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Skeletal dysplasia v3.5 DVL2 Eleanor Williams Tag Q2_21_NHS_review was removed from gene: DVL2.
Tag Q2_22_rating was removed from gene: DVL2.
Tag Q2_22_expert_review was removed from gene: DVL2.
Skeletal dysplasia v3.5 DVL2 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 MYH3 Eleanor Williams Tag Q3_22_rating was removed from gene: MYH3.
Skeletal dysplasia v3.5 MYH3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 PRKAR1A Eleanor Williams Tag Q2_22_MOI was removed from gene: PRKAR1A.
Skeletal dysplasia v3.5 PRKAR1A Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, NOT imprintedfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 ANO5 Eleanor Williams Tag Q1_22_MOI was removed from gene: ANO5.
Skeletal dysplasia v3.5 ANO5 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, NOT imprintedfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 COL1A2 Eleanor Williams Tag Q2_22_MOI was removed from gene: COL1A2.
Tag Q2_22_expert_review was removed from gene: COL1A2.
Skeletal dysplasia v3.5 COL1A2 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, imprinted status unknownfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.
Nephrocalcinosis or nephrolithiasis v3.4 RRAGD Sarah Leigh Tag Q3_22_rating was removed from gene: RRAGD.
Tag Q3_22_MOI was removed from gene: RRAGD.
Tag Q3_22_NHS_review was removed from gene: RRAGD.
Skeletal dysplasia v3.5 LTBP3 Eleanor Williams Tag Q1_22_NHS_review was removed from gene: LTBP3.
Tag Q1_22_MOI was removed from gene: LTBP3.
Skeletal dysplasia v3.5 LTBP3 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Nephrocalcinosis or nephrolithiasis v3.4 ATP6V0A4 Sarah Leigh Tag Q3_21_MOI was removed from gene: ATP6V0A4.
Tag watchlist_moi was removed from gene: ATP6V0A4.
Skeletal dysplasia v3.5 COPB2 Eleanor Williams Tag watchlist_moi was removed from gene: COPB2.
Skeletal dysplasia v3.5 COPB2 Eleanor Williams Tag Q1_22_MOI was removed from gene: COPB2.
Skeletal dysplasia v3.5 COPB2 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Nephrocalcinosis or nephrolithiasis v3.4 SLC34A3 Sarah Leigh Tag Q3_22_MOI was removed from gene: SLC34A3.
Tag Q3_22_NHS_review was removed from gene: SLC34A3.
Skeletal dysplasia v3.5 COL9A1 Eleanor Williams Tag Q4_21_MOI was removed from gene: COL9A1.
Skeletal dysplasia v3.5 COL9A1 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 DROSHA Eleanor Williams Tag Q2_22_rating was removed from gene: DROSHA.
Skeletal dysplasia v3.5 DROSHA Eleanor Williams changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remainsamber. The reviewers note that there is insufficient evidence for link to skeletal dysplasia, primarily neurological. Only 2 cases with missense variants, minor skeletal anomalies and link to gene not proven.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The reviewers note that there is insufficient evidence for link to skeletal dysplasia, primarily neurological. Only 2 cases with missense variants, minor skeletal anomalies and link to gene not proven.
Nephrocalcinosis or nephrolithiasis v3.4 SLC34A3 Sarah Leigh commented on gene: SLC34A3
Nephrocalcinosis or nephrolithiasis v3.4 RRAGD Sarah Leigh reviewed gene: RRAGD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v3.4 ATP6V0A4 Sarah Leigh commented on gene: ATP6V0A4
Skeletal dysplasia v3.5 CSNK1G1 Eleanor Williams Tag Q1_22_rating was removed from gene: CSNK1G1.
Skeletal dysplasia v3.5 HHAT Eleanor Williams commented on gene: HHAT: The rating of this gene has been updated to greenfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 AFF3 Eleanor Williams reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v3.5 STT3A Eleanor Williams reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v3.5 DVL2 Eleanor Williams edited their review of gene: DVL2: Added comment: The rating of this gene has been updated togreenand the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Skeletal dysplasia v3.5 MYH3 Eleanor Williams commented on gene: MYH3: The rating of this gene has been updated togreenand the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 PRKAR1A Eleanor Williams commented on gene: PRKAR1A: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, NOT imprintedfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 ANO5 Eleanor Williams commented on gene: ANO5: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, NOT imprintedfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 COL1A2 Eleanor Williams commented on gene: COL1A2: The mode of inheritance of this gene has been updated toMONOALLELIC, autosomal or pseudoautosomal, imprinted status unknownfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 LTBP3 Eleanor Williams commented on gene: LTBP3: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 COPB2 Eleanor Williams commented on gene: COPB2: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 COL9A1 Eleanor Williams commented on gene: COL9A1: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.
Skeletal dysplasia v3.5 DROSHA Eleanor Williams reviewed gene: DROSHA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v3.5 CSNK1G1 Eleanor Williams reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v3.4 STT3A Eleanor Williams Source Expert Review Green was added to STT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v3.4 PRKAR1A Eleanor Williams Mode of inheritance for gene PRKAR1A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v3.4 MYH3 Eleanor Williams Source Expert Review Green was added to MYH3.
Source NHS GMS was added to MYH3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v3.4 LTBP3 Eleanor Williams Mode of inheritance for gene LTBP3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v3.4 HHAT Eleanor Williams Source Expert Review Green was added to HHAT.
Source NHS GMS was added to HHAT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v3.4 DVL2 Eleanor Williams Source Expert Review Green was added to DVL2.
Source NHS GMS was added to DVL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v3.4 COPB2 Eleanor Williams Mode of inheritance for gene COPB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v3.4 COL9A1 Eleanor Williams Mode of inheritance for gene COL9A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v3.4 COL1A2 Eleanor Williams Mode of inheritance for gene COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v3.4 ANO5 Eleanor Williams Mode of inheritance for gene ANO5 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v3.4 AFF3 Eleanor Williams Source Expert Review Green was added to AFF3.
