Nikolaos M Marinakis, Afrodite Kampouraki, Danai Veltra, Faidon-Nikolaos Tilemis, Maria Vasilopoulou, Aikaterini Dokou, Elissavet Georgiadou, Euthalia Karavergou, Maria Christolouka, Alexis Alexopoulos, Dimitra Kirillidi, Maria Goudesidou, Konstantina Kosma, Christalena Sofocleous, Periklis Makrythanasis
{"title":"揭示WDR91的作用:一个以前未被认识的临床实体的病例报告。","authors":"Nikolaos M Marinakis, Afrodite Kampouraki, Danai Veltra, Faidon-Nikolaos Tilemis, Maria Vasilopoulou, Aikaterini Dokou, Elissavet Georgiadou, Euthalia Karavergou, Maria Christolouka, Alexis Alexopoulos, Dimitra Kirillidi, Maria Goudesidou, Konstantina Kosma, Christalena Sofocleous, Periklis Makrythanasis","doi":"10.1111/cge.70012","DOIUrl":null,"url":null,"abstract":"<p><p>WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Unraveling the Role of WDR91: Case Report of a Previously Unrecognized Clinical Entity.\",\"authors\":\"Nikolaos M Marinakis, Afrodite Kampouraki, Danai Veltra, Faidon-Nikolaos Tilemis, Maria Vasilopoulou, Aikaterini Dokou, Elissavet Georgiadou, Euthalia Karavergou, Maria Christolouka, Alexis Alexopoulos, Dimitra Kirillidi, Maria Goudesidou, Konstantina Kosma, Christalena Sofocleous, Periklis Makrythanasis\",\"doi\":\"10.1111/cge.70012\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.</p>\",\"PeriodicalId\":10354,\"journal\":{\"name\":\"Clinical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cge.70012\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70012","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Unraveling the Role of WDR91: Case Report of a Previously Unrecognized Clinical Entity.
WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease