Unraveling the Role of WDR91: Case Report of a Previously Unrecognized Clinical Entity.
| Title: | Unraveling the Role of WDR91: Case Report of a Previously Unrecognized Clinical Entity. |
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| Authors: | Marinakis NM; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Research University Institute for the Study and Prevention of Genetic and Malignant Disease of Childhood, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Kampouraki A; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Veltra D; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Research University Institute for the Study and Prevention of Genetic and Malignant Disease of Childhood, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Tilemis FN; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Research University Institute for the Study and Prevention of Genetic and Malignant Disease of Childhood, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Vasilopoulou M; B' Pediatric Clinic, Agia Sofia Children's Hospital, Athens, Greece.; Dokou A; B' Pediatric Clinic, Agia Sofia Children's Hospital, Athens, Greece.; Georgiadou E; First Department of Paediatrics, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Karavergou E; First Department of Paediatrics, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Christolouka M; First Department of Paediatrics, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens, Greece.; Alexopoulos A; Special Unit of Dermatology, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Agia Sofia Children's Hospital, Athens, Greece.; Kirillidi D; Neonatal Intensive Care Unit (NICU) of the Department of Pediatrics, University of Thessaly, University General Hospital of Larissa, Larissa, Greece.; Goudesidou M; Neonatal Intensive Care Unit (NICU) of the Department of Pediatrics, University of Thessaly, University General Hospital of Larissa, Larissa, Greece.; Kosma K; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Sofocleous C; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Makrythanasis P; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Biomedical Research Foundation of the Academy of Athens, Athens, Greece.; Department of Genetic Medicine and Development, Medical School, University of Geneva, Geneva, Switzerland. |
| Source: | Clinical genetics [Clin Genet] 2026 Jan; Vol. 109 (1), pp. 176-180. Date of Electronic Publication: 2025 Jun 23. |
| Publication Type: | Journal Article; Case Reports |
| Language: | English |
| Journal Info: | Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Copenhagen, Munksgaard. |
| MeSH Terms: | Carrier Proteins*/genetics ; Genetic Predisposition to Disease*; Microcephaly/genetics ; Humans ; Male ; Female ; Pedigree ; Exome Sequencing ; Phenotype ; Mutation ; Child, Preschool ; Child ; Consanguinity |
| Abstract: | 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.; (© 2025 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.) |
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| Contributed Indexing: | Keywords: WDR91; brain malformations; loss of function; neurodevelopmental disorder |
| Substance Nomenclature: | 0 (Carrier Proteins) |
| Entry Date(s): | Date Created: 20250623 Date Completed: 20251203 Latest Revision: 20251229 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12674976 |
| DOI: | 10.1111/cge.70012 |
| PMID: | 40550703 |
| Database: | MEDLINE |
Journal Article; Case Reports