GLDN

Inheritance Pattern: AR

Disease ID:MONDO:0014965

Submitter: ClinGen

GLDN encodes gliomedin, a Schwann cell–secreted adhesion protein required for the initiation and stabilization of nodes of Ranvier through interactions with axonal Neurofascin-186 (NF186) and Schwann cell NrCAM. This process is essential for clustering sodium channels and establishing normal peripheral nerve conduction. The gene–disease association was first established by Maluenda et al., (PMID: 27616481) who identified biallelic GLDN variants in individuals with fetal akinesia and congenital contractures. Since the initial description, multiple unrelated families have been reported with nonsense, frameshift, canonical splice, and missense variants segregating with disease in an autosomal recessive pattern. Many pathogenic variants localize to the conserved extracellular olfactomedin domain critical for NF186 binding (PMIDs: 28726266, 35806855, 39713852). Multiple recurrent and non-recurrent variants comprising missense, nonsense, frameshift, and splice variants have been reported in affected individuals, some of which segregated with disease in multiple affected individuals within families. Variants from more than 10 independent publications have been scored as part of this curation and the maximum score for genetic evidence (+12pts) has been reached. The mechanism of pathogenicity is loss of function, and in vitro studies demonstrate that pathogenic GLDN variants impair gliomedin trafficking to the cell surface and abolish NF186 binding (PMID: 27616481). Mouse models lacking gliomedin show disrupted Schwann cell microvilli organization and failure of early sodium channel clustering at heminodes without defects in myelination (PMID: 20188654). Double knockout mice lacking both gliomedin and NrCAM show nodal defects and motor abnormalities closely mirroring the human phenotype (PMID: 24719088). Prenatal ultrasound findings commonly include polyhydramnios, decreased or absent fetal movements, arthrogryposis multiplex congenita, fixed limb joints, short long bones, hydrops fetalis, and pulmonary hypoplasia, with detection often late in gestation (mean 30-32 weeks) (PMID: 35806855). Outcomes include neonatal death, elective termination, or survival with significant respiratory and neuromuscular morbidity. Although initially described as uniformly lethal, later reports demonstrate phenotypic variability, with survival beyond infancy and into adolescence documented in a subset of individuals receiving intensive supportive care (PMIDs: 35806855, 39713852). These observations support a continuous phenotypic spectrum rather than distinct disease entities. In summary, the Prenatal Gene Curation Expert Panel concludes that GLDN has DEFINITIVE evidence for autosomal recessive Lethal Congenital Contracture Syndrome 11. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 11/18/2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0014965

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014965

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014965

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014965

Submitter: Labcorp Genetics (formerly Invitae)