Adult onset neurodegenerative disorder

Gene: JAM2

Green List (high evidence)

Comment on list classification: There are more than 3 unrelated individuals reported in literature with brain calcifications and biallelic JAM2 variants. Common symptoms included parkinsonism, cognitive decline, cerebellar syndrome, and dysarthria. Knockout mouse model recapitulated the human phenotype. Based on available evidence, JAM2 should be updated to Green at the next GMS update.

Created: 16 Mar 2026, 11:04 a.m. | Last Modified: 16 Mar 2026, 11:06 a.m.

Panel Version: 8.18

PMID: 31851307 Cen et al., 2020
Reported 3 unrelated families with primary familial brain calcification. Probands harboured biallelic JAM2 variants: homozygous c.140delT, p.L48Ter; homozygous c.1A>G, p.M1? and compound heterozygous mutations [c.504G>C, p.W168C & c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL]. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and asymptomatic at the time of report (1 patient at age 37 years); disease onset ages: 20-38 years. 4/4 patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas.

PMID: 32142645 Schottlaender et al., 2023
Report of 7 individuals from 4 families with primary familial brain calcification. Detected biallelic JAM2 variants: homozygous c.685C>T, p.Arg229Ter (2 families); comp het c.395−1dupG, c.323G>A & IVS4-1dupG, p.Arg108His; homozygous c.177_180delCAGA, p.Arg60Ter.
Age of onset: childhood (3/7), teenage (2/7), 20s-30s (2/7).
Phenotype: cerebellar syndrome (6/7), Parkinsonism (5/7), dystonia (3/7), cognitive decline (5/6 assessed), brain calcification (7/7).

Functional evidence: JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient’s fibroblasts; human phenotype of brain calcification is replicated in the jam2 complete knockout mouse (jam2 KO).

JAM2 is associated with Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824 (OMIM accesed 16th Mar 2026).

Created: 16 Mar 2026, 10:38 a.m. | Last Modified: 16 Mar 2026, 10:59 a.m.

Panel Version: 8.16

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824

Publications

• 31851307
• 32142645

Green List (high evidence)

Sources: Literature

Created: 4 Mar 2026, 9:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Basal ganglia calcification 8, 618824; Primary familial brain calcification; Fahr syndrome

Publications

• 31851307
• 37446066