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Intellectual disability

Gene: PDZD8

Green List (high evidence)
PDZD8 (PDZ domain containing 8)
EnsemblGeneIds (GRCh38): ENSG00000165650
EnsemblGeneIds (GRCh37): ENSG00000165650
OMIM: 614235, Gene2Phenotype
PDZD8 is in 1 panel

4 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Eleanor Williams (Genomics England Curator)

removed the Q3_22_MOI tag as this is not a new gene added since the last sign off (although it was grey).
Created: 11 Oct 2022, 1:51 p.m. | Last Modified: 11 Oct 2022, 1:51 p.m.
Panel Version: 3.1742
Created: 11 Oct 2022, 1:51 p.m.
Last Modified: 11 Oct 2022, 1:51 p.m.
Panel version: 3.1742

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Not associated with a phenotype in OMIM (last edited: 02/21/2018), Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.
Created: 23 Aug 2022, 2:04 p.m. | Last Modified: 23 Aug 2022, 2:06 p.m.
Panel Version: 3.1680
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 23 Aug 2022, 1:51 p.m. | Last Modified: 23 Aug 2022, 1:51 p.m.
Panel Version: 3.1680
Created: 23 Aug 2022, 1:51 p.m.
Last Modified: 23 Aug 2022, 2:06 p.m.
Panel version: 3.1680

Konstantinos Varvagiannis (Other)

I don't know

Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Created: 6 Mar 2022, 4:58 p.m. | Last Modified: 6 Mar 2022, 4:59 p.m.
Panel Version: 3.1506

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature

Publications

Created: 6 Mar 2022, 4:58 p.m.
Last Modified: 6 Mar 2022, 4:59 p.m.
Panel version: 3.1506

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Autistic behavior
  • Behavioral abnormality
  • Myopathy
  • Abnormality of the face
  • Hypertelorism
  • Seizures
  • Disproportionate tall stature
OMIM
614235
Clinvar variants
Variants in PDZD8
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: PDZD8.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to PDZD8. Source Expert Review Green was added to PDZD8. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

11 Oct 2022, Gel status: 2

Removed Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_22_MOI was removed from gene: PDZD8.

23 Aug 2022, Gel status: 2

Added Tag, Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: PDZD8. Tag Q3_22_MOI tag was added to gene: PDZD8.

23 Aug 2022, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: pdzd8 has been classified as Amber List (Moderate Evidence).

6 Mar 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: PDZD8 was added gene: PDZD8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDZD8 were set to 35227461 Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature Penetrance for gene: PDZD8 were set to Complete Review for gene: PDZD8 was set to AMBER