Source NHS GMS was added to AFF3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.26 COL9A3 Achchuthan Shanmugasundram commented on gene: COL9A3: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the rating and mode of inheritance of this gene.
Retinal disorders v3.26 COL9A2 Achchuthan Shanmugasundram commented on gene: COL9A2: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.
Retinal disorders v3.26 COL9A1 Achchuthan Shanmugasundram commented on gene: COL9A1: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.
Retinal disorders v3.26 COL2A1 Achchuthan Shanmugasundram commented on gene: COL2A1: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.
Retinal disorders v3.26 COL11A1 Achchuthan Shanmugasundram commented on gene: COL11A1: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.
Retinal disorders v3.26 IRX6 Achchuthan Shanmugasundram reviewed gene: IRX6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 IRX5 Achchuthan Shanmugasundram reviewed gene: IRX5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 PRPF6 Achchuthan Shanmugasundram reviewed gene: PRPF6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 POMGNT2 Achchuthan Shanmugasundram commented on gene: POMGNT2: The rating of this gene has been updated to Amber and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Retinal disorders v3.26 STN1 Achchuthan Shanmugasundram commented on gene: STN1: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Retinal disorders v3.26 SSBP1 Achchuthan Shanmugasundram commented on gene: SSBP1
Retinal disorders v3.26 RNU4ATAC Achchuthan Shanmugasundram reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 PEX6 Achchuthan Shanmugasundram commented on gene: PEX6
Retinal disorders v3.26 ARSG Achchuthan Shanmugasundram reviewed gene: ARSG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 AFG3L2 Achchuthan Shanmugasundram commented on gene: AFG3L2
Retinal disorders v3.26 ACO2 Achchuthan Shanmugasundram commented on gene: ACO2
Retinal disorders v3.26 RGR Achchuthan Shanmugasundram reviewed gene: RGR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 POMT1 Achchuthan Shanmugasundram reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Retinal disorders v3.26 COL2A1 Achchuthan Shanmugasundram edited their review of gene: COL2A1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Retinal disorders v3.25 STN1 Achchuthan Shanmugasundram Source NHS GMS was added to STN1.
Source Expert Review Green was added to STN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.25 SSBP1 Achchuthan Shanmugasundram Source NHS GMS was added to SSBP1.
Mode of inheritance for gene SSBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v3.25 RNU4ATAC Achchuthan Shanmugasundram Source NHS GMS was added to RNU4ATAC.
Source Expert Review Green was added to RNU4ATAC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.25 RGR Achchuthan Shanmugasundram Source Expert Review Green was added to RGR.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.25 POMT1 Achchuthan Shanmugasundram Source NHS GMS was added to POMT1.
Source Expert Review Green was added to POMT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.25 POMGNT2 Achchuthan Shanmugasundram Source NHS GMS was added to POMGNT2.
Retinal disorders v3.25 PEX6 Achchuthan Shanmugasundram Source NHS GMS was added to PEX6.
Mode of inheritance for gene PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v3.25 COL2A1 Achchuthan Shanmugasundram Source Expert Review Green was added to COL2A1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Retinal disorders v3.25 ARSG Achchuthan Shanmugasundram Source Expert Review Green was added to ARSG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Retinal disorders v3.25 AFG3L2 Achchuthan Shanmugasundram Mode of inheritance for gene AFG3L2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v3.25 ACO2 Achchuthan Shanmugasundram Mode of inheritance for gene ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v3.7 TFG Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: TFG.
Dilated and arrhythmogenic cardiomyopathy v2.4 RRAGD Arina Puzriakova Tag Q3_22_rating was removed from gene: RRAGD.
Dilated and arrhythmogenic cardiomyopathy v2.4 TBX5 Arina Puzriakova reviewed gene: TBX5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 SPEG Arina Puzriakova reviewed gene: SPEG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 RRAGD Arina Puzriakova reviewed gene: RRAGD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 RPL3L Arina Puzriakova reviewed gene: RPL3L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 NRAP Arina Puzriakova reviewed gene: NRAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 MYLK3 Arina Puzriakova reviewed gene: MYLK3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.4 FLII Arina Puzriakova reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v2.3 RRAGD Arina Puzriakova Source NHS GMS was added to RRAGD.
Skeletal ciliopathies v2.5 CSPP1 Eleanor Williams Tag Q4_21_rating was removed from gene: CSPP1.
Skeletal ciliopathies v2.5 CSPP1 Eleanor Williams commented on gene: CSPP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Skeletal ciliopathies v2.4 CSPP1 Eleanor Williams Source Expert Review Green was added to CSPP1.
Source NHS GMS was added to CSPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.7 SSBP1 Achchuthan Shanmugasundram Tag Q1_22_MOI was removed from gene: SSBP1.
Optic neuropathy v3.7 SPG7 Achchuthan Shanmugasundram Tag Q3_22_MOI was removed from gene: SPG7.
Tag Q3_22_NHS_review was removed from gene: SPG7.
Optic neuropathy v3.7 SLC44A1 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: SLC44A1.
Optic neuropathy v3.7 OPA1 Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: OPA1.
Optic neuropathy v3.7 NDUFA12 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: NDUFA12.
Nephrocalcinosis or nephrolithiasis v3.3 SLC34A3 Sarah Leigh Source NHS GMS was added to SLC34A3.
Mode of inheritance for gene SLC34A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v3.3 RRAGD Sarah Leigh Source Expert Review Green was added to RRAGD.
Source NHS GMS was added to RRAGD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v3.3 ATP6V0A4 Sarah Leigh Source NHS GMS was added to ATP6V0A4.
Mode of inheritance for gene ATP6V0A4 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v3.7 ISCA2 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: ISCA2.
Limb disorders v3.6 UBA2 Eleanor Williams Tag Q4_21_rating was removed from gene: UBA2.
