Fetal anomalies
Gene: POLG
This gene and phenotype were reviewed during a meeting on 2nd March 2023 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Lyn Chitty, (North Thames GLH), and Stephanie Allen, Denise Williams, Anna de Burca and Megan Horton-Bell (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Amber gene.Created: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.
Panel Version: 3.8
On 32 panels, inc. Fetal anomalies, DDG2P, IEM, severe paediatric disorders, neonatal cholestasis, arthrogryposis. Associated with Mitochondrial DNA depletion syndrome 4A (Alpers type) (AR) and 4B (MNGIE type) (AR); Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE) (AR); Progressive external ophthalmoplegia, autosomal dominant 1 and autosomal recessive 1. Later onset disorders and variable phenotype between patients. Wouldn't count scoliosis as congenital unless hemivertebrae. Notes on R21: 'DDG2P rating in original PAGE list: Confirmed for MITOCHONDRIAL DNA DEPLETION SYNDROME 4A. Outcome of review: Presentation of mitochondrial disorders can be variable, and most aren't obvious at birth. Therefore exclude unless the gene has been directly associated with a fetal presentation. Inbar-Feigenberg et al., 2018 PMID 29574624: 1st pregnancy: complicated with prenatal ultrasound findings of symmetric intrauterine growth restriction (IUGR), polyhydramnios and abnormal repetitive fetal movements suggestive of seizures, at 34 weeks gestation. At birth: facial dysmorphism (microcephaly, sloped forehead, hypotelorism, and micrognathia), hand and feet anomalies, skeletal anomalies (scoliosis, small skull, bell-shaped thorax). Head CT at 1do: small cerebellum, ventriculomegaly with supratentorial brain volume loss and internal capsule and white matter calcifications. Brain MRI at 2do: confirmed lateral ventriculomegaly with loss of the caudate nuclei giving rise to enlarged frontal horns. Basal ganglia abnormalities. Cerebella vermis was small and had irregular lobulation. The hemispheres were also small and lacking both foliation and myelination. The medulla was small, particularly ventrally in the expected region of the olives. Died 5do. 2nd pregnancy: slow cerebellum growth, clubbed feet and right clenched hand. TOP at 22wks. Autopsy: CNS abnormalities similar to previous pregnancy. Darin et al., 2021 PMID 33579567: Pregnancy complicated by IUGR. Frydman et al., 1993 PMID 8368248: The condition seen in family 1 is potentially recognizable prenatally by ultrasonographic demonstration of abnormal fetal mobility, micrognathia, joint constructures, and microcephaly. Conclusion: link to prenatal phenotypes (IUGR, neurological anomalies, polyhydramnios, fetal akinesia syndrome). RelevantCreated: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.
Panel Version: 3.8
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662
Publications
This gene was reviewed by Anna de Burca (Genomics England Clinical Team), and at a Fetal Working Group call on July 19th 2019 by Lyn Chitty, Anna de Burca, Richard Scott, Rhiannon Mellis, Rebecca Foulger and Ellen McDonagh. Outcome of review: Presentation of mitochondrial disorders can be variable, and most aren't obvious at birth. Therefore exclude unless the gene has been directly associated with a fetal presentation.Created: 25 Jul 2019, 8:04 a.m. | Last Modified: 25 Jul 2019, 8:04 a.m.
Panel Version: 0.311
DDG2P rating in original PAGE list: Confirmed for MITOCHONDRIAL DNA DEPLETION SYNDROME 4ACreated: 11 Dec 2018, 9:05 a.m.
In the original PAGE file, MOP listed as All missense/in frame.Created: 8 Nov 2018, 4:45 p.m.
Mode of pathogenicity
Other - please provide details in the comments
Phenotypes for gene: POLG were changed from Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; MITOCHONDRIAL DNA DEPLETION SYNDROME 4A; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662 to Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662
Publications for gene: POLG were set to
Source Expert Review Amber was added to POLG. Added phenotypes Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662 for gene: POLG Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Source Expert Review Red was added to POLG. Rating Changed from Green List (high evidence) to Red List (low evidence)
gene: POLG was added gene: POLG was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: POLG was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POLG were set to MITOCHONDRIAL DNA DEPLETION SYNDROME 4A