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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 |
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| Fetal anomalies v3.146 | RECQL4 | Arina Puzriakova Phenotypes for gene: RECQL4 were changed from RAPADILINO SYNDROME; ROTHMUND-THOMSON SYNDROME; BALLER-GEROLD SYNDROME to Baller-Gerold syndrome, OMIM:218600; RAPADILINO syndrome, OMIM:266280; Rothmund-Thomson syndrome, type 2, OMIM:268400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v3.2 | KIF21A |
Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to recommend this gene to NHS GMS for promoting to green rating. There are two unrelated families with homozygous loss of function variants in KIF21A were reported with severe fetal akinesia with arthrogryposis multiplex in PMID:34740919. Hannah Robinson (South West Genomic Laboratory Hub) reported an additional case identified in Exeter Genomics Laboratory exhibiting homozygous nonsense variant in KIF21A and was diagnosed with arthrogryposis. In addition, PMID:32686171 reports overlapping phenotypes observed in KIF21A null piglets, where a 63-bp insertion in exon 2 of the porcine KIF21A gene is associated with arthrogryposis multiplex congenita. |
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| Fetal anomalies v2.11 | RAB39B | Achchuthan Shanmugasundram Phenotypes for gene: RAB39B were changed from MENTAL RETARDATION X-LINKED TYPE 72 (MRX72) +/- PARKINSONS to Intellectual developmental disorder, X-linked 72, OMIM:300271; Waisman syndrome, OMIM:311510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.900 | CHRM3 |
Rhiannon Mellis gene: CHRM3 was added gene: CHRM3 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: CHRM3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHRM3 were set to PMID: 22077972; 31441039; 10944224 Phenotypes for gene: CHRM3 were set to Prune belly syndrome; Megacystis Review for gene: CHRM3 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Discussed as a potential cause of megacystis. Currently Red on Panelapp CAKUT panel (2016) because at that time there was only 1 reported family and a mouse model. The unpublished data mentioned in that panelapp review (from Adrian Woolf, Manchester) is now published so now 2 families PMID: 22077972; 31441039 plus a mouse model PMID: 10944224. However, prenatal findings (distended bladder and unilateral hydronephrosis) only documented for one individual. More evidence of prenatal phenotype would be helpful. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | DEPDC5 |
Rhiannon Mellis commented on gene: DEPDC5: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Currently rated Green on the following other PanelApp panel(s): Intellectual disability, Genetics epilepsies. Amber on cortical malformations panel. Details of review: Previously reviewed as Red because only associated with familial epilepsy without structural brain anomalies (AD - caused by het LOF variants) but data presented by Dr Lara Menzies at CGS Spring Meeting 2021 suggests that there may also be a biallelic phenotype with hypomorphic variants. 5 cases presented from 3 unrelated Irish traveller families with significant polymicrogyria and macrocephaly as well as seizures and severe dev delay. At least 2 of the cases had prenatal features: ventriculomegaly, macrocephaly and IUGR for one, polymicrogyria on MRI for another - fetal MRI done because of FHx of affected child. (Unpublished data) Liu et al 2020 (PMID: 32848577) report one case with homozygous missense variants in this gene, who had focal cortical dysplasia and seizures from 3yo |
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| Fetal anomalies v1.900 | ENG |
Rhiannon Mellis gene: ENG was added gene: ENG was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: ENG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ENG were set to Telangiectasia, hereditary hemorrhagic, type 1 Review for gene: ENG was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Consistency check because out of 4 known HHT genes EPHB4 and SMAD4 are on the fetal anomalies panel but ACVRL1 and ENG are not. No specific published reports of ENG variants detected prenatally but correlates with pulmonary AVMs which can present neonatally and can be detected on prenatal US (PMID: 17719943; PMID: 21988128). Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | PIGS |
Rhiannon Mellis gene: PIGS was added gene: PIGS was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGS were set to PMID: 30269814 Phenotypes for gene: PIGS were set to Developmental and epileptic encephalopathy 95 Review for gene: PIGS was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Currently red/amber on some other panels but reviewed on Congenital disorders of glycosylation panel as having sufficient evidence for green rating at next major review, in light of this same paper (PMID: 30269814). Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia to intellectual disability/epileptic encephalopathy. Fetal akinesia phenotype may be relevant for fetal anomalies panel. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | MRPS16 |
Rhiannon Mellis gene: MRPS16 was added gene: MRPS16 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: MRPS16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS16 were set to PMID: 28749478 Phenotypes for gene: MRPS16 were set to Combined oxidative phosphorylation deficiency 2 Review for gene: MRPS16 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Amber on mitochondrial/inborn errors of metabolism etc. Not Green on any panel. One previous case reported with "agenesis of the corpus callosum, dysmorphism, and fatal neonatal lactic acidosis. The patient was small at birth, with dysmorphic facies, low-set ears, nonpitting edema of the limbs, brachydactyly, and redundant skin over the neck. She died of intractable metabolic acidosis at age 3 days." PMID:15505824 (2004). One further fetal case reported by Shamseldin et al. 2018 (PMID: 28749478) with hydrops, very short long bones, and partial ACC Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | THSD1 |
Rhiannon Mellis gene: THSD1 was added gene: THSD1 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: THSD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: THSD1 were set to PMID: 28749478; 26036949 Phenotypes for gene: THSD1 were set to Intracerebral aneurysms; ?Hydrops fetalis Review for gene: THSD1 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence. Details of review: Not currently Green on any panels. Amber on Cerebral vascular malformations. (Heterozygous mutations identified in nine families with intracerebral aneurysms plus animal models but unclear on penetrance.) Shamseldin et al 2018 (PMID: 28749478) report a fetal case with hydrops and a HOMOZYGOUS likely pathogenic variant in THSD1. The same group previously identified this same founder mutation in THSD1 in another 3 families with hydrops/oedema (PMID: 26036949) Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | MYBPC3 |