Limb disorders v3.6 SCUBE3 Eleanor Williams Tag Q4_21_rating was removed from gene: SCUBE3.
Optic neuropathy v3.7 EPRS Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: EPRS.
Limb disorders v3.6 RAD51 Eleanor Williams Tag Q4_21_rating was removed from gene: RAD51.
Limb disorders v3.6 LTBP1 Eleanor Williams Tag Q3_21_rating was removed from gene: LTBP1.
Limb disorders v3.6 KCNN3 Eleanor Williams Tag Q2_21_rating was removed from gene: KCNN3.
Limb disorders v3.6 DLX5 Eleanor Williams Tag Q3_21_MOI was removed from gene: DLX5.
Limb disorders v3.6 DLX5 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Limb disorders v3.6 DLX5 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated toBOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomalfollowing NHS Genomic Medicine Service approval.
Limb disorders v3.6 HEATR3 Eleanor Williams Tag Q3_22_rating was removed from gene: HEATR3.
Tag Q3_22_MOI was removed from gene: HEATR3.
Limb disorders v3.6 UBA2 Eleanor Williams commented on gene: UBA2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Limb disorders v3.6 SCUBE3 Eleanor Williams edited their review of gene: SCUBE3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Limb disorders v3.6 RAD51 Eleanor Williams reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb disorders v3.6 LTBP1 Eleanor Williams commented on gene: LTBP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Limb disorders v3.6 KCNN3 Eleanor Williams reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb disorders v3.6 DLX5 Eleanor Williams commented on gene: DLX5
Limb disorders v3.6 HEATR3 Eleanor Williams reviewed gene: HEATR3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb disorders v3.5 UBA2 Eleanor Williams Source Expert Review Green was added to UBA2.
Source NHS GMS was added to UBA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 SCUBE3 Eleanor Williams Source Expert Review Green was added to SCUBE3.
Source NHS GMS was added to SCUBE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 RAD51 Eleanor Williams Source Expert Review Green was added to RAD51.
Source NHS GMS was added to RAD51.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 LTBP1 Eleanor Williams Source Expert Review Green was added to LTBP1.
Source NHS GMS was added to LTBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 KCNN3 Eleanor Williams Source Expert Review Green was added to KCNN3.
Source NHS GMS was added to KCNN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 HEATR3 Eleanor Williams Source Expert Review Green was added to HEATR3.
Source NHS GMS was added to HEATR3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb disorders v3.5 DLX5 Eleanor Williams Source NHS GMS was added to DLX5.
Mode of inheritance for gene DLX5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v3.7 C19orf12 Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: C19orf12.
Optic neuropathy v3.7 ATG7 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: ATG7.
Optic neuropathy v3.7 ACO2 Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: ACO2.
Tag Q2_22_NHS_review was removed from gene: ACO2.
Optic neuropathy v3.7 DNAJC30 Achchuthan Shanmugasundram reviewed gene: DNAJC30: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 TFG Achchuthan Shanmugasundram reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 SSBP1 Achchuthan Shanmugasundram commented on gene: SSBP1
Optic neuropathy v3.7 SPG7 Achchuthan Shanmugasundram commented on gene: SPG7
Optic neuropathy v3.7 SLC44A1 Achchuthan Shanmugasundram reviewed gene: SLC44A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 OPA1 Achchuthan Shanmugasundram commented on gene: OPA1
Optic neuropathy v3.7 NDUFA12 Achchuthan Shanmugasundram reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 ISCA2 Achchuthan Shanmugasundram reviewed gene: ISCA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 EPRS Achchuthan Shanmugasundram reviewed gene: EPRS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 C19orf12 Achchuthan Shanmugasundram commented on gene: C19orf12
Optic neuropathy v3.7 ATG7 Achchuthan Shanmugasundram reviewed gene: ATG7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v3.7 ACO2 Achchuthan Shanmugasundram commented on gene: ACO2
Optic neuropathy v3.6 TFG Achchuthan Shanmugasundram Source Expert Review Green was added to TFG.
Source NHS GMS was added to TFG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 SSBP1 Achchuthan Shanmugasundram Source NHS GMS was added to SSBP1.
Mode of inheritance for gene SSBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rating Changed from Green List (high evidence) to Red List (low evidence)
Optic neuropathy v3.6 SPG7 Achchuthan Shanmugasundram Source NHS GMS was added to SPG7.
Mode of inheritance for gene SPG7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Optic neuropathy v3.6 SLC44A1 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC44A1.
Source NHS GMS was added to SLC44A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 OPA1 Achchuthan Shanmugasundram Source NHS GMS was added to OPA1.
Mode of inheritance for gene OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v3.6 NDUFA12 Achchuthan Shanmugasundram Source Expert Review Green was added to NDUFA12.
Source NHS GMS was added to NDUFA12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 ISCA2 Achchuthan Shanmugasundram Source Expert Review Green was added to ISCA2.
Source NHS GMS was added to ISCA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 EPRS Achchuthan Shanmugasundram Source Expert Review Green was added to EPRS.
Source NHS GMS was added to EPRS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 DNAJC30 Achchuthan Shanmugasundram gene: DNAJC30 was added
gene: DNAJC30 was added to Optic neuropathy. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v3.6 C19orf12 Achchuthan Shanmugasundram Source NHS GMS was added to C19orf12.
Mode of inheritance for gene C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v3.6 ATG7 Achchuthan Shanmugasundram Source Expert Review Green was added to ATG7.
Source NHS GMS was added to ATG7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v3.6 ACO2 Achchuthan Shanmugasundram Source NHS GMS was added to ACO2.
Mode of inheritance for gene ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ophthalmological ciliopathies v2.6 TBC1D32 Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: TBC1D32.
Ophthalmological ciliopathies v2.6 LAMA1 Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: LAMA1.
Tag Q3_21_expert_review was removed from gene: LAMA1.
