American Journal of Medical Genetics Part A最新文献

{"title":"Advancing Equity in Rare Disease Research: Insights From the Undiagnosed Disease Network.","authors":"Nicholas A Borja, Rory J Tinker, Stephanie A Bivona, Carson A Smith, Theodore Krijnse Locker, Samuela Fernandes, John A Phillips, Justin Stoler, Herman Taylor, Stephan Zuchner, Mustafa Tekin","doi":"10.1002/ajmg.a.63904","DOIUrl":"10.1002/ajmg.a.63904","url":null,"abstract":"<p><p>Rare diseases affect 6%-8% of the population and present diagnostic challenges, particularly for historically marginalized ethnic and racial groups. The Undiagnosed Diseases Network (UDN) aims to enhance diagnosis rates and research participation among such minoritized groups. A retrospective review was conducted from 2015 to 2023, analyzing 2235 UDN participants to evaluate its progress toward this objective. Data on demographics, disease phenotypes, diagnostic outcomes, and socioeconomic factors were collected and statistical analyses assessed differences among ethnic and racial groups. This demonstrated that Hispanic and Black non-Hispanic groups were underrepresented, while White non-Hispanic participants were overrepresented in the UDN compared to the US population. Individuals whose primary language was not English were also significantly underrepresented. Diagnosis rates varied, with the highest rates among Asian non-Hispanic (39.5%) and Hispanic (35.3%) groups and the lowest rate in the White non-Hispanic group (26.8%) (p < 0.001). Binomial logistic regression found, however, that only participant age and disease phenotype predicted the likelihood of receiving a diagnosis (p < 0.001). Persistent ethnic and racial disparities in UDN participation appear to be associated with major differences in application rates. Under-enrollment of historically marginalized ethnic and racial groups may be due to economic hardships and language barriers. No differences in the diagnostic yield among ethnic and racial groups were observed after controlling for other factors. This work highlights the value of comprehensive genetic evaluations for addressing healthcare disparities and suggests priorities for advancing inclusion in rare disease research.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63904"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associated Anomalies in Radial Ray Deficiency.","authors":"Claude Stoll, Yves Alembik, Marie-Paule Roth","doi":"10.1002/ajmg.a.63874","DOIUrl":"10.1002/ajmg.a.63874","url":null,"abstract":"<p><p>Radial ray deficiency (RRD) may be isolated, without other congenital anomalies or co-occurring with other, non-RRD, congenital anomalies. The prevalence and the types of co-occurring anomalies are variable in the reported studies. The aim of this study was to obtain the prevalence and the types of co-occurring congenital anomalies among cases with RRD in a geographically well-characterized population of 387,067 consecutive births in northeastern France from 1979 to 2007 including live births, stillbirths and terminations of pregnancy. During the study period 83 cases with RRD were ascertained (prevalence of 2.14 per 10,000 births), 63 cases (75.9%) had co-occurring anomalies. Cases with co-occurring anomalies were divided into chromosomal anomalies (18 cases, 22%), syndromic conditions (syndromes and associations, 23 cases, 28%), and multiple congenital anomalies (MCA) (22 cases, 26%). Trisomies 18 and autosomal deletions were the most common chromosomal abnormalities. Thrombocytopenia absent radii syndrome, VACTERL association, Fanconi anemia, Roberts syndrome, and Holt-Oram syndrome were the most common syndromic conditions. Anomalies in the musculoskeletal, the cardiovascular, the urinary, and the orofacial system were the most common co-occurring anomalies in cases with MCA. As cases with RRD have often co-occurring congenital anomalies, a multidisciplinary checkup of these cases is recommended.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63874"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306949","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":"Periodic Paralysis in a Child With Thermosensitive Mitochondrial Trifunctional Protein Deficiency.","authors":"Fatema Al-Amrani, Jos P N Ruiter, Mirjam Doolaard, Alok Kumar, Sacha Ferdinandusse, Khalid Al-Thihli","doi":"10.1002/ajmg.a.63900","DOIUrl":"10.1002/ajmg.a.63900","url":null,"abstract":"<p><p>Mitochondrial trifunctional protein (MTP) deficiency is a fatty acid oxidation disorder associated with a spectrum of phenotypes. Patients with high residual enzyme activity tend to have milder phenotypes, and recently, fever-induced episodic myopathy was reported in association with a thermosensitive form of MTP deficiency. We report a 10-year-old male with recurrent episodes of acute flaccid paralysis involving upper and lower extremities in association with bulbar muscle weakness in the context of febrile illness, a phenotype reminiscent of recurrent periodic paralysis. The episodes started at the age of 3 years and have always been followed by full recovery within 1-2 weeks with no residual weakness. Whole exome sequencing revealed a homozygous c.2132C > T, p.