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Intellectual disability v3.1519 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Intellectual disability v3.1515 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Intellectual disability v3.1511 SFXN4 Arina Puzriakova Tag for-review was removed from gene: SFXN4.
Intellectual disability v3.1510 SFXN4 Sarah Leigh commented on gene: SFXN4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1509 SFXN4 Arina Puzriakova Source Expert Review Green was added to SFXN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1453 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia 229300; Friedreich ataxia with retained reflexes 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Intellectual disability v3.1074 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Intellectual disability v3.966 FXN_GAA Arina Puzriakova Tag curated_removed tag was added to STR: FXN_GAA.
Intellectual disability v3.421 FXN Arina Puzriakova Source Expert Review Red was added to FXN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.251 FXN Arina Puzriakova commented on gene: FXN
Intellectual disability v3.230 SFXN4 Sarah Leigh Classified gene: SFXN4 as Amber List (moderate evidence)
Intellectual disability v3.230 SFXN4 Sarah Leigh Gene: sfxn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.229 SFXN4 Sarah Leigh Tag for-review tag was added to gene: SFXN4.
Intellectual disability v3.229 SFXN4 Sarah Leigh Phenotypes for gene: SFXN4 were changed from Combined oxidative phosphorylation deficiency 18, MIM#615578 to Combined oxidative phosphorylation deficiency 18 615578
Intellectual disability v3.3 SFXN4 Zornitza Stark gene: SFXN4 was added
gene: SFXN4 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: SFXN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SFXN4 were set to 31059822; 24119684
Phenotypes for gene: SFXN4 were set to Combined oxidative phosphorylation deficiency 18, MIM#615578
Review for gene: SFXN4 was set to GREEN
gene: SFXN4 was marked as current diagnostic
Added comment: Three unrelated families reported, mild ID as well as other neurological features are part of the phenotype.
Sources: Expert list
Intellectual disability v3.0 FXN Zornitza Stark reviewed gene: FXN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen; to: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
gene: PMPCB was marked as current diagnostic
Added comment: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.573 FXN_GAA Louise Daugherty Classified STR: FXN_GAA as No list
Intellectual disability v2.573 FXN_GAA Louise Daugherty Str: fxn_gaa has been removed from the panel.
Intellectual disability v2.572 FXN_GAA Louise Daugherty Normal Number of Repeats for FXN_GAA was changed from 33 to 44.
Intellectual disability FXN Ellen McDonagh Added STR to panel
Intellectual disability FXN BRIDGE consortium edited their review of FXN
Intellectual disability FXN BRIDGE consortium edited their review of FXN
Intellectual disability FXN Louise Daugherty classified FXN as amber
Intellectual disability FXN Louise Daugherty commented on FXN
Intellectual disability FXN BRIDGE consortium reviewed FXN