American Journal of Medical Genetics Part A最新文献

{"title":"A Homozygous Nonsense Variant in the BICC1 Gene Associated With Fetal Cystic Kidney Disease and Lower Limb Post-Axial Polydactyly.","authors":"Vasundhara Parag Tamhankar, Malathy Prasad, Shalin Vaniawala, Sandhya Nair, Shilpa Mithbawkar, Parag M Tamhankar","doi":"10.1002/ajmg.a.63958","DOIUrl":"https://doi.org/10.1002/ajmg.a.63958","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63958"},"PeriodicalIF":1.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799040","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":"Does It Run in Your Family? Inherited Truncating PSMD12 Variants Broaden the Phenotypic Spectrum of Stankiewicz-Isidor Syndrome.","authors":"Agnese Feresin, Beatrice Spedicati, Stefania Zampieri, Anna Morgan, Andrea Magnolato, Alessandra Tesser, Alberto Tommasini, Maria Teresa Bonati, Giorgia Girotto, Flavio Faletra","doi":"10.1002/ajmg.a.63953","DOIUrl":"https://doi.org/10.1002/ajmg.a.63953","url":null,"abstract":"<p><p>Alteration in the ubiquitin-proteasome system results in human disorders with neurological and/or autoinflammatory presentation. Haploinsufficiency of PSMD12, which encodes a subunit of the core component of the proteasome, causes Stankiewicz-Isidor syndrome (STISS), characterized by intellectual disability, autism spectrum disorder, craniofacial dysmorphisms, with or without other congenital anomalies, and autoinflammation. We described six patients (four adults) from two unrelated families carrying a known p.(Arg289*) or a novel p.(Tyr111*) PSMD12 variant. Portraying a completely penetrant condition with inter- and intra-familiar clinical variability, all individuals presented with developmental delay, intellectual disability, craniofacial, and skeletal anomalies. Novel findings in our cohort included unilateral ectopic fingernail, cholesteatoma, oligodontia, and the occurrence of an ovarian teratoma. Most subjects had acne, short stature, and developed obesity since late childhood. Eating behavior was reported. Good sociality and behavioral concern emerged as well. None presented clinical manifestations of autoinflammation and the detected IFN-I signature perturbations were not specific. Together with a complete literature review, we expanded the clinical spectrum of STISS, highlighting the relevance of inherited variants, and discussing challenges in diagnosis and management. We finally consider the intriguing role of PSMD12 in human development and propose to index \"onychoheterotopia\" among the Human Phenotype Ontology terms.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63953"},"PeriodicalIF":1.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783813","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":"Vitamin B5 Monotherapy Improves Symptoms in a 7-Year-Old Girl With TANGO2 Deficiency Disorder.","authors":"Hua Li, Zheng Xu, Jing Guo, Peiqi Zhang, Xiaoli Dong, Liming Zhao","doi":"10.1002/ajmg.a.63938","DOIUrl":"https://doi.org/10.1002/ajmg.a.63938","url":null,"abstract":"<p><p>TANGO2 deficiency disorder is often underdiagnosed and lacks an optimal treatment strategy. A 7-year-old Chinese girl presented with epilepsy, developmental delay, neuroregression, and episodes of dyskinesia. Additionally, she lapsed into a comatose state following her the last generalized tonic-clonic seizure. Trio whole-exome sequencing revealed compound heterozygous variants of the TANGO2 gene. Eventually, her clinical signs and symptoms significantly improved following treatment with vitamin B5. TANGO2 deficiency disorder is a severe neurodegenerative condition that can be diagnosed via trio whole-exome sequencing. This report highlights the potential therapeutic effects of vitamin B5 against this disease and suggests that high-dose vitamin B5 administration may be safe for the treatment of TANGO2 deficiency disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63938"},"PeriodicalIF":1.