c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report
Abstract Background Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and mode...
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2025-08-01
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| Online Access: | https://doi.org/10.1186/s13256-025-05456-z |
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| author | Talyta Alves da Silva Campos Alex Honda Bernardes Irene Plaza Pinto Hiane Aparecida da Silva Teixeira Juliana Ferreira da Silva Victor Cortázio do Prado Santos Raffael Zatarin Aparecido Divino da Cruz |
| author_facet | Talyta Alves da Silva Campos Alex Honda Bernardes Irene Plaza Pinto Hiane Aparecida da Silva Teixeira Juliana Ferreira da Silva Victor Cortázio do Prado Santos Raffael Zatarin Aparecido Divino da Cruz |
| author_sort | Talyta Alves da Silva Campos |
| collection | DOAJ |
| description | Abstract Background Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability. The USP9X gene plays critical roles in protein turnover and the regulation of essential pathways during neural development. This work describes the case of a Brazilian patient with female-restricted X-linked syndromic intellectual developmental disorder-99 with a variant not found in databases such as Decipher and ClinVar. Information was obtained from the Center for Rehabilitation and Readaptation Dr. Henrique Santillo electronic medical record system, and exams were conducted by partner laboratories of the Unified Health System. Documenting cases in different populations enriches the knowledge of genetic variations, guides personalized treatments, and expands the field of medical genetics, underscoring the importance of this study. Case presentation A 3-year-old female patient of Pardo admixed ethnicity from northern Brazil was referred to the Center for Rehabilitation and Readaptation Dr. Henrique Santillo for suspected genetic disorders. The child was born after an uneventful pregnancy but faced neonatal complications, including cardiopulmonary arrest and jaundice, requiring intensive care unit admission. She was diagnosed with nonprogressive encephalopathy and neuropsychomotor developmental delay. Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene, associated with female-restricted X-linked syndromic intellectual developmental disorder-99. Conclusion We report the case of a child with a heterozygous pathogenic variant in the USP9X gene, located at Xp11.4 and presenting a wide range of phenotypes. The cytosine-to-thymine substitution resulted in a premature stop codon, causing female-restricted X-linked syndromic intellectual developmental disorder-99. The mutation leads to protein function loss due to haploinsufficiency, resulting in a dominant X-linked disorder. Loss-of-function mutations in the USP9X gene cause intellectual disability and congenital anomalies, with several craniofacial anomalies observed in the patient. Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk. Genetic investigation confirmed the variant’s pathogenicity, highlighting diagnostic challenges and the importance of genetic research in understanding and managing female-restricted X-linked syndromic intellectual developmental disorder-99. Graphical Abstract |
| format | Article |
| id | doaj-art-e53296e4e1f74189ad8d29e197f073eb |
| institution | DOAJ |
| issn | 1752-1947 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Medical Case Reports |
| spelling | doaj-art-e53296e4e1f74189ad8d29e197f073eb2025-08-20T03:05:23ZengBMCJournal of Medical Case Reports1752-19472025-08-011911810.1186/s13256-025-05456-zc.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case reportTalyta Alves da Silva Campos0Alex Honda Bernardes1Irene Plaza Pinto2Hiane Aparecida da Silva Teixeira3Juliana Ferreira da Silva4Victor Cortázio do Prado Santos5Raffael Zatarin6Aparecido Divino da Cruz7Replicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásReplicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásReplicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásReplicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásReplicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásClinical Genetics Service, Center for Rehabilitation and Readaptation Dr. Henrique Santillo, State Health Secretary of GoiásClinical Genetics Service, Center for Rehabilitation and Readaptation Dr. Henrique Santillo, State Health Secretary of GoiásReplicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of GoiásAbstract Background Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability. The USP9X gene plays critical roles in protein turnover and the regulation of essential pathways during neural development. This work describes the case of a Brazilian patient with female-restricted X-linked syndromic intellectual developmental disorder-99 with a variant not found in databases such as Decipher and ClinVar. Information was obtained from the Center for Rehabilitation and Readaptation Dr. Henrique Santillo electronic medical record system, and exams were conducted by partner laboratories of the Unified Health System. Documenting cases in different populations enriches the knowledge of genetic variations, guides personalized treatments, and expands the field of medical genetics, underscoring the importance of this study. Case presentation A 3-year-old female patient of Pardo admixed ethnicity from northern Brazil was referred to the Center for Rehabilitation and Readaptation Dr. Henrique Santillo for suspected genetic disorders. The child was born after an uneventful pregnancy but faced neonatal complications, including cardiopulmonary arrest and jaundice, requiring intensive care unit admission. She was diagnosed with nonprogressive encephalopathy and neuropsychomotor developmental delay. Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene, associated with female-restricted X-linked syndromic intellectual developmental disorder-99. Conclusion We report the case of a child with a heterozygous pathogenic variant in the USP9X gene, located at Xp11.4 and presenting a wide range of phenotypes. The cytosine-to-thymine substitution resulted in a premature stop codon, causing female-restricted X-linked syndromic intellectual developmental disorder-99. The mutation leads to protein function loss due to haploinsufficiency, resulting in a dominant X-linked disorder. Loss-of-function mutations in the USP9X gene cause intellectual disability and congenital anomalies, with several craniofacial anomalies observed in the patient. Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk. Genetic investigation confirmed the variant’s pathogenicity, highlighting diagnostic challenges and the importance of genetic research in understanding and managing female-restricted X-linked syndromic intellectual developmental disorder-99. Graphical Abstracthttps://doi.org/10.1186/s13256-025-05456-zMRXS99FUSP9XNeurodevelopmental disorderDevelopmental delayCase report |
| spellingShingle | Talyta Alves da Silva Campos Alex Honda Bernardes Irene Plaza Pinto Hiane Aparecida da Silva Teixeira Juliana Ferreira da Silva Victor Cortázio do Prado Santos Raffael Zatarin Aparecido Divino da Cruz c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report Journal of Medical Case Reports MRXS99F USP9X Neurodevelopmental disorder Developmental delay Case report |
| title | c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report |
| title_full | c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report |
| title_fullStr | c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report |
| title_full_unstemmed | c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report |
| title_short | c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report |
| title_sort | c 7156c t p gln2386 variant causes loss of function of the usp9x gene in a female restricted x linked syndromic intellectual disability a case report |
| topic | MRXS99F USP9X Neurodevelopmental disorder Developmental delay Case report |
| url | https://doi.org/10.1186/s13256-025-05456-z |
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