Ophthalmological ciliopathies v2.6 ARL3 Achchuthan Shanmugasundram Tag Q4_21_rating was removed from gene: ARL3.
Ophthalmological ciliopathies v2.6 TBC1D32 Achchuthan Shanmugasundram reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Ophthalmological ciliopathies v2.6 ARL3 Achchuthan Shanmugasundram reviewed gene: ARL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Ophthalmological ciliopathies v2.6 LAMA1 Achchuthan Shanmugasundram reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Ophthalmological ciliopathies v2.5 TBC1D32 Achchuthan Shanmugasundram Source Expert Review Green was added to TBC1D32.
Source NHS GMS was added to TBC1D32.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ophthalmological ciliopathies v2.5 LAMA1 Achchuthan Shanmugasundram Source Expert Review Green was added to LAMA1.
Source NHS GMS was added to LAMA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ophthalmological ciliopathies v2.5 ARL3 Achchuthan Shanmugasundram Source Expert Review Green was added to ARL3.
Source NHS GMS was added to ARL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Catecholaminergic polymorphic VT v3.3 TECRL Arina Puzriakova Tag Q3_21_rating was removed from gene: TECRL.
Catecholaminergic polymorphic VT v3.3 TECRL Arina Puzriakova Source Expert Review Green was added to TECRL.
Source NHS GMS was added to TECRL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Catecholaminergic polymorphic VT v3.2 TECRL Arina Puzriakova reviewed gene: TECRL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paediatric or syndromic cardiomyopathy v2.6 SPRED2 Arina Puzriakova Tag Q1_22_rating was removed from gene: SPRED2.
Paediatric or syndromic cardiomyopathy v2.6 LMOD2 Arina Puzriakova Tag Q2_22_rating was removed from gene: LMOD2.
Tag Q2_22_NHS_review was removed from gene: LMOD2.
Paediatric or syndromic cardiomyopathy v2.6 RRAGD Arina Puzriakova Tag Q3_22_rating was removed from gene: RRAGD.
Paediatric or syndromic cardiomyopathy v2.6 SPRED2 Arina Puzriakova reviewed gene: SPRED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paediatric or syndromic cardiomyopathy v2.6 LMOD2 Arina Puzriakova reviewed gene: LMOD2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paediatric or syndromic cardiomyopathy v2.6 RRAGD Arina Puzriakova reviewed gene: RRAGD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paediatric or syndromic cardiomyopathy v2.5 SPRED2 Arina Puzriakova Source Expert Review Green was added to SPRED2.
Source NHS GMS was added to SPRED2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric or syndromic cardiomyopathy v2.5 RRAGD Arina Puzriakova Source Expert Review Green was added to RRAGD.
Source NHS GMS was added to RRAGD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric or syndromic cardiomyopathy v2.5 LMOD2 Arina Puzriakova Source Expert Review Green was added to LMOD2.
Source NHS GMS was added to LMOD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cardiac arrhythmias - additional genes v2.5 ANK2 Arina Puzriakova Tag Q3_22_rating was removed from gene: ANK2.
Tag Q3_22_expert_review was removed from gene: ANK2.
Cardiac arrhythmias - additional genes v2.5 GNB5 Arina Puzriakova Tag Q4_21_rating was removed from gene: GNB5.
Cardiac arrhythmias - additional genes v2.5 GNB5 Arina Puzriakova Source Expert Review Green was added to GNB5.
Source NHS GMS was added to GNB5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cardiac arrhythmias - additional genes v2.5 ANK2 Arina Puzriakova Source Expert Review Red was added to ANK2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Cardiac arrhythmias - additional genes v2.4 GNB5 Arina Puzriakova commented on gene: GNB5: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Cardiac arrhythmias - additional genes v2.4 ANK2 Arina Puzriakova reviewed gene: ANK2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Childhood solid tumours v3.4 MAX Arina Puzriakova Tag Q3_22_rating was removed from gene: MAX.
Tag Q3_22_expert_review was removed from gene: MAX.
Childhood solid tumours v3.4 CDKN1C Arina Puzriakova Phenotypes for gene: CDKN1C were changed from Beckwith-Wiedemann Syndrome; Wilms Tumor; Beckwith-Wiedemann syndrome, 130650; IMAGE syndrome, 614732; Silver-Russell Syndrome; Beckwith-Wiedemann syndrome to Beckwith-Wiedemann syndrome, OMIM:130650
Childhood solid tumours v3.3 CDKN1C Arina Puzriakova Tag Q2_22_MOI was removed from gene: CDKN1C.
Childhood solid tumours v3.3 MAX Arina Puzriakova edited their review of gene: MAX: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Childhood solid tumours v3.3 CDKN1C Arina Puzriakova commented on gene: CDKN1C
Childhood solid tumours v3.2 MAX Arina Puzriakova Source Expert Review Green was added to MAX.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Childhood solid tumours v3.2 CDKN1C Arina Puzriakova Mode of inheritance for gene CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Corneal dystrophy v2.3 TGFBI Achchuthan Shanmugasundram Tag Q1_22_MOI was removed from gene: TGFBI.
Corneal dystrophy v2.3 TGFBI Achchuthan Shanmugasundram commented on gene: TGFBI
Corneal dystrophy v2.2 TGFBI Achchuthan Shanmugasundram Source NHS GMS was added to TGFBI.
Mode of inheritance for gene TGFBI was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sarcoma susceptibility v1.73 FANCC Arina Puzriakova Tag Q3_22_rating was removed from gene: FANCC.
Tag Q3_22_expert_review was removed from gene: FANCC.
Sarcoma susceptibility v1.73 FANCC Arina Puzriakova commented on gene: FANCC: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. Expert review indicated that there is not sufficient evidence for this gene-disease association at this time.
Ovarian cancer pertinent cancer susceptibility v1.13 BRCA1 Arina Puzriakova Tag Q2_22_MOI was removed from gene: BRCA1.