Rhiannon Mellis gene: MYBPC3 was added gene: MYBPC3 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: MYBPC3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: MYBPC3 were set to PMID: 28749478; 19858127 Phenotypes for gene: MYBPC3 were set to Cardiomyopathy; ?Congenital myopathy Review for gene: MYBPC3 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence. Currently rated Green on the following other PanelApp panel(s): Various cardiomyopathy panels. Amber on congenital myopathy panel. Details of review: Previously only one (AR) case with skeletal muscle phenotype, although is a known cardiomyopathy gene (PMID: 19858127). One fetal case reported by Shamseldin et al 2018 (PMID: 28749478) with hydrops. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | CACNA1S |
Rhiannon Mellis gene: CACNA1S was added gene: CACNA1S was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACNA1S were set to PMID: 33060286; 28012042 Phenotypes for gene: CACNA1S were set to Congenital myopathy; arthrogryposis Review for gene: CACNA1S was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Previously only monoallelic variants reported associated with malignant hyperthermia and periodic paralysis but more recently biallelic variants have been associated with congenital myopathy. In Ravenscroft et al 2020 (PMID: 33060286) the reported biallelic variants were VUS but strong suspicion of causality: the proband had polyhydramnios, scalp oedema, bilateral wrist contractures, bilateral talipes and reduced fetal movements, ToP at 26/40. Mild facial dysmorphic features were noted on autopsy, including low anterior hairline, mild hypertelorism and moderate retrognathia. A previous pregnancy was affected with polyhydramnios and reduced fetal movements, delivered at 32/40 due to placental abruption and died at 10 days. On photos the baby had ptosis and broad nasal tip. The biallelic variants segregated within the family (parents and the 2 unaffected sibs all het). No cell lines available for functional studies. Another study (PMID: 28012042) reports 7 families with congenital myopathy and CACNA1S mutations (both recessive and dominant), of whom 3 had cases with antenatal onset (reduced fetal movements). Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | NDUFB10 |
Rhiannon Mellis gene: NDUFB10 was added gene: NDUFB10 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: NDUFB10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NDUFB10 were set to PMID: 31130284; 28040730 Phenotypes for gene: NDUFB10 were set to Mitochondrial complex I deficiency Review for gene: NDUFB10 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Not Green on any other panels (Amber/Red because only 1 case reported, with functional studies). Causes Mitochondrial complex 1 deficiency. One fetal case reported by Monies et al 2019 (PMID: 31130284) with Non-immune hydrops fetalis and died after birth. The previous reported case on OMIM (from PMID: 28040730) was a female infant with IUGR, hydrops, lung hypoplasia and fetal cardiomyopathy - neonatal death with rapidly progressive lactic acidosis and PM found decreased complex 1 activity in skeletal muscle, heart, liver. Previous child of parents also had hydrops and died on day 1 of life. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | FTO |
Rhiannon Mellis gene: FTO was added gene: FTO was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117 Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism Review for gene: FTO was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Details of review: Not Green on any panels (only 2 families reported to date). On OMIM: Growth retardation, developmental delay, facial dysmorphism. One fetal case reported by Monies et al 2019 (PMID: 31130284) with Dandy-Walker malformation, IUGR, and polyhydramnios. This fits with the phenotype reported in one consanguineous family with 9 affected individuals reported by Boissel 2009 PMID: 19559399. The other reported case is PMID: 26378117 - a homozygous missense variant in FTO was identified in a 21-month old girl who presented with growth retardation, failure to thrive, severely delayed development, Dysmorphic facial features, decreased brain parenchyma, delayed myelination, and a thin corpus callosum. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | ASXL3 |
Rhiannon Mellis edited their review of gene: ASXL3: Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but still limited evidence, support keeping as Amber gene for now. Details of review: Previously reviewed as Amber as 2 fetal cases in literature: one from PMID: 32565546 with short CC and metopic synostosis, one from PMID: 29316359 with distal arthrogryposis and cerebellar vermian hypoplasia. Now there is one more fetal case reported with arthrogryposis - PMID: 33820833; Changed publications to: PMID: 33820833; Changed phenotypes to: Arthrogryposis |
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| Fetal anomalies v1.900 | AGT |
Rhiannon Mellis gene: AGT was added gene: AGT was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGT were set to PMID: 28976722 Phenotypes for gene: AGT were set to Renal dysgenesis Review for gene: AGT was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene pending more evidence. Currently rated Green on the following other PanelApp panel(s): CAKUT and unexplained kidney failure in young people Details of review: Fu et al 2018 (PMID: 28976722) report one fetal case with Right multicystic dysplastic kidney Sources: Literature, Expert Review |
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| Fetal anomalies v1.900 | UNC13D |
Rhiannon Mellis gene: UNC13D was added gene: UNC13D was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: UNC13D was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC13D were set to PMID: 33249554 Phenotypes for gene: UNC13D were set to Pancytopenia; ?Hydrops fetalis Review for gene: UNC13D was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Currently rated Green on the following other PanelApp panel(s): primary immunodeficiency Details of review: One fetal case reported in Diderich et al 2020 (PMID: 33249554) with hydrops, presumed secondary to fetal anaemia. Sources: Literature, Expert Review |
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| Fetal anomalies v1.900 | SERPINA11 |
Rhiannon Mellis gene: SERPINA11 was added gene: SERPINA11 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINA11 were set to PMID: 31742715; 28749478 Phenotypes for gene: SERPINA11 were set to ?Hydrops fetalis Review for gene: SERPINA11 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene to watch for further evidence. Not currently rated Green on any other PanelApp panel(s). Details of review: No OMIM disease association currently. Reported as a novel genotype-phenotype association in Aggarwal 2020 (PMID: 31742715) in a fetus with homozygous nonsense variant. Fetus presented with pericardial effusion and on post-mortem was found to have serous cavity effusions, and generalised blebs of gelatinous material on the visceral surfaces. Histopathology and stains showed derangement of ECM and collagen fibres. Consanguineous couple with one similarly affected previous pregnancy. This gene is also reported in Shamseldin et al 2018 (PMID: 28749478) as a candidate gene in a fetus with hydrops. Sources: Expert Review, Literature |
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| Fetal anomalies v1.900 | LOX |
Rhiannon Mellis gene: LOX was added gene: LOX was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: LOX was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LOX were set to PMID: 31742715 Phenotypes for gene: LOX were set to Aortopathy Review for gene: LOX was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene. Currently rated Green on the following other PanelApp panel(s): familial thoracic aortic aneurysm Details of review: Reported as a novel genotype-phenotype association in Aggarwal et al 2020 (PMID: 31742715), in a fetus with homozygous missense variants. Heterozygous variants in this gene are known to cause thoracic aortic aneurysm. The fetus presented with unexplained IUD and on post-mortem had: Excessive skin folds, emphysematous bullae on lung surface, Facial dysmorphism, distal joint contractures, internal haemorrhages. Histopathology and special stains confirmed degradation of collagen and elastin in the aorta, pleura and skin. If we are going to add to panel suggest putting MOI as biallelic only (and accept that this would be an incidental finding for carrier parents that would lead to them needing monitoring for aortic aneurysm) Sources: Expert Review, Literature |
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| Fetal anomalies v1.880 | SPTA1 |
Rhiannon Mellis gene: SPTA1 was added gene: SPTA1 was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: SPTA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SPTA1 were set to PMID: 34132406; PMID: 31333484 Phenotypes for gene: SPTA1 were set to Hydrops fetalis; Congenital anaemia Review for gene: SPTA1 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH). Outcome of review: Likely that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as an Amber gene, pending further evidence and review of other congenital anaemia genes that may cause hydrops. Currently rated Green on the following other PanelApp panel(s): Congenital anaemias Details of review: The fetal case in Wagner et al 2021 (PMID: 34132406) had hydrops secondary to severe fetal anaemia at 28/40. Chonat et al 2019 (PMID: 31333484) also report 3 further unrelated cases with hydrops/fetal anaemia. Sources: Literature, Expert Review |
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| Fetal anomalies v1.880 | PLOD3 |
Rhiannon Mellis gene: PLOD3 was added gene: PLOD3 was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLOD3 were set to PMID: 18834968; PMID: 33743358 Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency; IUGR; Contractures Review for gene: PLOD3 was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH). Outcome of review: May be fetally relevant, support adding to the Fetal anomalies panel as an Amber gene, pending more evidence. Rated Green on the following other PanelApp panel(s): Cataracts Details of review: Phenotype on OMIM includes potentially fetally detectable phenotypes: IUGR, contractures, cataracts (?whether congenital). Salo et al 2008 (PMID: 18834968) describes a proband with IUGR, flat facial profile, simple, low-set ears, shallow orbits, short, upturned nose, and downturned corners of the mouth. Skeletal features included talipes equinovarus, progressive scoliosis, osteopenia, and several pathologic fractures. A sib had IUGR and was stillborn, with finger contractures (but didn't seem to have molecular testing?). The fetal case in Cao et al 2021 had NT 5.2 mm (12/40), Reduced fetal movement (12/40), FGR (24/40), Enlarged posterior fossa (24/40), Intracranial haemorrhage (24/40), Clenched hands and fixated extended knees (24/40). Sources: Literature, Expert Review |
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| Fetal anomalies v1.880 | NEXN |
Rhiannon Mellis gene: NEXN was added gene: NEXN was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: NEXN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEXN were set to PMID: 32058062; PMID: 33027564 Phenotypes for gene: NEXN were set to Cardiomyopathy Review for gene: NEXN was set to AMBER Added comment: This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH). Outcome of review: Gene usually causes adult-onset AD cardiomyopathy. However, there may be a fetally relevant phenotype with biallelic variants. Support adding to the Fetal anomalies panel as an Amber gene, pending more evidence of fetal phenotype (only 2 reported unrelated cases to date). Currently rated Green on the following other PanelApp panel(s): Cardiomyopathy (dilated) Details of review: The fetal case in Sparks et al (PMID: 33027564) had pericardial effusion, ascites, cardiomegaly, dilation and hypertrophy of cardiac ventricles, hypoplastic and dysplastic aortic valve, diminished systolic function, fetal growth restriction, and was stillborn. 2 NEXN variants found in the fetus (1 mat inherited, 1 de novo) but unable to confirm phase. The fetal case in Rinaldi et al 2021 (PMID: 32058062) had Cardiomegaly, low contractility/outflow, fibroelastosis of right ventricle. The fetus was compound het for NEXN variants and parents were both unaffected het with normal echos. They'd had one previous pregnancy with same phenotype. Sources: Literature, Expert Review |
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| Fetal anomalies v1.836 | DONSON | Arina Puzriakova Tag for-review was removed from gene: DONSON. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.836 | DONSON | Arina Puzriakova commented on gene: DONSON: The rating of this gene has been updated following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.835 | DONSON |
Arina Puzriakova Source Expert Review Green was added to DONSON. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Fetal anomalies v1.818 | PHF6 | Ivone Leong Phenotypes for gene: PHF6 were changed from BOERJESON-FORSSMAN-LEHMANN SYNDROME to Borjeson-Forssman-Lehmann syndrome, OMIM:301900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.749 | POLR1B |
Rhiannon Mellis gene: POLR1B was added gene: POLR1B was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POLR1B were set to PMID: 31649276 Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome 4 Review for gene: POLR1B was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already flagged for upgrade to Green on the following other PanelApp panel(s): Clefting, Skeletal dysplasias Details of review: PMID: 31649276 - Sanchez et al 2020 - using exome sequencing identified 6 patients (5 unrelated families) with Treacher Collins syndrome with heterozygous missense variants in POLR1B. Sources: Expert Review, Literature |
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| Fetal anomalies v1.749 | CSF1R |
Rhiannon Mellis gene: CSF1R was added gene: CSF1R was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSF1R were set to PMID: 30982608 Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) Review for gene: CSF1R was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Details of review: Homozygous variants cause Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Skeletal phenotype is osteopetrosis, dysosteosclerosis, platyspondyly, widened metaphyses. Brain anomalies include ACC and Dandy walker. At least one reported case of prenatal presentation with multiple brain anomalies - PubMed: 30982608 NB Bilallelic LOF variants cause this condition with fetally relevant phenotype but Monoallelic variants with dominant-negative effect cause an adult-onset neurodegenerative disease. Only for fetal reporting in BIALLELIC form Sources: Expert Review |
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| Fetal anomalies v1.749 | LMNB2 |
Rhiannon Mellis gene: LMNB2 was added gene: LMNB2 was added to Fetal anomalies. Sources: Expert Review,Literature Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMNB2 were set to PMID: 33033404 Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending) Details of review: Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic). Sources: Expert Review, Literature |
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| Fetal anomalies v1.749 | LMNB1 |
Rhiannon Mellis gene: LMNB1 was added gene: LMNB1 was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMNB1 were set to PMID: 33033404 Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant Review for gene: LMNB1 was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending) Details of review: Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic). Sources: Literature, Expert Review |
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| Fetal anomalies v1.749 | EIF5A |
Rhiannon Mellis gene: EIF5A was added gene: EIF5A was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EIF5A were set to PMID: 33547280 Phenotypes for gene: EIF5A were set to Faundes-Banka syndrome Review for gene: EIF5A was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Details of review: Faundes et al 2021 (PMID: 33547280) report this as a novel disease gene associated with micrognathia, microcephaly, IUGR and Kabuki-like phenotype. Now on OMIM as of August 2021. 7 unrelated patients in this publication. Sources: Literature, Expert Review |
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| Fetal anomalies v1.749 | PRIM1 |
Rhiannon Mellis gene: PRIM1 was added gene: PRIM1 was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIM1 were set to PMID: 33060134 Phenotypes for gene: PRIM1 were set to Primordial dwarfism Review for gene: PRIM1 was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Details of review: Parry et al 2020 (PMID: 33060134) report this as a novel disease gene - biallelic LOF mutations in 5 patients (from 4 families) with primordial dwarfism phenotype, including prenatal features of IUGR and extreme microcephaly with simplified gyri. Sources: Literature, Expert Review |
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| Fetal anomalies v1.749 | MN1 |
Rhiannon Mellis commented on gene: MN1: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Agreed that the phenotype is fetally relevant (structural brain abnormalities e.g. polymicrogyria, cerebellar hypoplasia, craniofacial features etc.) support adding to the Fetal anomalies panel as a Green gene. |
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| Fetal anomalies v1.749 | GREB1L |
Rhiannon Mellis commented on gene: GREB1L: This gene and phenotype were re-reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene as per previous reviews (unclear on reason for change from Green to Amber previously) |
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| Fetal anomalies v1.749 | FLNC |
Rhiannon Mellis changed review comment from: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Distal myopathies Details of review: In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth. Sources: Literature, Expert Review; to: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Distal myopathies; Neuromuscular disorders; flagged for upgrade to Green on Arthrogryposis panel Details of review: In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth. Sources: Literature, Expert Review |
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| Fetal anomalies v1.749 | FLNC |
Rhiannon Mellis gene: FLNC was added gene: FLNC was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FLNC were set to PMID: 33060286; 29858533 Phenotypes for gene: FLNC were set to Arthrogryposis Review for gene: FLNC was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Distal myopathies Details of review: In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth. Sources: Literature, Expert Review |
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| Fetal anomalies v1.749 | CDK8 |
Rhiannon Mellis gene: CDK8 was added gene: CDK8 was added to Fetal anomalies. Sources: Literature,Expert Review Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDK8 were set to PMID: 31742715; 30905399 Phenotypes for gene: CDK8 were set to Syndromic developmental disorder with hypotonia and behavioural abnormalities Review for gene: CDK8 was set to GREEN Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene. Already rated Green on the following other PanelApp panel(s): Intellectual disability; Severe paediatric disorders Details of review: Aggarwal et al 2020 report a heterozygous nonsense variant in a fetus with ventriculomegaly and Ebstein anomaly resulting in IUFD. Post-mortem found additionally congenital diaphragmatic hernia, common atrium and facial dysmorphism. This nonsense variant is at the same position as a hotspot for missense variants reported in a paediatric cohort (Calpena et al 2019, PMID: 30905399) with overlapping but milder phenotype: half of the 12 children in that cohort had cardiac defects, most had dysmorphic features - hence Aggarwal et al propose that this is a more severe (prenatal) presentation of the same multiple malformation syndrome, caused here by a nonsense rather than missense mutation. Sources: Literature, Expert Review |
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| Fetal anomalies v1.736 | AAAS | Zornitza Stark reviewed gene: AAAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-addisonianism-alacrimia syndrome, MIM#231550; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.727 | BMPR1B |
Arina Puzriakova changed review comment from: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.; to: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel. ----- Confirmed with clinical team that this is the appropriate MOI for this panel. |
