Biallelic variants in the ERAD pathway gene JKAMP cause a neurodevelopmental disorder with urogenital manifestations

JKAMP

Biallelic deleterious JKAMP variants, a transmembrane protein of the ERAD protein quality-control pathway, including a founder splicing variant

JKAMP encodes a transmembrane protein involved in ER-associated degradation (ERAD), a protein quality-control pathway. Ten individuals aged 1 to 25 years from six unrelated families with a syndromic neurodevelopmental disorder underwent genomic and clinical investigations. Three biallelic deleterious JKAMP variants were identified, including a founder splicing variant in four families originating from the same region of Palestine. The phenotype combines moderate to severe global developmental delay, intellectual disability, hypotonia, seizures and urogenital manifestations, sometimes with microcephaly and dystonia, with a progressive course marked by facial coarsening, gait abnormalities and cerebral atrophy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The authors present JKAMP as a new cause, but a first description of biallelic loss-of-function JKAMP variants in a neurodevelopmental syndrome was published in AJHG in March 2026: this paper is therefore an independent confirmation. Its practical contribution is the founder splicing variant, to be looked for first in patients from that region, and the description of a progressive course. The lack of functional evidence in the abstract weakens the case for the splicing variant.

Analysis by Dr Thibaut Benquey