(Pro711Leu) variant in HADHA. The variant leads to mildly reduced long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain ketoacyl-CoA thiolase (LCKAT) enzyme activities and reduced MTP protein expression in patient's fibroblasts when cultured at 37°C. Enzyme activities and MTP protein expression diminished when fibroblasts were cultured at 40°C. This is the first published report of confirmed recurrent periodic paralysis as a manifestation of a thermosensitive form of MTP deficiency, and it calls for this condition to be considered when evaluating patients with recurrent periodic paralysis given therapeutic implications.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63900"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363961","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 Distinctive Type of Mosaic Variegated Aneuploidy: Case Report and Review of the Literature.","authors":"Annalisa Frattini, Giovanni Micheloni, Antonio Musio, Marika Bini Antunes, José Barbot, Emília Costa, Patricia Seabra, Rossana Righi, Francesco Orsini, Giuseppe Montalbano, Francesco Acquati, Giovanni Porta, Francesco Pasquali, Roberto Valli","doi":"10.1002/ajmg.a.63901","DOIUrl":"10.1002/ajmg.a.63901","url":null,"abstract":"<p><p>Mosaic variegated aneuploidy (MVA) is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies, and most patients present with intrauterine growth delay, microcephaly, and a broad spectrum of congenital abnormalities. We report a patient with a distinctive type of MVA discovered in bone marrow (BM) when she was 3-month-old due to neutropenia and hypocellular bone marrow. She was followed up for more than 20 years, and different trisomic cells were repeatedly discovered in different tissues, whereas her clinical picture has never been severe. The main sign remained intermittent neutropenia, not cyclic and often not too severe, occasionally with anemia and thrombocytopenia. Retromicrognathia was the only dysmorphic sign. Unlike other patients with MVA, the trisomies in all tissues involved almost invariably chromosomes 18 and 19. Therefore, the peculiarities of our patient were the clinical and the atypical cytogenetic pictures. Nevertheless, we looked for mutations in the seven causative genes of the known types of MVA, but the results were negative. Then, we analyzed the entire exome to find out other possible causing mutations, but also this attempt failed to discover a possible cause of this distinctive form of MVA.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63901"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399111","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":"An Unusual Presentation of Leber Hereditary Optic Neuropathy-Plus Case Caused by a Novel DNAJC30 Variant.","authors":"Hüseyin Bahadır Şenol, Didem Soydemir, Ayşe İpek Polat, Adem Aydın, Ayşe Semra Hız, Uluç Yiş","doi":"10.1002/ajmg.a.63902","DOIUrl":"10.1002/ajmg.a.63902","url":null,"abstract":"<p><p>Leber hereditary optic neuropathy (LHON) is characterized by vision loss due to the degeneration of retinal ganglion cells. LHON-Plus refers to LHON with additional extraocular findings. Neurological conditions observed in LHON-Plus include seizures, encephalopathy, movement disorders, neuropathy, and myopathy. Herein, we present a case with atypical LHON-Plus caused by a novel DNAJC30 disease-causing gene variant. A 15-year-old boy presented with acute headache, and blurred and decreased vision in both eyes. Although initial evaluation pointed toward idiopathic intracranial hypertension, the subsequent diagnostic process revealed unusual features like area postrema syndrome and T2 hyperintensity in brain magnetic resonance imaging. Consequently, antibody-negative neuromyelitis optica spectrum disorder (NMOSD) was diagnosed and treatment was commenced. Recurrent episodes of elevated intracranial pressure necessitated the insertion of a ventriculoperitoneal shunt. Exome sequencing (ES) revealed a novel homozygous variant in the DNAJC30 gene 2 years after symptom onset. Atypical LHON presentations due to nuclear gene mutations may mimic other neuroinflammatory conditions like NMOSD, necessitating thorough clinical evaluation and genetic testing. ES plays a crucial role in diagnosing complex neurological cases, enabling the identification of novel genetic variants associated with