elements in FA pathogenesis. Clinical data revealed variable phenotypic presentations among affected individuals, highlighting the challenge of establishing genotype-phenotype correlations even in the presence of identical FANCA pathogenic variants. We carried out an easy and effective PCR-based diagnostic test for detecting this mutation, enabling precise diagnosis and genetic counseling for affected individuals and their families. This study provides valuable insights into the molecular mechanisms underlying FA pathogenesis and offers a practical approach for genetic diagnosis in affected individuals, particularly those of Turkish descent.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63945"},"PeriodicalIF":1.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764984","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":"Constitutional Mosaic Pericentromeric Trisomy 8 in a Female Patient With Aplastic Anemia.","authors":"Min Gao, Yunjia Chen, Pongtawat Lertwilaiwittaya, Anna C E Hurst, Ali Al-Beshri, Andrew J Carroll, Fady M Mikhail","doi":"10.1002/ajmg.a.63951","DOIUrl":"https://doi.org/10.1002/ajmg.a.63951","url":null,"abstract":"<p><p>Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.21q11.21 correlates with hematologic disorders. We report a 19-year-old female with constitutional mosaic pericentromeric trisomy 8 presenting with menorrhagia, vitamin B12 deficiency, familial short stature, pancytopenia, and bone marrow aplasia. G-banded chromosome and FISH analyses of her bone marrow and blood samples revealed constitutional mosaic pericentromeric trisomy 8. Chromosomal microarray analysis confirmed mosaic duplications in the 8p12q11.21 region spanning 51 OMIM genes, with 16 identified as OMIM morbid genes, and including 9 genes with autosomal dominant inheritance patterns. FGFR1, ASH2L, ANK1, KAT6A, IKBKB, PLAT, and CEBPD are implicated in hematologic disorders, with FGFR1, ASH2L, KAT6A, and IKBKB showing notable triplosensitivity scores. These regions overlap with 13 published cases (12 papers), of which three displayed hematologic disorders, including neutropenia and juvenile myelomonocytic leukemia. Our case underscores the 8p12q11.21 region as a potential causal region for aplastic anemia, emphasizing the need for further investigation of this patient for possible progression to hematologic malignancy.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63951"},"PeriodicalIF":1.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764989","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":"From Desbuquois Dysplasia to Multiple Epiphyseal Dysplasia: The Clinical Impact of a CANT1 Variant Across Five Unrelated Families.","authors":"Tuğba Daşar, Gizem Ürel Demir, Gözde İmren, Gülen Eda Utine, Güney Yilmaz, Pelin Özlem Şimşek Kiper","doi":"10.1002/ajmg.a.63950","DOIUrl":"https://doi.org/10.1002/ajmg.a.63950","url":null,"abstract":"<p><p>Multiple epiphyseal dysplasia (MED) is a heterogeneous group of chondrodysplasia characterized by arthralgia, early onset osteoarthropathy, and the radiographic findings of small, flat, and irregular-shaped epiphyses. Some patients with MED have mild short stature as well. MED is genetically heterogeneous caused by pathogenic variants in COMP, MATN3, COL9A1, COL9A2, COL9A3, and SLC26A2. In 2017, pathogenic variants in CANT1, which are responsible for Desbuquois dysplasia, have also been reported in the genetic etiology of MED. To date, only three patients have been reported with CANT1-related MED. Herein, we present clinical and radiographic findings of six additional patients from five unrelated families, all sharing the same c.375G > C; p.(Trp125Cys) variant in CANT1 gene. These patients exhibited the features of multiple epiphyseal dysplasia, along with some similarities to Desbuquois dysplasia, thereby broadening the clinical spectrum of CANT1-related disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63950"},"PeriodicalIF":1.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765286","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":"Dr. Peter Emil Becker and the Third Reich: Correspondence.","authors":"Tilman Becker","doi":"10.1002/ajmg.a.63955","DOIUrl":"https://doi.org/10.1002/ajmg.a.63955","url":null,"abstract":"<p><p>Peter Emil Becker was a German neurologist who is remembered for his studies of muscular dystrophies. Becker muscular dystrophy and Becker myotonia are named after him. His biography appeared in the American Journal of Medical Genetics in 1985. Later, an article by Frank Hill in the same journal was focusing on the role of Becker in the Third Reich. The article by Hill makes conjectures about the involvement of Becker in the T4 Euthanasia Program based on an incorrect interpretation of literature references and by artificially constructing connections of Becker to this program. This needs to be corrected. The \"Nazi Past\" of Becker was investigated very thoroughly in an article in the Journal of Child Neurology. Peter Emil Becker had no leading positions in Nazi organizations nor was he involved in Nazi crimes. He did not praise the leader state, like other researchers in his field did. A thorough inspection of his work shows that he was avoiding national socialistic topics such as racial biology and eugenics. But to further his academic career, however, he became a member of Nazi organizations.