Intellectual disability - microarray and sequencing
Gene: ATP9AComment on phenotypes: Adding the OMIM phenotype which was added to OMIM in Feb 2023.Created: 14 Mar 2023, 9:45 p.m. | Last Modified: 14 Mar 2023, 9:45 p.m.
Panel Version: 4.125
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants reported in four unrelated families with a neurodevelopmental disorder (PMIDs: 34379057, 34764295). Model Atp9a−/− mice had neurobehavioural disabilities reminiscent to the behavioral patterns in the publications quoted here (PMID: 27626380).Created: 23 Nov 2021, 1:06 p.m. | Last Modified: 23 Nov 2021, 1:06 p.m.
Panel Version: 3.1465
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 23 Nov 2021, 12:54 p.m. | Last Modified: 23 Nov 2021, 12:54 p.m.
Panel Version: 3.1465
Publications
Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.Created: 21 Sep 2021, 10:54 a.m. | Last Modified: 21 Sep 2021, 10:54 a.m.
Panel Version: 3.1290
Vogt, Verheyen et al (2021 - http://dx.doi.org/10.1136/jmedgenet-2021-107843) report 3 affected individuals from 2 unrelated consanguineous families.
Features included DD, variable ID (Fam1: sib1-mild, sib2-possible, Fam2: severe), postnatal microcephaly (-2.33 to -3.58 SD), failure to thrive as well as gastrointestinal symptoms (nausea, vomiting, GE reflux).
These subjects were homozygous for pLoF ATP9A variants private to each family.
Previous investigations incl. karyotype, aCGH and transferrin electophoresis (CDGs) and were unremarkable.
Diagnosis was made by exome sequencing and homozygosity mapping. Affected sibs from the first family were homozygous for a stopgain variant [NM_006045.3:c.868C>Τ / p.(Arg290*)]. The subject from the second family was homozygous for a variant affecting the consensus (donor) splice site [c.642+1G>A - same RefSeq]. Both variants were absent from gnomAD. Sanger sequencing was used to confirm variants, carrier status of the parents and unaffected sibs in both families.
Sequencing of cDNA from the individual homozygous for the splicing variant demonstrated skipping of exon 7 with the variant likely leading to frameshift and introduction of a premature stop codon.
qPCR in dermal fibroblasts from affected individuals from both families revealed expression downregulation of ATP9A (14% and 4% respectively for the stopgain and splice variant). Study at the protein level was not possible due to absence of antibody against endogenous ATP9A.
ATP9A encodes ATPase phospholipid transporting 9A (similarly to ATP9B) belonging to the subclass 2 of the P4-ATPase family. As the authors comment, the protein is mainly expressed in the brain although the precise function or subcellular distribution of endogenous ATP9A are unknown.
A previous study showed that overexpressed ATP9A in HeLa cells localizes to early/recycling endosomes and the trans-Golgi network, being required for endocytic recycling of the transferrin receptor to the plasma membrane. ATP9A (in complex with DOP1B and MON2) functionally interacts with the SNX3-retromer. A previous ATP9A knockdown cell line suggested dysregulation of >100 genes with ARPC3 (actin-related protein 2/3 complex subunit 3) being strongly upregulated.
Overall ATP9A appears to have a role in endosome trafficking pathways as well as to inhibit secretion of exosomes at the plasma membrane likely due to alteration of the actin cytoskeleton.
In line with the role of APT9A in early/recycling endosomes and identified interactions, the authors demonstrated overexpression of ARPC3 and SNX3. Study of genes encoding other known interacting proteins was not possible due to poor expression in fibroblasts.
As the authors note, mutations in genes encoding proteins of the Golgi and endosomal trafficking are important for brain development and have been associated with postnatal microcephaly.
In OMIM, G2P, SysID there is no associated phenotype.
The gene is included in the ID panel of PanelApp AUS with amber rating.
Sources: Literature, OtherCreated: 24 Jul 2021, 4:37 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen
Publications
Tag gene-checked was removed from gene: ATP9A.
Phenotypes for gene: ATP9A were changed from Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen; Neurodevelopmental disorder with poor growth and behavioral abnormalities, OMIM:620242
Tag gene-checked tag was added to gene: ATP9A.
Tag Q4_21_rating was removed from gene: ATP9A.
Source Expert Review Green was added to ATP9A. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: ATP9A were set to 34379057; 34764295
Gene: atp9a has been classified as Amber List (Moderate Evidence).
Tag Q4_21_rating tag was added to gene: ATP9A.
Publications for gene: ATP9A were set to 34379057
Publications for gene: ATP9A were set to
Gene: atp9a has been classified as Amber List (Moderate Evidence).
gene: ATP9A was added gene: ATP9A was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP9A were set to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen Penetrance for gene: ATP9A were set to Complete Review for gene: ATP9A was set to AMBER