da Silva Campos Talyta Alves, Bernardes Alex Honda, Pinto Irene Plaza, da Silva Teixeira Hiane Aparecida, da Silva Juliana Ferreira, do Prado Santos Victor Cortázio, Zatarin Raffael, da Cruz Aparecido Divino
Replicon Research Center, Master Program in Genetics, School of Medical Science and Health, Pontifical Catholic University of Goiás, Goiânia, Goiás, Brazil.
Clinical Genetics Service, Center for Rehabilitation and Readaptation Dr. Henrique Santillo, State Health Secretary of Goiás, Goiânia, GO, Brazil.
J Med Case Rep. 2025 Aug 1;19(1):380. doi: 10.1186/s13256-025-05456-z.
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.
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.
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.
女性限制性X连锁综合征性智力发育障碍99型是一种极为罕见的与X染色体相关的神经发育障碍，因USP9X基因突变在女性个体中表现出来。其特征为发育迟缓、行为改变以及中度至重度智力残疾。USP9X基因在蛋白质周转以及神经发育过程中关键通路的调控方面发挥着重要作用。本研究描述了一名巴西女性限制性X连锁综合征性智力发育障碍99型患者的病例，该患者存在一个在诸如Decipher和ClinVar等数据库中未发现的变异。信息取自恩里克·桑蒂略康复与重新适应中心的电子病历系统，检查由统一卫生系统的合作实验室进行。记录不同人群中的病例可丰富对基因变异的认识，指导个性化治疗，并拓展医学遗传学领域，凸显了本研究的重要性。
一名来自巴西北部的3岁帕尔多混血族裔女性患者因疑似遗传疾病被转诊至恩里克·桑蒂略康复与重新适应中心。该患儿妊娠过程顺利，但出生后出现新生儿并发症，包括心肺骤停和黄疸，需入住重症监护病房。她被诊断为非进行性脑病和神经精神运动发育迟缓。进一步检查发现了结构异常，如胼胝体发育不全和先天性髋关节发育不良。进行了多项基因检测，但只有全外显子测序揭示了USP9X基因中的一个致病变异，与女性限制性X连锁综合征性智力发育障碍99型相关。
我们报告了一名儿童的病例，其USP9X基因存在杂合致病变异，位于Xp11.4，呈现出广泛的表型。胞嘧啶到胸腺嘧啶的替换导致了一个过早的终止密码子，引发了女性限制性X连锁综合征性智力发育障碍99型。该突变由于单倍体不足导致蛋白质功能丧失，从而引发一种显性X连锁疾病。USP9X基因的功能丧失突变会导致智力残疾和先天性异常，该患者出现了多种颅面异常。尽管大多数功能丧失变异是新发的，但对母亲进行检测对于评估复发风险至关重要。基因研究证实了该变异的致病性，凸显了诊断挑战以及基因研究在理解和管理女性限制性X连锁综合征性智力发育障碍99型方面的重要性。