Tag Q2_22_expert_review was removed from gene: BRCA1.
Ovarian cancer pertinent cancer susceptibility v1.13 BRCA1 Arina Puzriakova commented on gene: BRCA1: The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Ovarian cancer pertinent cancer susceptibility v1.12 BRCA1 Arina Puzriakova Source NHS GMS was added to BRCA1.
Mode of inheritance for gene BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v3.3 RAD21 Arina Puzriakova Tag Q4_22_promote_green was removed from gene: RAD21.
Tag Q4_22_expert_review was removed from gene: RAD21.
Haematological malignancies cancer susceptibility v3.3 MBD4 Arina Puzriakova Tag Q3_22_rating was removed from gene: MBD4.
Tag Q3_22_expert_review was removed from gene: MBD4.
Haematological malignancies cancer susceptibility v3.3 RPS15 Arina Puzriakova Tag Q3_22_rating was removed from gene: RPS15.
Tag Q3_22_expert_review was removed from gene: RPS15.
Haematological malignancies cancer susceptibility v3.3 RPL27 Arina Puzriakova Tag Q3_22_rating was removed from gene: RPL27.
Tag Q3_22_expert_review was removed from gene: RPL27.
Haematological malignancies cancer susceptibility v3.3 ERCC6L2 Arina Puzriakova Tag Q2_22_rating was removed from gene: ERCC6L2.
Tag Q2_22_NHS_review was removed from gene: ERCC6L2.
Haematological malignancies cancer susceptibility v3.3 RAD21 Arina Puzriakova edited their review of gene: RAD21: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Haematological malignancies cancer susceptibility v3.3 MBD4 Arina Puzriakova edited their review of gene: MBD4: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Haematological malignancies cancer susceptibility v3.3 RPS15 Arina Puzriakova edited their review of gene: RPS15: Added comment: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.; Changed rating: RED
Haematological malignancies cancer susceptibility v3.3 RPL27 Arina Puzriakova reviewed gene: RPL27: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Haematological malignancies cancer susceptibility v3.3 ERCC6L2 Arina Puzriakova reviewed gene: ERCC6L2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Haematological malignancies cancer susceptibility v3.2 RPS15 Arina Puzriakova Source NHS GMS was added to RPS15.
Source Expert Review Red was added to RPS15.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Haematological malignancies cancer susceptibility v3.2 RPL27 Arina Puzriakova Source NHS GMS was added to RPL27.
Source Expert Review Red was added to RPL27.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Haematological malignancies cancer susceptibility v3.2 RAD21 Arina Puzriakova Source Expert Review Green was added to RAD21.
Source NHS GMS was added to RAD21.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Haematological malignancies cancer susceptibility v3.2 MBD4 Arina Puzriakova Source Expert Review Green was added to MBD4.
Source NHS GMS was added to MBD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Haematological malignancies cancer susceptibility v3.2 ERCC6L2 Arina Puzriakova Source Expert Review Green was added to ERCC6L2.
Source NHS GMS was added to ERCC6L2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.7 FOXI1 Arina Puzriakova Tag to_be_confirmed_NHSE tag was added to gene: FOXI1.
Monogenic hearing loss v3.7 COL9A3 Arina Puzriakova Tag to_be_confirmed_NHSE tag was added to gene: COL9A3.
Bilateral congenital or childhood onset cataracts v3.3 CDK9 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: CDK9.
Tag Q3_22_MOI was removed from gene: CDK9.
Bilateral congenital or childhood onset cataracts v3.3 CDK9 Achchuthan Shanmugasundram reviewed gene: CDK9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Bilateral congenital or childhood onset cataracts v3.2 CDK9 Achchuthan Shanmugasundram Source Expert Review Green was added to CDK9.
Source NHS GMS was added to CDK9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Breast cancer pertinent cancer susceptibility v1.8 BRCA1 Arina Puzriakova Tag Q2_22_MOI was removed from gene: BRCA1.
Tag Q2_22_expert_review was removed from gene: BRCA1.
Monogenic hearing loss v3.7 USP48 Arina Puzriakova Tag Q4_21_rating was removed from gene: USP48.
Monogenic hearing loss v3.7 SPATA5L1 Arina Puzriakova Tag Q1_22_rating was removed from gene: SPATA5L1.
Monogenic hearing loss v3.7 RNF220 Arina Puzriakova Tag Q4_21_rating was removed from gene: RNF220.
Monogenic hearing loss v3.7 PBX1 Arina Puzriakova Tag Q4_21_rating was removed from gene: PBX1.
Monogenic hearing loss v3.7 OGDHL Arina Puzriakova Tag Q3_22_rating was removed from gene: OGDHL.
Monogenic hearing loss v3.7 LMX1A Arina Puzriakova Tag Q1_22_MOI was removed from gene: LMX1A.
Monogenic hearing loss v3.7 KCNJ16 Arina Puzriakova Tag Q2_22_rating was removed from gene: KCNJ16.
Monogenic hearing loss v3.7 GREB1L Arina Puzriakova Tag Q2_21_rating was removed from gene: GREB1L.
Monogenic hearing loss v3.7 GGPS1 Arina Puzriakova Tag Q4_21_rating was removed from gene: GGPS1.
Breast cancer pertinent cancer susceptibility v1.8 BRCA1 Arina Puzriakova commented on gene: BRCA1: The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Breast cancer pertinent cancer susceptibility v1.7 BRCA1 Arina Puzriakova Source NHS GMS was added to BRCA1.
Mode of inheritance for gene BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v3.7 CRYM Arina Puzriakova Tag Q2_21_rating was removed from gene: CRYM.
Monogenic hearing loss v3.7 CLDN9 Arina Puzriakova Tag Q4_21_rating was removed from gene: CLDN9.
Monogenic hearing loss v3.7 CEACAM16 Arina Puzriakova Tag Q4_21_MOI was removed from gene: CEACAM16.
