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Fetal anomalies v6.103 PLD1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PLD1.
Tag Q3_25_expert_review tag was added to gene: PLD1.
Fetal anomalies v6.103 PLD1 Arina Puzriakova commented on gene: PLD1: This gene was previously downgraded from Green to Amber following review by Jesse Hayesmoore highlighting the presence of homozygotes in population databases, including some patient variants. However, additional cases have continued to be published albeit often with limited information and no extensive functional studies. This gene-condition has been reviewed by multiple resources including:

- ClinGen: definitive (classified on 12-02-2024) - https://search.clinicalgenome.org/CCID:008897
- G2P: definitive (classified on 19-02-2025) - https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03704
- PanelApp Australia: green on multiple panels - https://panelapp-aus.org/panels/entities/PLD1
- OMIM (last updated on 30-09-2022) - https://www.omim.org/entry/212093

Given the classification on Genomics England PanelApp currently conflicts with multiple other resources, this gene will be flagged for additional expert review during the next GMS panel release.
Fetal anomalies v6.103 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 33645542; 27799408; 33142350
Fetal anomalies v6.102 PLD1 Arina Puzriakova Added comment: Comment on phenotypes: Updated OMIM:212093 phenotype from 'Cardiac valvular defect, developmental' to 'Cardiac valvular dysplasia 1' (accessed on 20-10-2025)
Fetal anomalies v6.102 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations to Cardiac valvular dysplasia 1, OMIM:212093; Congenital heart malformations
Fetal anomalies v6.101 PLD1 Arina Puzriakova edited their review of gene: PLD1: Added comment: Additional cases reported (not reviewed previously):

- PMID: 38171566 - based on the abstract (translated from Chinese, full-text not available) a fetus with generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes was identified with compound heterozygous variants (c.1460G>A (p.W487*); c.2977C>T (p.R993*)) in the PLD1 gene. No functional studies mentioned.

- PMID: 39553471 - a fetus with compound heterozygous variants (c.1937G>C (p.G646A); c.1062-59A>G) was found with congenital heart disease including pulmonary atresia, regurgitation and tricuspid valve dysplasia. In silico analysis of c.1062-59A>G indicated the variant affected splicing, and subsequent RT-PCR and TA clone sequencing revealed a 76-bp intron retention and skipping of exon 11, causing a frameshift and premature stop codon in PLD1. Both variants were classified as VUS according to ACMG guidelines.

- PMID: 39681445 - title 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.; Changed publications to: 27799408, 33142350, 33645542, 35380090, 36923242, 37770978, 38171566, 39553471, 39681445; Changed phenotypes to: Cardiac valvular dysplasia 1, OMIM:212093; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PLD1 Achchuthan Shanmugasundram Tag Q1_25_ demote_amber was removed from gene: PLD1.
Tag Q1_25_ NHS_review was removed from gene: PLD1.
Tag Q2_24_expert_review was removed from gene: PLD1.
Fetal anomalies v5.78 PLD1 Achchuthan Shanmugasundram edited their review of gene: PLD1: Added comment: The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.; Changed rating: AMBER
Fetal anomalies v5.77 PLD1 Achchuthan Shanmugasundram Source Expert Review Amber was added to PLD1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v5.74 PLD1 Achchuthan Shanmugasundram Tag Q2_24_demote_red was removed from gene: PLD1.
Tag Q1_25_ demote_amber tag was added to gene: PLD1.
Tag Q1_25_ NHS_review tag was added to gene: PLD1.
Fetal anomalies v5.16 PLD1 Achchuthan Shanmugasundram commented on gene: PLD1
Fetal anomalies v5.15 PLD1 Sarah Graham reviewed gene: PLD1: Rating: AMBER; Mode of pathogenicity: ; Publications: 33645542, 27799408; Phenotypes: Cardiac valvular dysplasia 1, MIM#212093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.13 PLD1 Achchuthan Shanmugasundram Publications for gene: PLD1 were updated from 27799408; 33645542; 33142350 to 33645542; 27799408; 33142350
Fetal anomalies v3.157 PLD1 Arina Puzriakova changed review comment from: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.; to: Comment on list classification: This Green gene was signed off in Mar 2023 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.157 PLD1 Arina Puzriakova Classified gene: PLD1 as Green List (high evidence)
Fetal anomalies v3.157 PLD1 Arina Puzriakova Added comment: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.157 PLD1 Arina Puzriakova Gene: pld1 has been classified as Green List (High Evidence).
Fetal anomalies v3.156 PLD1 Arina Puzriakova Tag Q2_24_demote_red tag was added to gene: PLD1.
Tag Q2_24_expert_review tag was added to gene: PLD1.
Fetal anomalies v3.156 PLD1 Arina Puzriakova commented on gene: PLD1: Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Fetal anomalies v2.10 PLD1 Arina Puzriakova Tag Q2_21_rating was removed from gene: PLD1.
Tag Q3_22_NHS_review was removed from gene: PLD1.
Fetal anomalies v2.10 PLD1 Arina Puzriakova edited their review of gene: PLD1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v2.9 PLD1 Arina Puzriakova Source Expert Review Green was added to PLD1.
Source NHS GMS was added to PLD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v1.892 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093 to Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations
Fetal anomalies v1.891 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 27799408; 33645542
Fetal anomalies v1.890 PLD1 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: PLD1.
Fetal anomalies v1.880 PLD1 Rhiannon Mellis reviewed gene: PLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33142350; Phenotypes: Cardiomyopathy, Congenital heart malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.655 PLD1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: PLD1.
Fetal anomalies v1.655 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 33645542
Fetal anomalies v1.654 PLD1 Arina Puzriakova Classified gene: PLD1 as Amber List (moderate evidence)
Fetal anomalies v1.654 PLD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Suzanne Drury (Congenica). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a fetally-relevant gene-disease association. This gene should be rated Green at the next review.
Fetal anomalies v1.654 PLD1 Arina Puzriakova Gene: pld1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.653 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from HP:0001654; HP:0001627; HP:0001638 to Cardiac valvular defect, developmental, OMIM:212093
Fetal anomalies v1.637 PLD1 Suzanne Drury gene: PLD1 was added
gene: PLD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD1 were set to 33645542
Phenotypes for gene: PLD1 were set to HP:0001654; HP:0001627; HP:0001638
Review for gene: PLD1 was set to GREEN
Added comment: PMID 33645542 identified 30 patients from 21 unrelated families of different ancestries with biallelic PLD1 variants. All 30 patients were diagnosed with severe congenital heart disease or
cardiomyopathy at the fetal or neonatal stage. PLD1 can also cause neonatal cardiomyopathy in the absence of congenital heart defects.
Sources: Literature