Biallelic variants in the ERAD pathway gene JKAMP cause a neurodevelopmental disorder with urogenital manifestations
Year: 2026
Type: article
Study design: Case Report
Abstract: PURPOSE: JKAMP encodes a transmembrane protein involved in the ER-associated degradation (ERAD) pathway, a cellular mechanism essential for protein quality control. Variants in ERAD-related genes have been linked to rare neurodevelopmental disorders. This study aims to show that biallelic JKAMP variants cause an autosomal recessive ERAD pathway neurodevelopmental disorder, and to characterize the clinical and genetic features of the condition. METHODS: We conducted comprehensive genomic and clinical investigations of ten individuals (ages 1-25) from six unrelated families affected by a syndromic neurodevelopmental disorder. RESULTS: In this study we identify three biallelic deleterious JKAMP variants including a founder splicing variant in four unrelated families originating from the same region in Palestine. The cardinal clinical features of JKAMP-related disorder involve moderate/severe global developmental delay, intellectual disability, hypotonia, seizures, and urogenital manifestations. Additional features include microcephaly and dystonia. The disorder shows a progressive course, characterized by coarsening of facial features, gait abnormalities, and cerebral atrophy. The clinical phenotype closely parallels disorders linked to other ERAD pathway components, suggesting a shared pathogenic mechanism. CONCLUSION: Our data define biallelic JKAMP variants as a new cause of ERAD pathway-associated neurodevelopmental disorder and expand the genotypic and phenotypic spectrum of this group of conditions.
Source: Genetics in Medicine
Authors: Reham Khalaf-Nazzal, Fida' Al-Hijawi, Bader Alhaddad, Huthaifa Haj Ahmad, Laura Harrold, James Fasham, Khadijah Bakur, Sarar Mohamed, Mosab Maree, Nishanka Ubeyratna, Jana Zaid, Michael Day, Eleanor Walker, Rebecca J. Almond, Imad Dweikat, May Bader, Hani Abu-Eitah, Lettie Rawlins, Peter D. Turnpenny, Andrew H. Crosby, Fowzan S. Alkuraya, Emma L. Baple, Joseph S. Leslie
Institutions: University of Exeter, Arab American University, Royal Devon & Exeter NHS Foundation Trust, Royal Devon University Healthcare NHS Foundation Trust, Riyadh Armed Forces Hospital, Alfaisal University, National University, Western University, An-Najah National University, University of Jordan, King Faisal Specialist Hospital & Research Centre
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,110
OpenAlex ID: W7225290276