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783817","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":"The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.","authors":"C Angwin, P Byers, E Dulfer, N Ghali, Juliette Harris, I Hausser, Abigail McElroy, G Sobey, F S van Dijk","doi":"10.1002/ajmg.a.63957","DOIUrl":"https://doi.org/10.1002/ajmg.a.63957","url":null,"abstract":"<p><p>Dermatosparaxis Ehlers Danlos syndrome (dEDS) is a very rare monogenic EDS that occurs due to biallelic pathogenic variants in ADAMTS2. Fifteen individuals with dEDS have been reported in the literature, with the oldest being 19 years at follow-up. Given the lack of information regarding adults with dEDS, our aim was to describe adults with dEDS to inform management recommendations in adulthood. We report five individuals (2:3 male:female) with an age range of 22-42 years. Complications include extreme skin fragility resulting in iatrogenic injury, redundant skin folds often requiring surgical resection, severe complications following a gastric volvulus secondary to a diaphragmatic hernia, and multiple fractures. Discussion of management considerations includes thorough investigations of acute pain, careful consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone mineral density after low-impact fracture and/or post-menopause.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63957"},"PeriodicalIF":1.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783815","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":"CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant.","authors":"Eszter Sara Arany, David Zocche, Jemima E Mellerio, Muriel Holder-Espinasse, Jan Cobben","doi":"10.1002/ajmg.a.63962","DOIUrl":"https://doi.org/10.1002/ajmg.a.63962","url":null,"abstract":"<p><p>CHIME syndrome is a variable condition characterized by ichthyosiform dermatosis, accompanied by intellectual disability, ocular colobomas, ear anomalies, and heart defects. It is an autosomal recessive condition caused by biallelic pathogenic variants in the PIGL gene. Until now, all reports of individuals affected with CHIME syndrome showed the PIGL c.500T>C p.Leu167Pro DNA variant on one allele of the PIGL gene, in combination with another PIGL DNA variant on the other allele. This has led to the hypothesis that the p.Leu167Pro variant determines to a mild phenotypic effect only and that the core phenotype is determined by the second PIGL DNA variant. We report the first individual with CHIME syndrome, a 6-year-old girl, with homozygous PIGL p.Leu167Pro variants, defusing this hypothesis as she is not mildly affected. As CHIME is a very rare condition, it is expected that a significant proportion of cases will be due to homozygous gene variants, especially of founder DNA variants, and offspring of consanguineous parents. We speculate that the lack of homozygous p.Leu167Pro DNA variants so far has been due to chance and that other homozygous cases will be identified in future reports of affected individuals.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63962"},"PeriodicalIF":1.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783811","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":"Subacute Neuropathy Post-Liver Transplantation in Zellweger Spectrum Disorder: A Case Report.","authors":"Clarissa Gonzalez, Madelyn J Cohen, Juhee Hong, Daniel Calame, Kavitha Marri, Sanjiv Harpavat, Michael F Wangler, Krupa Mysore","doi":"10.1002/ajmg.a.63941","DOIUrl":"10.1002/ajmg.a.63941","url":null,"abstract":"<p><p>Peroxisome biogenesis disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare genetic disease caused by mutations in the genes involved in peroxisome biogenesis. PBD-ZSD presentations vary in severity, and treatment of PBD-ZSD remains supportive focused on specific complications. A few reported cases of the use of liver transplantation to treat either neurological symptoms or liver dysfunction and cirrhosis in PBD-ZSD have been published. In this case report, we document the course of a 16-year-old boy diagnosed with PBD-ZSD and a delayed and unexpected neuropathy that developed after undergoing orthotopic liver transplantation (OLT) for which the indication was liver cirrhosis. Following OLT, the patient's gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine transaminase (ALT), and albumin normalized; however, he developed a polyneuropathy, the cause of which was investigated with conditions such as inflammatory neuropathies (Guillain Barré syndrome: GBS/chronic inflammatory demyelinating polyneuropathy: CIDP), drug effect, or underlying complication of PBD-ZSD all considered possible. His neuropathic symptoms improved and therefore this case represents an exploration of an apparent delayed and resolving subacute neuropathy in PBD-ZSD after OLT.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63941"},"PeriodicalIF":1.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779127","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":"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":"https://doi.org/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}