LHON and related disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63902"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455910","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":"SF3B2 Haploinsufficiency Associated With Hirschprung Disease and Complex Cardiac Defect Without Craniofacial Microsomia.","authors":"Florencia Del Viso, Dihong Zhou, Susan Starling, Emily Fleming, Carol Saunders","doi":"10.1002/ajmg.a.63886","DOIUrl":"10.1002/ajmg.a.63886","url":null,"abstract":"<p><p>Haploinsufficiency of SF3B2 is associated with craniofacial microsomia, characterized by mandibular hypoplasia and microtia, often with preauricular tags or pits, epibulbar dermoids, and cleft palate. In addition, extracraniofacial anomalies may be present, such as skeletal, cardiac renal, and abnormalities of the central nervous system. Variants have been either de novo or inherited, and both inter- and intrafamilial variability has been observed. Here we describe a patient referred for exome sequencing for a complex congenital heart defect and Hirschsprung disease found by exome sequencing to be heterozygous for a loss of function variant, c.945dup (p.Val316SerfsTer5), in SF3B2. This variant was inherited from a parent with an isolated cardiac defect. Interestingly, neither have the defining craniofacial features or other dysmorphisms. This report further illustrates the degree of phenotypic variability seen in SF3B2-related disease and expands the spectrum to include Hirschsprung disease.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63886"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278985","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":"Examining Roles, Challenges, and Opportunities Within the Metabolic Genetics Workforce.","authors":"Kara Simpson, Stephanie Offord, Chanel Suares, Jerry Vockley","doi":"10.1002/ajmg.a.63889","DOIUrl":"10.1002/ajmg.a.63889","url":null,"abstract":"<p><p>The metabolic genetics clinic is a crucial hub for the management of patients with inborn errors of metabolism and other complex genetic conditions. Because more patients are being identified due to the expanded diagnostics, including newborn screening, and living longer with the advent of improved therapies, the multidisciplinary metabolic genetics team has been challenged in growing proportionally to meet patients' needs. Insufficient rates of recruitment to the field and increased levels of attrition have led to concerns about a rising shortage of metabolic genetics health care providers and necessitate creative solutions to grow the workforce. Here, we describe the roles and responsibilities of the multidisciplinary metabolic genetics team and describe opportunities to support patient care and promote clinician work-life balance in a rapidly changing field.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63889"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339238","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":"Hospital Visits Associated With Oral Infections in Patients With Neurofibromatosis Type 1: A Register-Based Analysis.","authors":"Vivian Reinhold, Roope A Kallionpää, Mikko Valtanen, Kari Auranen, Stina Syrjänen, Sirkku Peltonen, Juha Peltonen","doi":"10.1002/ajmg.a.63887","DOIUrl":"10.1002/ajmg.a.63887","url":null,"abstract":"<p><p>Various forms of oral involvement have been reported in patients with neurofibromatosis 1 (NF1). Here, we analyze register-based associations between NF1 and hospital visits related to oral infections. The Finnish NF1 cohort encompasses all individuals with verified NF1 who have visited the Finnish central and university hospitals in 1987-2011. The Finnish Care Register for Health Care allowed the follow-up of 1349 individuals with NF1, their 1894 siblings without NF1, and 13,870 matched controls for diagnoses related to oral infections in 1998-2014. We observed clearly increased hazards for hospital visits associated with dental caries (ICD-10 K02; NF1 vs. controls, hazard ratio [HR] 4.42, 95% CI 3.23-6.04), diseases of pulp and periapical tissues (K04; HR 3.85, 95% CI 2.68-5.54), and gingivitis and periodontal diseases (K05; HR 3.63, 95% CI 2.37-5.56). In contrast, hospital visits related to diseases of salivary glands (K11), and stomatitis and related lesions (K12) did not show significantly increased hazard in NF1 compared with the controls or the non-NF1 siblings. In conclusion, the findings suggest that hospital visits related to oral infections are relatively common among individuals with NF1. The results highlight the need for early detection, proactive prevention, and timely treatment of oral infections in individuals with NF1.