Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study
<b>Background:</b> Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the <i>NF1</i> gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. <b>...
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2025-01-01
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| author | Klára Veres Benedek Nagy Zsófia Ember Judit Bene Kinga Hadzsiev Márta Medvecz László Szabó Zsuzsanna Zsófia Szalai |
| author_facet | Klára Veres Benedek Nagy Zsófia Ember Judit Bene Kinga Hadzsiev Márta Medvecz László Szabó Zsuzsanna Zsófia Szalai |
| author_sort | Klára Veres |
| collection | DOAJ |
| description | <b>Background:</b> Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the <i>NF1</i> gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. <b>Methods:</b> We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1–33 years). The data were collected over 15 years. <b>Results:</b> Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). <b>Conclusions:</b> In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype. |
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| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-cad6e6aec5284bd6b8ed7910d5bae3ca2025-01-24T13:24:10ZengMDPI AGBiomedicines2227-90592025-01-0113114610.3390/biomedicines13010146Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective StudyKlára Veres0Benedek Nagy1Zsófia Ember2Judit Bene3Kinga Hadzsiev4Márta Medvecz5László Szabó6Zsuzsanna Zsófia Szalai7Department of Pediatric Dermatology, Heim Pal National Pediatric Institute, 1089 Budapest, HungaryFaculty of Medicine, Semmelweis University, 1085 Budapest, HungaryFaculty of Medicine, Semmelweis University, 1085 Budapest, HungaryDepartment of Medical Genetics, Clinical Center, Medical School, University of Pécs, 7622 Pécs, HungaryDepartment of Medical Genetics, Clinical Center, Medical School, University of Pécs, 7622 Pécs, HungaryDepartment of Dermatology, Venereology and Dermatooncology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine, Heim Pal National Pediatric Institute, 1089 Budapest, HungaryDepartment of Pediatric Dermatology, Heim Pal National Pediatric Institute, 1089 Budapest, Hungary<b>Background:</b> Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the <i>NF1</i> gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. <b>Methods:</b> We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1–33 years). The data were collected over 15 years. <b>Results:</b> Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). <b>Conclusions:</b> In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype.https://www.mdpi.com/2227-9059/13/1/146rare diseasesgenotype–phenotype analysesNGStype 1 neurofibromatosissplice-site mutations<i>NF1</i> gene |
| spellingShingle | Klára Veres Benedek Nagy Zsófia Ember Judit Bene Kinga Hadzsiev Márta Medvecz László Szabó Zsuzsanna Zsófia Szalai Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study Biomedicines rare diseases genotype–phenotype analyses NGS type 1 neurofibromatosis splice-site mutations <i>NF1</i> gene |
| title | Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study |
| title_full | Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study |
| title_fullStr | Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study |
| title_full_unstemmed | Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study |
| title_short | Increased Phenotype Severity Associated with Splice-Site Variants in a Hungarian Pediatric Neurofibromatosis 1 Cohort: A Retrospective Study |
| title_sort | increased phenotype severity associated with splice site variants in a hungarian pediatric neurofibromatosis 1 cohort a retrospective study |
| topic | rare diseases genotype–phenotype analyses NGS type 1 neurofibromatosis splice-site mutations <i>NF1</i> gene |
| url | https://www.mdpi.com/2227-9059/13/1/146 |
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