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| Fetal anomalies v1.720 | WLS |
Zornitza Stark gene: WLS was added gene: WLS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WLS were set to 34587386 Phenotypes for gene: WLS were set to structural congenital anomalies Review for gene: WLS was set to GREEN Added comment: - Homozygous variants in 10 affected persons from 5 unrelated families. - Affected individuals had multiorgan defects, including microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature |
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| Fetal anomalies v1.720 | WNT9B |
Zornitza Stark gene: WNT9B was added gene: WNT9B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WNT9B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WNT9B were set to 34145744 Phenotypes for gene: WNT9B were set to Renal agenesis/hypoplasia/dysplasia Review for gene: WNT9B was set to AMBER Added comment: WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. WNT9B−/− mice have renal agenesis/hypoplasia and reproductive tract abnormalities. Lemire et al. (2021) report 4 individuals from 2 unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 had bilateral renal cystic dysplasia and chronic kidney disease, with 2 deceased siblings with bilateral renal hypoplasia/agenesis. The 3 affected family members were homozygous for a Gly317Arg missense variant in WNT9B. Proband from Family 2 had renal hypoplasia/dysplasia, chronic kidney disease, and was homozygous for a Pro5Alafs*52 nonsense variant in WNT9B. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. I wasn't sure which panel this is more pertinent to: we have added this gene to our CAKUT panel. Sources: Literature |
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| Fetal anomalies v1.696 | BMPR1B | Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.595 | SMS | Arina Puzriakova Phenotypes for gene: SMS were changed from SNYDER-ROBINSON SYNDROME to Mental retardation, X-linked, Snyder-Robinson type, OMIM:309583; Syndromic X-linked intellectual disability Snyder type, MONDO:0010664 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.385 | EED | Arina Puzriakova Phenotypes for gene: EED were changed from Weaver-like overgrowth syndrome to Cohen-Gibson syndrome, OMIM:617561; Cohen-Gibson syndrome, MONDO:0060510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.371 | DONSON | Arina Puzriakova Classified gene: DONSON as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.371 | DONSON | Arina Puzriakova Gene: donson has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.370 | DONSON | Arina Puzriakova Tag for-review tag was added to gene: DONSON. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.215 | DONSON |
Rhiannon Mellis gene: DONSON was added gene: DONSON was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: DONSON was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DONSON were set to Microcephaly-micromelia syndrome, 251230; Microcephaly, short stature, and limb abnormalities, 617604 Review for gene: DONSON was set to GREEN Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene. Green on related panel(s): Severe microcephaly Sources: Expert list |
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| Fetal anomalies v1.215 | EED | Rhiannon Mellis reviewed gene: EED: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cohen-Gibson syndrome, 617561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.187 | SMS | Rhiannon Mellis reviewed gene: SMS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SNYDER-ROBINSON SYNDROME; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.185 | TNNT3 |
Rhiannon Mellis gene: TNNT3 was added gene: TNNT3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TNNT3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TNNT3 were set to 32779773 Phenotypes for gene: TNNT3 were set to Arthrogryposis, distal, type 2B2 Mode of pathogenicity for gene: TNNT3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TNNT3 was set to GREEN Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene. Additional comment: Clearly documented phenotype of distal arthrogryposis. Also, recent paper in Prenatal Diagnosis reporting a het pathogenic variant in TNNT3 in a fetus with FADS; that variant has previously only been described in a family with much milder distal arthrogryposis phenotype. PMID: 32779773 (copied from OMIM): In in vitro studies, Robinson et al. (2007) demonstrated that the TNNI2 R174Q (191043.0001) and R156X (191043.0002) mutations and the TNNT3 mutation R63H (600692.0001) resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. In patients, Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA2B. Sources: Literature |
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| Fetal anomalies v1.122 | AAAS | Arina Puzriakova Phenotypes for gene: AAAS were changed from ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.4 | CEP55 | Rebecca Foulger commented on gene: CEP55: PMID:28295209. Bondeson et al report a Swedish couple with 2 affected male fetuses homozygous for CEP55 p.Arg86*. Although the phenotype differed between fetuses, both exhibited kidney phenotypes (including renal dysplaisa). Segregation analysis supported the gene:disease association, and Haplotype analysis suggested a founder effect. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.342 | ANAPC1 | Rebecca Foulger commented on gene: ANAPC1: Added ANAPC1 to the Fetal anomalies panel and rated Green on approval from Anna de Burca and Richard Scott (Genomics England Clinical team). Note yet associated with a disorder in OMIM but evidence comes from PMID:31303264 (Ajeawung et al., 2019) where they report 10 individuals (7 families including 3 families of Amish ancestry) with Rothmund-Thomson Syndrome Type 1 and biallelic variants in ANAPC1. Phenotype includes skeletal abnormalities and short stature. All individuals carried an intronic splicing variant (NM_022662.3:c.2705−198C>T): in 3 Amish families plus individual 4, this intronic variant was found in a homozygous state. In the remaining families, the intronic variant was found in trans with one of three other LOF variants. Therefore sufficient cases to support a Green rating plus fetally-relevant phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.342 | ANAPC1 |
Rebecca Foulger gene: ANAPC1 was added gene: ANAPC1 was added to Fetal anomalies. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ANAPC1 were set to 31303264 Phenotypes for gene: ANAPC1 were set to Rothmund-Thomson Syndrome Type 1 |