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63887"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306950","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":"Assessment of Adaptive Functioning and the Impact of Seizures in KBG Syndrome.","authors":"Kathleen P Sarino, Lily Guo, Edward Yi, Jiyeon Park, Ola Kierzkowska, Drake Carter, Elaine Marchi, Gholson J Lyon","doi":"10.1002/ajmg.a.63896","DOIUrl":"10.1002/ajmg.a.63896","url":null,"abstract":"<p><p>This study aimed to examine the adaptive functioning status and the impact of epileptic seizures on neurocognitive outcomes in KBG syndrome, a rare genetic neurodevelopmental disorder characterized by pathogenic variants in ANKRD11. A single clinician interviewed individuals and families with genetically confirmed cases of KBG syndrome. Trained professionals also conducted assessments using the Vineland-3 Adaptive Behavior Scales. The assessment covered the domains of communication, daily living skills, socialization, and maladaptive behaviors, and then compared individuals with and without epilepsy. Further comparisons were made with data from interviews and participants' medical records. Thirty-nine individuals (22 males, 17 females) with KBG syndrome, confirmed through genetic analysis, were interviewed via videoconferencing, followed by Vineland-3 assessment by trained raters. Individuals with KBG syndrome came from 36 unique families spanning 11 countries. While the KBG cohort displayed lower overall adaptive behavior composite scores compared with the average population, several members displayed standard scores at or higher than average, as well as higher scores compared with those with the neurodevelopmental disorder Ogden syndrome. Within the KBG cohort, males consistently scored lower than females across all domains, but none of these categories reached statistical significance. While the group with epilepsy exhibited overall lower scores than the nonseizure group in every category, statistical significance was only reached in the written communication subdomain. Our research provides insights that can aid in epilepsy screening and inform assessment strategies for neurocognitive functioning in those with this condition. The cohort performed overall higher than expected, with outliers existing in both directions. Although our results suggest that seizures might influence the trajectory of KBG syndrome, the approaching but overall absence of statistical significance between study groups underscores the need for a more extensive cohort to discern subtle variations in functioning.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63896"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370742","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":"Non-Hotspot PIK3CA Variants Have Higher Variant Allele Frequency and are More Common in Syndromic Vascular Malformations.","authors":"Themis-Areti A Andreoti, Massimo Maiolo, Aleksandra Tuleja, Yvonne Döring, André Schaller, Erik Vassella, Laurence M Boon, Iris Baumgartner, Sarah M Bernhard, Christiane Zweier, Miikka Vikkula, Jochen Rössler","doi":"10.1002/ajmg.a.63883","DOIUrl":"10.1002/ajmg.a.63883","url":null,"abstract":"<p><p>PIK3CA variants are known to cause vascular malformations. We were interested in studying the phenotypic spectrum, the location within the PIK3CA gene, and the variant allele frequency (VAF) of somatic PI3KCA variants in vascular malformations. Clinical data of consecutive patients with extracranial/extraspinal vascular malformations were collected in the context of the VASCOM cohort (2008-2022, n = 558). Starting October 2020, biopsy samples were tested with the TSO500 gene panel (Illumina). All consenting patients with PIK3CA variants were included in this study. Eighty-nine patients had available genetic results by June 2022. PIK3CA variants (n = 25) were found in 16 simple/combined (nonsyndromic) vascular malformations and in nine vascular malformations associated with other anomalies (syndromic). Four hotspot variants in exons 9 and 20 (c.1624G>A, c.1633G>A, c.3140A>G, c.3140A>T) were identified in 16/25 patients (VAF 0.9%-9.7%). Six non-hotspot variants (c.328_330del, c.323_337del, c.353G>A, c.1258T>C, c.3132T>A, c.3195_3203delinsT) were detected in nine patients (VAF 3.6%-31.7%). Non-hotspot variants were more frequent in syndromic than nonsyndromic vascular malformations (p = 0.0034) and exhibited a higher VAF than hotspot variants (p = 0.0253). Our study contributes to the growing body of knowledge of the genetic background in vascular malformations. Further studies will enrich the ever-growing list of pathogenic PIK3CA variants associated with vascular malformations.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63883"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387250","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}