Structural basal ganglia disorders

Gene: AP1S2

Comment on mode of inheritance: Changed MOI from 'XL, biallelic in females' to 'XL, monoallelic in females'.

Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.

Created: 18 Oct 2021, 11:54 a.m. | Last Modified: 18 Oct 2021, 11:54 a.m.

Panel Version: 1.21

Comment when marking as ready: Associated with phenotype in OMIM and as a confirmed G2P. At least 5 variants reported.

Created: 16 Mar 2017, 11:25 a.m.

Comment on publications: 17617514 - identification of AP1S2 variants in a large 4-generation French family, and a Scottish family, marked calcifications of the basal ganglia were reported in affected individuals in both families
18428203 - an additional two families reported "Studying four patients in two unrelated families in which AP1S2 nonsense and splicesite mutations segregated, we found that affected individuals presented, in addition to previously described features, with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive behavior, brain calcifications, and elevated CSF protein levels."

Created: 16 Mar 2017, 11:23 a.m.

Comment on phenotypes: PETTIGREW SYNDROME

Created: 14 Mar 2017, 6:06 p.m.

Green List (high evidence)

Not that many families with Basal Ganglia changes but probably should include in this panel

Created: 1 Mar 2017, 1:54 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)