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| Fetal anomalies v0.319 | TERT | Rebecca Foulger commented on gene: TERT: This gene was reviewed by Anna de Burca (Genomics England clinical team) and Melita Irving. Melita couldn't see any reason for inclusion on this panel, so have demoted rating from Green to Red. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.230 | COG4 | Rebecca Foulger Phenotypes for gene: COG4 were changed from COG4-CDG to COG4-CDG; Saul-Wilson syndrome, 618150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.222 | TBX22 | Rebecca Foulger commented on gene: TBX22: 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: Phenotype is fetally-relevant but limited evidence: include on the Fetal anomalies panel as an Amber gene. Additional notes from clinical review: Amber for Abruzzo-Erickson syndrome (MIM: 302905) due to the limited evidence. The clefting phenotype has sufficient cases but is isolated cleft palate so unlikely to be seen prenatally (confirmed by Lyn Chitty, 26th April 2019). Therefore demote from Green to Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.222 | RAB39B | Rebecca Foulger edited their review of gene: RAB39B: 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Don't include on panel because of incidental finding issue with Parkinsons. Two papers in which macrocephaly is mentioned: PMID:20159109 dont specify age of onset, and in PMID:29152164 macrocephaly was detected in early childhood. Action taken: Demoted RAB39B gene rating from Green to Red.; Changed publications: 20159109, 29152164 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.222 | LDB3 | Rebecca Foulger edited their review of gene: LDB3: 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. Originally rated Amber based on DDG2P Disease confidence of 'both DD and IF' for at least one disorder. Outcome of review: Phenotype is not fetally-relevant. Additional notes from clinical review: Concluded that myopathy is unlikely to produce Fetal hydrops in this instance. Although PMID:17394203 report a proband with variants in both TAZ and LDB3, where the mother had five miscarriages (plus two sons who died in infancy and 2 surviving children) the LDB3 variant is paternally-inherited, and therefore the maternally-inherited TAZ allele is more relevant. Action taken: Demoted LDB3 gene rating from Amber to Red.; Changed rating: RED; Changed publications: 17394203 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.199 | COG4 | Rebecca Foulger commented on gene: COG4: The evidence for Saul-Wilson syndrome (MIM:618150) comes from one 2018 paper (PMID:30290151): Ferreira et al. (PMID:30290151, 2018) identified 2 different de novo heterozygous vaiants in the COG4 gene in 14 individuals, c.1546G-A and c.1546G-C both of which give rise to an identical missense mutation (G516R). Functional analysis shows that a stable protein is produced and, despite Golgi collapse, glycosylation is relatively normal. Given the DD-G2P Disease confidence rating is 'probable' (March 2019), only a missense variant has been reported, and functional evidence doesn't yet show the effect of the protein alteration, I have kept the MOI for COG4 on the Fetal anomalies panel as biallelic (for the confirmed glycosylation disorder) and not included the monoallelic Saul-Wilson syndrome on the panel at this stage. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.199 | COG4 |
Rebecca Foulger commented on gene: COG4: COG4 is Green on the fetal panel based on 'confirmed' rating for a biallelic glycosylation disorder (COG4-CDG) and expert clinical review. A probable gene:disease disorder also exists in DD-Gene2Phenotype: Saul-Wilson syndrome. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: all missense/in frame, gain of function. DDG2P mode of inheritance: monoallelic. Saul-Wilson syndrome is a rare form of primordial dwarfism with severe pre-and postnatal growth retardation, and characteristic facial and radiographic features (PMID:30290151). Fetal relevance was confirmed by Anna de Burca but the evidence requires further investigation before the MOI is expanded to include monoallelic variants. |
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| Fetal anomalies v0.166 | HYDIN | Rebecca Foulger edited their review of gene: HYDIN: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but can exclude from causing situs defects. According to PMID:30166424 (Best et al., 2019) plus email correspondance from Hannah Mitchison (UCL), there is fairly firm evidence that mutations in HYDIN cause PCD without laterality defects/Situs Invertis. Variant flagged as Potentially Clinically Useful from PAGE study. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.166 | GAS8 | Rebecca Foulger edited their review of gene: GAS8: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but highly unlikely to cause situs defects. According to PMID:30166424 (Best et al., 2019), GAS8 has not previously been associated with Situs defects in the literature. Plus email correspondance from Hannah Mitchison (UCL) that mutations in GAS8 are not associated with laterality defects, including in mice. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED; Changed publications: 30166424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.166 | CCDC65 | Rebecca Foulger edited their review of gene: CCDC65: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but highly unlikely to cause situs defects. According to PMID:30166424 (Best et al., 2019), CCDC65 (DRC2) has not previously been associated with Situs defects in the literature. Plus email correspondance from Hannah Mitchison (UCL) that mutations in CCDC65/DRC2 are not associated with laterality defects, including in mice. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED; Changed publications: 30166424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.166 | CCNO | Rebecca Foulger edited their review of gene: CCNO: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but can exclude from causing situs defects. According to PMID:30166424 (Best et al., 2019) plus email correspondance from Hannah Mitchison (UCL), there is fairly firm evidence that mutations in CCNO cause PCD without laterality defects/Situs Invertis. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED; Changed publications: 30166424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.166 | RSPH3 | Rebecca Foulger edited their review of gene: RSPH3: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but can exclude from causing situs defects. According to PMID:30166424 (Best et al., 2019), RSPH3 has not previously been associated with Situs defects in the literature. Plus email correspondance from Hannah Mitchison (UCL) that there is fairly firm evidence that mutations in RSPH3 cause PCD without laterality defects/Situs Invertis. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED; Changed publications: 30166424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.166 | RSPH1 | Rebecca Foulger edited their review of gene: RSPH1: Added comment: This gene and phenotype were discussed during review of borderline cases in 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: Phenotype is not fetally-relevant. Additional notes from clinical review: Primary Ciliary Dyskinesia (PCD) but can exclude from causing situs defects. According to PMID:30166424 (Best et al., 2019) plus email correspondance from Hannah Mitchison (UCL), there is fairly firm evidence that mutations in RSPH1 cause PCD without laterality defects/Situs Invertis. Action taken: Demoted gene rating from Green to Red.; Changed rating: RED; Changed publications: 30166424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.161 | SON | Rebecca Foulger edited their review of gene: SON: 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 v0.158 | TBX22 | Rebecca Foulger Added comment: Comment on phenotypes: Added '?Abruzzo-Erickson syndrome, 302905' based on OMIM and clinical review that Abruzzo-Erickson syndrome phenotype is clinically relevant. Kept the question-mark because evidence for this gene:disease association is limited (1 family reported in Pauws et al., 2013 (PMID:22784330). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.158 | TBX22 | Rebecca Foulger Phenotypes for gene: TBX22 were changed from CLEFT PALATE, X-LINKED to CLEFT PALATE, X-LINKED; ?Abruzzo-Erickson syndrome, 302905 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.110 | LMNA | Rebecca Foulger commented on gene: LMNA: Changed rating to Amber to reflect DDG2P Disease confidence of 'DD and IF' for CARDIOMYOPATHY DILATED TYPE 1A; CARDIOMYOPATHY DILATED WITH HYPERGONADOTROPIC HYPOGONADISM; FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2; CHARCOT-MARIE-TOOTH DISEASE TYPE 2B1; HUTCHINSON-GILFORD PROGERIA SYNDROME; MUSCULAR DYSTROPHY CONGENITAL LMNA-RELATED; MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY; EMERY-DREIFUSS MUSCULAR DYSTROPHY TYPE 2; LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 1B; LETHAL TIGHT SKIN CONTRACTURE SYNDROME; HEART-HAND SYNDROME SLOVENIAN TYPE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.110 | ATP1A3 | Rebecca Foulger commented on gene: ATP1A3: Changed rating to Amber to reflect DDG2P Disease confidence of 'DD and IF' for RAPID-ONSET DYSTONIA-PARKINSONISM;ALTERNATING HEMIPLEGIA OF CHILDHOOD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.110 | ATP13A2 | Rebecca Foulger commented on gene: ATP13A2: Changed rating to Amber to reflect DDG2P Disease confidence of 'DD and IF' for PARKINSON DISEASE 9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.70 | KYNU | Rebecca Foulger commented on gene: KYNU: Communication from Deirdre Cilliers, Oxford University Hospitals (via email, February 2019) to support Green rating: Only 2 cases – amber (although for me it would be a yes for the reasons below). Ultrasound findings, although variable in the condition, may be identified, e.g. short long bones, hypoplastic Lt heart, VU reflux, talipes, dysplastic kidney and absent kidney. Combinations of these features would make interpretation of a variant possible. Also, the reported variants so far were truncating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.70 | HAAO | Rebecca Foulger commented on gene: HAAO: Communication from Deirdre Cilliers, Oxford University Hospitals (via email, February 2019) to support Green rating: Only 2 cases – amber (although for me it would be a yes for the reasons below). Ultrasound findings, although variable in the condition, may be identified, e.g. short long bones, hypoplastic Lt heart, VU reflux, talipes, dysplastic kidney and absent kidney. Combinations of these features would make interpretation of a variant possible. Also, the reported variants so far were truncating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.68 | CHRNA1 | Rebecca Foulger commented on gene: CHRNA1: Communication from Deirdre Cilliers, Oxford University Hospitals (via email, February 2019) to support Green rating: Yes [CHRNA1 should be on the Fetal anomalies panel]. The phenotype would be clear on ultrasound scan and variant interpretation would be easier because of this. In general, arthrogryposis can be variable, but the extent would be relatively obvious on scan and would be the reason for the test request. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.43 | ACTB | Rebecca Foulger Added comment: Comment on mode of pathogenicity: Anna notes that there is good evidence for GOF variants causing Baraitser-Winter syndrome but there is also a paper from DDD (PMID:29220674) reporting LOF variants associated predominantly with developmental delay but in some cases structural anomalies including congenital heart defects and/or CAKUT- this may not be a severe enough prenatal phenotype for inclusion in a fetal panel but overall Anna notes that it is probably reasonable to report any variants in this gene, whether GOF or LOF. Therefore no exception to LOF was added to the MOP section. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.31 | TPM2 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Rated Green on relevant V1 panel(s) PLUS phenotype (ARTHROGRYPOSIS, DISTAL, TYPE 1 ) appropriate for fetal panel, as noted by Helen Brittain and Anna de Burca (Genomics England Clinical team). 2 unrelated cases listed in OMIM for ARTHROGRYPOSIS disorders- TPM2 is Green on the Arthrogryposis panel based on these cases plus two Green reviews. Therefore reasonable to promote to Green on this fetal panel based on ARTHROGRYPOSIS phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | SON | Rebecca Foulger reviewed gene: SON: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | OFD1 | Rebecca Foulger commented on gene: OFD1: DDG2P rating in original PAGE list: Confirmed for ORAL-FACIAL-DIGITAL SYNDROME TYPE 1, Confirmed for SIMPSON-GOLABI-BEHMEL SYNDROME TYPE 2 and Confirmed for JOUBERT SYNDROME TYPE 10. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | HDAC8 | Rebecca Foulger commented on gene: HDAC8: DDG2P rating in original PAGE list: Confirmed for CORNELIA DE LANGE-LIKE SYNDROME and Confirmed for WILSON-TURNER SYNDROME. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | GDF5 | Rebecca Foulger commented on gene: GDF5: DDG2P rating in original PAGE list: Confirmed for ACROMESOMELIC CHONDRODYSPLASIA GREBE TYPE, Confirmed for BRACHYDACTYLY TYPE C, Confirmed for DU PAN SYNDROME, Confirmed for MULTIPLE SYNOSTOSES SYNDROME TYPE 2, Confirmed for BRACHYDACTYLY TYPE A1, Confirmed for SYMPHALANGISM PROXIMAL SYNDROME, Confirmed for ACROMESOMELIC CHONDRODYSPLASIA HUNTER-THOMPSON TYPE and Confirmed for BRACHYDACTYLY TYPE A2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | FGFR2 | Rebecca Foulger commented on gene: FGFR2: DDG2P rating in original PAGE list: Confirmed for CROUZON SYNDROME, Confirmed for APERT SYNDROME, Confirmed for LACRIMO-AURICULO-DENTO-DIGITAL SYNDROME, Confirmed for FAMILIAL SCAPHOCEPHALY SYNDROME, Confirmed for JACKSON-WEISS SYNDROME, Confirmmed for ANTLEY-BIXLER SYNDROME, Confirmed for BEARE-STEVENSON CUTIS GYRATA SYNDROME, and Confirmed for ACROCEPHALOSYNDACTYLY TYPE V. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | ANKH | Rebecca Foulger commented on gene: ANKH: DDG2P rating in original PAGE list: Confirmed for CRANIOMETAPHYSEAL DYSPLASIA JACKSON TYPE and Confirmed for CHONDROCALCINOSIS 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.7 | LMNA | Rebecca Foulger commented on gene: LMNA: Rating in original PAGE file: 'both DD and IF' for CARDIOMYOPATHY DILATED TYPE 1A, CARDIOMYOPATHY DILATED WITH HYPERGONADOTROPIC HYPOGONADISM, FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2, CHARCOT-MARIE-TOOTH DISEASE TYPE 2B1, HUTCHINSON-GILFORD PROGERIA SYNDROME, MUSCULAR DYSTROPHY CONGENITAL LMNA-RELATED, MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, EMERY-DREIFUSS MUSCULAR DYSTROPHY TYPE 2, LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 1B, LETHAL TIGHT SKIN CONTRACTURE SYNDROME and HEART-HAND SYNDROME SLOVENIAN TYPE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.7 | ATP1A3 | Rebecca Foulger commented on gene: ATP1A3: Rating in original PAGE file: 'both DD and IF' for both RAPID-ONSET DYSTONIA-PARKINSONISM and ALTERNATING HEMIPLEGIA OF CHILDHOOD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.6 | ATP1A3 | Rebecca Foulger commented on gene: ATP1A3: Rating in original PAGE file: 'Both DD and IF' for both RAPID-ONSET DYSTONIA-PARKINSONISM and ALTERNATING HEMIPLEGIA OF CHILDHOOD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | ZEB2 |
Rebecca Foulger gene: ZEB2 was added gene: ZEB2 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: ZEB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ZEB2 were set to MOWAT-WILSON SYNDROME |
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| Fetal anomalies v0.1 | UBR1 |
Rebecca Foulger gene: UBR1 was added gene: UBR1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: UBR1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: UBR1 were set to JOHANSON-BLIZZARD SYNDROME |
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| Fetal anomalies v0.1 | SON |
Rebecca Foulger gene: SON was added gene: SON was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: SON was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SON were set to Intellectual Disability, Congenital Malformations, and Failure to Thrive |
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| Fetal anomalies v0.1 | SMS |
Rebecca Foulger gene: SMS was added gene: SMS was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber Mode of inheritance for gene: SMS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: SMS were set to SNYDER-ROBINSON SYNDROME |
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| Fetal anomalies v0.1 | SLC9A6 |
Rebecca Foulger gene: SLC9A6 was added gene: SLC9A6 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: SLC9A6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: SLC9A6 were set to MENTAL RETARDATION SYNDROMIC X-LINKED CHRISTIANSON TYPE |
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| Fetal anomalies v0.1 | SLC6A3 |
Rebecca Foulger gene: SLC6A3 was added gene: SLC6A3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: SLC6A3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC6A3 were set to PARKINSONISM-DYSTONIA, INFANTILE |
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| Fetal anomalies v0.1 | RECQL4 | Rebecca Foulger Added phenotypes ROTHMUND-THOMSON SYNDROME for gene: RECQL4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | RAB39B |
Rebecca Foulger gene: RAB39B was added gene: RAB39B was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: RAB39B was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: RAB39B were set to MENTAL RETARDATION X-LINKED TYPE 72 (MRX72) +/- PARKINSONS |
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| Fetal anomalies v0.1 | PHF6 |
Rebecca Foulger gene: PHF6 was added gene: PHF6 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: PHF6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: PHF6 were set to BOERJESON-FORSSMAN-LEHMANN SYNDROME |
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| Fetal anomalies v0.1 | OFD1 | Rebecca Foulger Added phenotypes SIMPSON-GOLABI-BEHMEL SYNDROME TYPE 2 for gene: OFD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | NF1 | Rebecca Foulger Added phenotypes WATSON SYNDROME for gene: NF1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | LMNA | Rebecca Foulger Added phenotypes HUTCHINSON-GILFORD PROGERIA SYNDROME for gene: LMNA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | INSR | Rebecca Foulger Added phenotypes Rabson-Mendenhall syndrome 262190 for gene: INSR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | HDAC8 | Rebecca Foulger Added phenotypes WILSON-TURNER SYNDROME for gene: HDAC8 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | GPC3 |
Rebecca Foulger gene: GPC3 was added gene: GPC3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: GPC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: GPC3 were set to SIMPSON-GOLABI-BEHMEL SYNDROME, TYPE 1 |
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| Fetal anomalies v0.1 | GDF5 | Rebecca Foulger Added phenotypes ACROMESOMELIC CHONDRODYSPLASIA HUNTER-THOMPSON TYPE for gene: GDF5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | FGFR2 | Rebecca Foulger Added phenotypes BEARE-STEVENSON CUTIS GYRATA SYNDROME for gene: FGFR2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | FGFR2 | Rebecca Foulger Added phenotypes JACKSON-WEISS SYNDROME for gene: FGFR2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | EIF2AK3 |
Rebecca Foulger gene: EIF2AK3 was added gene: EIF2AK3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: EIF2AK3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: EIF2AK3 were set to WOLCOTT-RALLISON SYNDROME |
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| Fetal anomalies v0.1 | ATP1A3 |
Rebecca Foulger gene: ATP1A3 was added gene: ATP1A3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ATP1A3 were set to RAPID-ONSET DYSTONIA-PARKINSONISM |
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| Fetal anomalies v0.1 | ATP13A2 |
Rebecca Foulger gene: ATP13A2 was added gene: ATP13A2 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: ATP13A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP13A2 were set to PARKINSON DISEASE 9 |
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| Fetal anomalies v0.1 | ANKH |
Rebecca Foulger gene: ANKH was added gene: ANKH was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ANKH were set to CRANIOMETAPHYSEAL DYSPLASIA JACKSON TYPE |
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| Fetal anomalies v0.1 | ALDH3A2 |
Rebecca Foulger gene: ALDH3A2 was added gene: ALDH3A2 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ALDH3A2 were set to SJOEGREN-LARSSON SYNDROME |
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| Fetal anomalies v0.1 | AAAS |
Rebecca Foulger gene: AAAS was added gene: AAAS was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: AAAS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AAAS were set to ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME |
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