Monogenic hearing loss v3.7 AP1S1 Arina Puzriakova Tag Q2_21_rating was removed from gene: AP1S1.
Monogenic hearing loss v3.7 ADGRV1 Arina Puzriakova Tag Q1_22_MOI was removed from gene: ADGRV1.
Monogenic hearing loss v3.7 FOXI1 Arina Puzriakova commented on gene: FOXI1
Monogenic hearing loss v3.7 COL9A3 Arina Puzriakova commented on gene: COL9A3
Monogenic hearing loss v3.7 USP48 Arina Puzriakova reviewed gene: USP48: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 SPATA5L1 Arina Puzriakova reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 RNF220 Arina Puzriakova reviewed gene: RNF220: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 PBX1 Arina Puzriakova reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 OGDHL Arina Puzriakova edited their review of gene: OGDHL: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Monogenic hearing loss v3.7 LMX1A Arina Puzriakova commented on gene: LMX1A
Monogenic hearing loss v3.7 KCNJ16 Arina Puzriakova reviewed gene: KCNJ16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 GREB1L Arina Puzriakova reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 GGPS1 Arina Puzriakova reviewed gene: GGPS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 CRYM Arina Puzriakova reviewed gene: CRYM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 CLDN9 Arina Puzriakova reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 CEACAM16 Arina Puzriakova commented on gene: CEACAM16
Monogenic hearing loss v3.7 AP1S1 Arina Puzriakova reviewed gene: AP1S1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v3.7 ADGRV1 Arina Puzriakova commented on gene: ADGRV1
Monogenic hearing loss v3.6 USP48 Arina Puzriakova Source NHS GMS was added to USP48.
Source Expert Review Green was added to USP48.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 SPATA5L1 Arina Puzriakova Source NHS GMS was added to SPATA5L1.
Source Expert Review Green was added to SPATA5L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 RNF220 Arina Puzriakova Source NHS GMS was added to RNF220.
Source Expert Review Green was added to RNF220.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 PBX1 Arina Puzriakova Source NHS GMS was added to PBX1.
Source Expert Review Green was added to PBX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 OGDHL Arina Puzriakova Source NHS GMS was added to OGDHL.
Source Expert Review Green was added to OGDHL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 LMX1A Arina Puzriakova Source NHS GMS was added to LMX1A.
Mode of inheritance for gene LMX1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v3.6 KCNJ16 Arina Puzriakova Source NHS GMS was added to KCNJ16.
Source Expert Review Green was added to KCNJ16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 GREB1L Arina Puzriakova Source NHS GMS was added to GREB1L.
Source Expert Review Green was added to GREB1L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 GGPS1 Arina Puzriakova Source NHS GMS was added to GGPS1.
Source Expert Review Green was added to GGPS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 CRYM Arina Puzriakova Source NHS GMS was added to CRYM.
Source Expert Review Green was added to CRYM.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 CLDN9 Arina Puzriakova Source NHS GMS was added to CLDN9.
Source Expert Review Green was added to CLDN9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 CEACAM16 Arina Puzriakova Source NHS GMS was added to CEACAM16.
Mode of inheritance for gene CEACAM16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v3.6 AP1S1 Arina Puzriakova Source NHS GMS was added to AP1S1.
Source Expert Review Green was added to AP1S1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v3.6 ADGRV1 Arina Puzriakova Source NHS GMS was added to ADGRV1.
Mode of inheritance for gene ADGRV1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.215 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Hereditary isolated diabetes insipidus v0.0 Sarah Leigh Added Panel Neuropophyseal diabetes insipidus
Set panel types to: GMS Rare Disease
Inherited prostate cancer v0.0 Sarah Leigh Added Panel Inherited prostate cancer
Set panel types to: GMS Rare Disease
Intellectual disability v4.51 KDM2B Mike Spiller gene: KDM2B was added
gene: KDM2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to PMID: 36322151; 35128353; 35710456
Review for gene: KDM2B was set to GREEN
Added comment: van Jaarsveld et al 2022 PMID: 36322151

Majority of variants are missense, strong evidence for hotspot in CXXC domain.(7 different de Novo missenses + 1 de Novo in frame del. Same inframe del also found de novo in NHS GMS patient. All absent from gnomAD, region highly constrained).

Also 3 LOF SNVs and 3 patients with deletions including this gene, although not all are de novo and most also have potential alternate causes.

All have developmental delay. Almost all have intellectual disability ranging from mild to moderate, speech delay common..7 with cardiac abnormalities, 4 with kidney abnormalities.

Also 2 variants published in this region in PMID: 35710456, 35904121.

KDM2B methylation episignature recorded. CXXC variants show strong clustering, highly distinct from control dataset. LOF variants (including dels) also reported to show distinct episignature from controls, and from CXXC variants. While the data supports a KDM2B LOF episignature, this is not as clear, and may not be as specific, as the CXXC signature.

Mouse model also supports importance of CXXC domain, with mice heterozygous for CXXC-deleted KDM2B showing neurological defects (PMID: 35128353).

Evidence very strong for CXXC missenses less clear for haploinsufficiency.

Overall sufficient evidence from cases and episignature evidence to include as green for ID.
Sources: Literature
Intellectual disability v4.51 ZMYM3 Sarah Leigh edited their review of gene: ZMYM3: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. Using the MatchMaker Exchange, PMID: 36586412 reports 23 ZMYM3 variants in 27 individuals (24 males, 3 females) with a neurodevelopmental delay phenotype. Of those assessed 17/20 had intellectual disability, there were other features that overlapped between the individuals including speech delay, motor delay, ASD traits, behavioral problems, facial dys-morphism, microcephaly, short stature.; Changed rating: GREEN; Changed publications to: 36586412; Changed phenotypes to: neurodevelopmental delay
Intellectual disability v4.51 ZMYM3 Sarah Leigh Classified gene: ZMYM3 as Amber List (moderate evidence)
Intellectual disability v4.51 ZMYM3 Sarah Leigh Gene: zmym3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.50 ZMYM3 Sarah Leigh Classified gene: ZMYM3 as Red List (low evidence)
Intellectual disability v4.50 ZMYM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.50 ZMYM3 Sarah Leigh Gene: zmym3 has been classified as Red List (Low Evidence).