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63955"},"PeriodicalIF":1.7,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754512","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":"Implementing a Quality Improvement Initiative to Screen for Dementia in a Down Syndrome Specialty Clinic.","authors":"Stephanie L Santoro, Ayesha Harisinghani, Caroline Bregman, Clorinda Cottrell, Margaret B Pulsifer, Mikayla Shaffer, Amy Torres, Brian G Skotko, Nicolas M Oreskovic","doi":"10.1002/ajmg.a.63948","DOIUrl":"https://doi.org/10.1002/ajmg.a.63948","url":null,"abstract":"<p><p>Using quality improvement methods, we aimed to implement a protocol to assess for dementia among adults with Down syndrome (DS). To track implementation, interval retrospective chart review of patients with DS with visits to the Massachusetts General Hospital DS Program (MGH DSP) was conducted quarterly. The impact of a newly implemented protocol created and informed by clinical experts in the MGH DSP including laboratory tests, imaging, referrals, and screening tools for dementia and mental health concerns, was analyzed using statistical process control charts. From December 2021 to December 2022, the MGH DSP developed and implemented a new clinical protocol to screen for dementia in 44 adults with DS, ages 40 and above, at a total of 48 visits. We found high rates of completion of two screening surveys (85% and 81%, respectively) and an 84% adherence to our overall protocol elements by clinical staff. Among those with dementia-like symptoms, medical evaluation was collected and summarized. We show that it is possible to successfully implement a new protocol, including the use of a dementia screener, in line with published evidence-based care guidelines for adults with DS. We present our protocol as one successful approach focused on pre-visit screening for symptoms of dementia and mental health concerns and evaluating for co-occurring medical conditions in adults with DS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63948"},"PeriodicalIF":1.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738099","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":"Health Care Transition Programs for Adolescents and Young Adults With Hereditary Cancer Predisposition: A Scoping Review.","authors":"Jazmine Gabriel, Tierney Lyons, Victoria Schlieder, Sarah Zultevicz, Bryel Frasch, Thomas W Davis, Adam H Buchanan, Gemme Campbell-Salome","doi":"10.1002/ajmg.a.63931","DOIUrl":"https://doi.org/10.1002/ajmg.a.63931","url":null,"abstract":"<p><p>Adolescents and young adults (AYA) with increased risk for cancer due to hereditary predisposition, previous cancer treatment, or both are eligible for increased surveillance, chemoprevention, and prophylactic surgery that can improve early detection and prevention of cancers. One way to ensure continuity of cancer prevention care is to support adolescents through the transition from pediatric to adult health care. Yet, there are limited data on the impl ementation of health care transition (HCT) programs for AYA with increased risk for cancer. We conducted a scoping review of the literature on transition programs for AYA at increased risk of cancer due to known germline risk or prior cancer diagnosis, with a focus on implementation factors relevant to designing, implementing, and sustaining a new program. Data from 54 articles were extracted and analyzed using the RE-AIM implementation science framework. Few HCT programs have been implemented for AYA with hereditary cancer syndromes. Several groups have done preimplementation work for future hereditary cancer programs, but programs for cancer survivors are farther along the translational spectrum. We identified implementation factors along the five RE-AIM dimensions to assist preimplementation planning for HCT programs for AYA with increased risk for cancer.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63931"},"PeriodicalIF":1.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714857","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}