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Intellectual disability v8.108 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Intellectual disability v8.107 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Intellectual disability v8.107 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.106 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Intellectual disability v3.1514 PNPT1 Arina Puzriakova Tag for-review was removed from gene: PNPT1.
Intellectual disability v3.1510 PNPT1 Sarah Leigh commented on gene: PNPT1
Intellectual disability v3.1509 PNPT1 Arina Puzriakova Source Expert Review Green was added to PNPT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1493 XPNPEP3 Sarah Leigh reviewed gene: XPNPEP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1493 XPNPEP3 Sarah Leigh Publications for gene: XPNPEP3 were set to 20179356
Intellectual disability v3.1492 XPNPEP3 Sarah Leigh Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, 613159 to Nephronophthisis-like nephropathy 1 OMIM:613159; nephronophthisis-like nephropathy 1 MONDO:0013163
Intellectual disability v3.792 PNPLA6 Catherine Snow Source: Expert Review Amber was removed from gene: PNPLA6
Intellectual disability v3.609 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Intellectual disability v3.608 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.246 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Intellectual disability v3.1 PNPT1 Zornitza Stark reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 13, MIM#614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1131 PNPT1 Rebecca Foulger commented on gene: PNPT1
Intellectual disability v2.1131 PNPT1 Rebecca Foulger Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934 to Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability
Intellectual disability v2.1131 PNPT1 Rebecca Foulger Publications for gene: PNPT1 were set to
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis changed review comment from: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairement due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.; to: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.
Intellectual disability v2.1129 PNPT1 Konstantinos Varvagiannis reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31752325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.468 XPNPEP3 Louise Daugherty Source Victorian Clinical Genetics Services was added to XPNPEP3.
Intellectual disability v2.468 PNPLA6 Louise Daugherty Source Victorian Clinical Genetics Services was added to PNPLA6.
Intellectual disability PNPO Louise Daugherty commented on PNPO
Intellectual disability PNPLA6 Louise Daugherty commented on PNPLA6
Intellectual disability PNPT1 BRIDGE consortium edited their review of PNPT1
Intellectual disability PNPO BRIDGE consortium edited their review of PNPO
Intellectual disability PNPLA6 BRIDGE consortium edited their review of PNPLA6
Intellectual disability PNPT1 BRIDGE consortium edited their review of PNPT1
Intellectual disability PNPO BRIDGE consortium edited their review of PNPO
Intellectual disability PNPLA6 BRIDGE consortium edited their review of PNPLA6
Intellectual disability PNPO Louise Daugherty classified PNPO as amber
Intellectual disability PNPO Louise Daugherty commented on PNPO
Intellectual disability PNPT1 Louise Daugherty classified PNPT1 as amber
Intellectual disability PNPT1 Louise Daugherty commented on PNPT1
Intellectual disability PNPLA6 Louise Daugherty classified PNPLA6 as amber
Intellectual disability PNPLA6 Louise Daugherty commented on PNPLA6
Intellectual disability PNPT1 BRIDGE consortium reviewed PNPT1
Intellectual disability PNPO BRIDGE consortium reviewed PNPO
Intellectual disability PNPLA6 BRIDGE consortium reviewed PNPLA6