Intellectual disability v4.49 ZMYM3 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: ZMYM3.
Intellectual disability v4.49 ZMYM3 Sarah Leigh Publications for gene: ZMYM3 were set to 26350204; 24721225; 8817323
Paediatric pseudo-obstruction syndrome v0.214 Arina Puzriakova List of related panels changed from to R438
Unexplained death in infancy and sudden unexplained death in childhood v3.24 Arina Puzriakova List of related panels changed from to R441
Li Fraumeni Syndrome v0.5 Eleanor Williams Panel status changed from public to internal
Hereditary diffuse gastric cancer v0.5 Eleanor Williams Panel status changed from public to internal
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.5 Eleanor Williams Panel status changed from public to internal
Ataxia telangiectasia - mutation testing v0.6 Eleanor Williams Panel status changed from public to internal
APC associated Polyposis v0.7 Eleanor Williams Panel status changed from public to internal
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.5 Eleanor Williams Panel status changed from public to internal
Alstrom syndrome v0.5 Eleanor Williams Panel status changed from public to internal
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.6 Eleanor Williams Panel status changed from public to internal
Agammaglobulinaemia with absent BTK expression v0.6 Eleanor Williams Panel status changed from public to internal
Acute intermittent porphyria v0.6 Eleanor Williams Panel status changed from public to internal
Auditory Neuropathy Spectrum Disorde v1.9 CABP2 Barbara Vona gene: CABP2 was added
gene: CABP2 was added to Auditory Neuropathy Spectrum Disorder. Sources: Literature
Mode of inheritance for gene: CABP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CABP2 were set to PMID: 28183797
Phenotypes for gene: CABP2 were set to Auditory neuropathy; auditory synaptopathy
Penetrance for gene: CABP2 were set to Complete
Mode of pathogenicity for gene: CABP2 was set to Other
Review for gene: CABP2 was set to RED
gene: CABP2 was marked as current diagnostic
Added comment: Variants in CABP2 have been reported to cause autosomal recessive non-syndromic hearing loss (DFNB93). In-depth functional studies and deep phenotyping of one of the originally published families with a homozygous loss-of-function variant (NM_016366.3:c.466G>T (p.Glu156Ter)/NM_001318496.2:c.484G>T, p.(Glu162Ter)); PMID: 22981119) presenting mid-frequency, moderate-to-severe hearing loss, uncovered transient evoked otoacoustic emissions (TEOAEs) in a 4 year-old affected individual (PMID: 28183797). The authors suggested, at least initially, that outer hair cell function is spared, thus showing the first individual with auditory synaptopathy/auditory neuropathy. A mouse model with a deletion of exons 3-4 of Cabp2 showed reduced auditory brainstem response recordings and present distortion product otoacoustic emissions. The lesion was identified to be most likely at the inner hair cell synapses, compatible with an auditory synaptopathy/auditory neuropathy. Although there are not abundant examples of CABP2 patients with auditory synapthpathy/auditory neuropathy in the literature, biallelic variants in CABP2 undoubtedly cause hearing impairment that should be further phenotyped in patients through OAE testing. Replication of this specific type of hearing deficit is needed; therefore, CABP2 merits being added to the Auditory Neuropathy gene panel.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v2.1 RRAS Dmitrijs Rots gene: RRAS was added
gene: RRAS was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: RRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAS were set to PMID: 34935735
Phenotypes for gene: RRAS were set to Pediatric Myelodysplastic Syndrome
Penetrance for gene: RRAS were set to unknown
Mode of pathogenicity for gene: RRAS 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: RRAS was set to GREEN
Added comment: 34935735 describes a new case and provides info from 3 cases from the literature with RASopathy AND pediatric MDS. Only de novo missense variants were found. Therefore, enough evidence for green rating.
Sources: Literature
Hereditary neuropathy or pain disorder v2.16 VCP Mafalda Gomes Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1; Charcot-Marie-Tooth disease, type 2Y to Charcot-Marie-Tooth disease, type 2Y, OMIM:616687
Hereditary neuropathy or pain disorder v2.15 VCP Mafalda Gomes Publications for gene: VCP were set to 26574898; 25878907; 25125609
Hereditary neuropathy or pain disorder v2.14 VCP Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: VCP.
Dystonia, chorea or related movement disorder, childhood onset v2.7 COX20 Mafalda Gomes Phenotypes for gene: COX20 were changed from Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054 to Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054
Dystonia, chorea or related movement disorder, childhood onset v2.7 COX20 Mafalda Gomes Phenotypes for gene: COX20 were changed from Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054 to Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054
Dystonia, chorea or related movement disorder, childhood onset v2.7 COX20 Mafalda Gomes Phenotypes for gene: COX20 were changed from to Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054
Dystonia, chorea or related movement disorder, childhood onset v2.6 COX20 Mafalda Gomes Publications for gene: COX20 were set to
Dystonia, chorea or related movement disorder, childhood onset v2.5 COX20 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: COX20.
Hereditary neuropathy or pain disorder v2.14 COX20 Mafalda Gomes Phenotypes for gene: COX20 were changed from Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054 to Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054
Hereditary neuropathy or pain disorder v2.13 COX20 Mafalda Gomes Phenotypes for gene: COX20 were changed from Neuropathy to Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054
Hereditary neuropathy or pain disorder v2.12 COX20 Mafalda Gomes Publications for gene: COX20 were set to 33751098; 30656193; 24202787
Hereditary neuropathy or pain disorder v2.11 COX20 Mafalda Gomes Publications for gene: COX20 were set to 33751098
Hereditary neuropathy or pain disorder v2.10 COX20 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: COX20.
