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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 v1.988 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304) showing that females can be symptomatic.

Therefore, the MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update. This also reflects the current MOI on all other relevant panels.
Fetal anomalies v1.626 OTUD5 Arina Puzriakova Added comment: Comment on list classification: At least 8 families reported with a multiple congenital anomaly disorder and distinct hemizygous variants in this gene (PMIDs: 33131077 and 33523931). Phenotype may conceivably be detected prenatally and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.620 MYL9 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as there are now two unrelated families presenting features of MMIHS, associated with different biallelic variants in the MYL9 gene (PMIDs: 29453416; 33031641).

Additional cases/functional evidence required prior to inclusion as diagnostic-grade.
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova changed review comment from: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 316089320). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag); to: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 31608932). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 316089320). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.137 B9D2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants reported in at least four unrelated cases (2 with Joubert syndrome, PMID: 26092869; and 2 with MKS, PMIDs: 21763481 and 31411728)

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) as sufficient number of unrelated cases with fetally-relevant phenotype due to variants in the B9D2 gene.
Fetal anomalies v1.31 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green: 3 unrelated fetal cases (PMIDs:27894351,28749478,30327448).
Fetal anomalies v0.311 TCTN2 Rebecca Foulger edited their review of gene: TCTN2: Added comment: This gene was reviewed by Anna de Burca (Genomics England Clinical Team) and at a Fetal Working Group call on July 19th 2019. Outcome of review: Rate Green because of diagnostic finding in PAGE study (PMID:30712880) plus additional case. There are 3 reported unrelated families with Joubert syndrome and 3 with Meckel syndrome (all homozygous variants in consanguineous families: PMIDs 21565611, 25118024, 21462283). PMID:25118024 comments that all cases have cerebellar vermis hypoplasia.; Changed rating: GREEN; Changed publications: 21565611, 25118024 & 21462283
Fetal anomalies v0.293 KIAA1109 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green after agreement from Anna de Burca (Genomics England clinical team). KIAA1109 is Green on the 'Hydrocephalus' and 'Arthrogryposis' panels. Sufficient cases in OMIM to support association with Alkuraya-Kucinskas syndrome (MIM:617822) which includes arthrogryposis and brain abnormalities: severe cases are incompatible with life. Multiple ultrasounds abnormalities reported in PMIDs 30485398 and 29290337.
Fetal anomalies v0.244 HNRNPK Rebecca Foulger commented on gene: HNRNPK: Added HNRNPK to the Fetal anomalies panel as a Green gene based on the DDG2P Disease confidence rating of 'confirmed' for Au-Kline syndrome. There is sufficient evidence (>3 unrelated cases from PMIDs:26173930,26954065,28771707,29904177) supporting a link between HNRNPK and Au-Kline syndrome. Plus the phenotype includes structural anomalies and PMID:29904177 report a prenatal presentation.
Fetal anomalies v0.225 SUZ12 Rebecca Foulger edited their review of gene: SUZ12: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March and April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: include on the Fetal anomalies panel as a Green gene. Additional notes from clinical review: Fetal relevance is borderline- PMIDs:28229514 and 30019515 report a set of features where it is unclear if they would be detected prenatally, including one case of increased head circumference at birth (but also one case with reduced head circumference at birth) some facial and limb features etc. Evidence wise, there are just enough cases from the literature (2 papers from the same group) to support inclusion: Imagawa et al., 2017 (PMID:28229514) identified a missense somatic mosaic mutation (c.1829A>T, p.Glu610Val) in SUZ12 in a patient with clinically suspected Weaver syndrome. Imagawa et al., 2018 (PMID:30019515) report two further Weaver syndrome-like patients with SUZ12 variants (a missense and a frameshift). On balance, it was decided that SUZ12 should be included on the Fetal anomalies panel.; Changed rating: GREEN; Changed publications: 28229514, 30019515
Fetal anomalies v0.205 ARL13B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: ARL13B is on the Additional gene list in the PAGE paper (Lord et al., 2019, PMID:30712880) based on prenatal presentation of a phenotype in the literature. Sufficient (3 unrelated cases in OMIM (Pakistani, American, Tunisian) with homozygous or compound heterozygous variants in ARL13B in patients with a Joubert phenotype (from PMIDs 18674751 and 25138100). Plus functional evidence to support impairment of ARL13B protein function (PMID:29255182). Therefore sufficient evidence to support threshold for Green rating.
Fetal anomalies v0.201 ADAMTS17 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: ADAMTS17 is listed as an Additional gene in the PAGE paper (Lord et al., 2019, PMID:30712880) and therefore fetally-relevant (phenotype includes short stature). For evidence, there are sufficient cases in OMIM (5 variants from 5 different families (3 families from PMID:19836009 and one each from PMIDs:22486325 and 24940034) to support a Green (diagnostic-grade) rating.
Fetal anomalies v0.134 IDS Rebecca Foulger edited their review of gene: IDS: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.; Changed rating: GREEN
Fetal anomalies v0.63 EPHB4 Rebecca Foulger edited their review of gene: EPHB4: Added comment: Additional details for change of rating from Amber ('probable' PAGE rating) to Green: Phenotype is fetally-relevant, and rated green on the 'Primary lymphoedema' panel. Sufficient evidence to support hydrops fetalis association as part of MIM:617300, with 3 variants listed in OMIM from 3 families, each with multiple affected individuals (PMIDs:27400125 and 29905864).; Changed rating: GREEN; Changed publications: 27400125, 29905864; Changed phenotypes: Lymphatic malformation 7, 617300
Fetal anomalies v0.9 IDS Rebecca Foulger reviewed gene: IDS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 IDS Rebecca Foulger gene: IDS was added
gene: IDS was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: IDS were set to MUCOPOLYSACCHARIDOSIS TYPE 2