Hereditary neuropathy or pain disorder v2.10 ACOX1 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.26 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.26 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, MIM# 617159; Childhood idiopathic epilepsy and sinus arrhythmia to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.25 CHD4 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: CHD4.
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.24 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.23 ASXL3 Mafalda Gomes Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830; 33151654
Early onset or syndromic epilepsy v3.23 ASXL3 Mafalda Gomes Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830
Early onset or syndromic epilepsy v3.22 ASXL3 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: ASXL3.
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.48 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.21 BAP1 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: BAP1.
Intellectual disability v4.47 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.47 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Intellectual disability; short stature; autism spectrum disorder to Kury-Isidor syndrome, OMIM:619762
Intellectual disability v4.46 BAP1 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: BAP1.
Hereditary neuropathy or pain disorder v2.10 TECPR2 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: TECPR2.
Hereditary neuropathy or pain disorder v2.10 TECPR2 Mafalda Gomes Phenotypes for gene: TECPR2 were changed from Hereditary sensory and autonomic neuropathy to Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031
Hereditary spastic paraplegia, childhood onset v3.7 TECPR2 Mafalda Gomes Phenotypes for gene: TECPR2 were changed from Spastic paraplegia 49, autosomal recessive, 615031 to Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031
Hereditary spastic paraplegia, childhood onset v3.6 TECPR2 Mafalda Gomes Publications for gene: TECPR2 were set to 23176824; 26542466
Hereditary spastic paraplegia, childhood onset v3.5 TECPR2 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: TECPR2.
Hereditary neuropathy or pain disorder v2.9 TECPR2 Mafalda Gomes changed review comment from: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss?of?function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.; to: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.
Hereditary spastic paraplegia, childhood onset v3.5 TECPR2 Mafalda Gomes changed review comment from: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss?of?function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.; to: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.
Hereditary spastic paraplegia, childhood onset v3.5 TECPR2 Mafalda Gomes reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33847017; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.27 TECPR2 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: TECPR2.
Ataxia and cerebellar anomalies - childhood onset v3.27 TECPR2 Mafalda Gomes Phenotypes for gene: TECPR2 were changed from to Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031
Ataxia and cerebellar anomalies - childhood onset v3.26 TECPR2 Mafalda Gomes Publications for gene: TECPR2 were set to
Ataxia and cerebellar anomalies - childhood onset v3.25 TECPR2 Mafalda Gomes changed review comment from: Neuser et al. (2021) report 17 unrelated cases with biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss?of?function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.; to: Neuser et al. (2021) report 17 unrelated cases with biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.
Hereditary neuropathy or pain disorder v2.9 VCP Mafalda Gomes reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: ; Publications: 25125609, 32165109, 25878907; Phenotypes: Charcot-Marie-Tooth disease, type 2Y, OMIM:616687; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - childhood onset v3.25 TECPR2 Mafalda Gomes reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33847017; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.9 TECPR2 Mafalda Gomes reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33847017; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v2.5 COX20 Mafalda Gomes reviewed gene: COX20: Rating: GREEN; Mode of pathogenicity: ; Publications: 30656193, 33751098, 24202787; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.9 COX20 Mafalda Gomes reviewed gene: COX20: Rating: GREEN; Mode of pathogenicity: ; Publications: 30656193, 33751098, 24202787; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 11, OMIM:619054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v3.5 ACOX1 Mafalda Gomes reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32169171; Phenotypes: Mitchell syndrome, OMIM:618960; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v2.9 ACOX1 Mafalda Gomes reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32169171; Phenotypes: Mitchell syndrome, OMIM:618960; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v3.21 CHD4 Mafalda Gomes reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: ; Publications: 34109749; Phenotypes: Sifrim-Hitz-Weiss syndrome, OMIM:617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v3.21 ASXL3 Mafalda Gomes reviewed gene: ASXL3: Rating: GREEN; Mode of pathogenicity: ; Publications: 34436830, 33151654; Phenotypes: Bainbridge-Ropers syndrome, OMIM:615115; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v4.46 BAP1 Mafalda Gomes commented on gene: BAP1: Kry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Early onset or syndromic epilepsy v3.21 BAP1 Mafalda Gomes commented on gene: BAP1: Kry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Hereditary neuropathy or pain disorder v2.8 VCP Mafalda Gomes Mode of inheritance for gene VCP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - childhood onset v3.24 TECPR2 Mafalda Gomes gene: TECPR2 was added
gene: TECPR2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.8 TECPR2 Mafalda Gomes Source Expert Review Amber was added to TECPR2.
Rating Changed from No List (delete) to Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v2.4 COX20 Mafalda Gomes Source Expert Review Amber was added to COX20.
Mode of inheritance for gene COX20 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v2.8 COX20 Mafalda Gomes Source Expert Review Amber was added to COX20.
Rating Changed from No List (delete) to Amber List (moderate evidence)
Monogenic hearing loss v3.4 ACOX1 Mafalda Gomes gene: ACOX1 was added
gene: ACOX1 was added to Monogenic hearing loss. Sources: Expert Review Amber
Mode of inheritance for gene: ACOX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v2.8 ACOX1 Mafalda Gomes Source Expert Review Amber was added to ACOX1.
Mode of inheritance for gene ACOX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.20 CHD4 Mafalda Gomes Source Expert Review Amber was added to CHD4.
Mode of inheritance for gene CHD4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.20 ASXL3 Mafalda Gomes Source Expert Review Amber was added to ASXL3.
Mode of inheritance for gene ASXL3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v4.45 BAP1 Mafalda Gomes Source Expert Review Amber was added to BAP1.
Mode of inheritance for gene BAP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.20 BAP1 Mafalda Gomes Source Expert Review Amber was added to BAP1.
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v4.44 TMEM147 Sarah Leigh Classified gene: TMEM147 as Amber List (moderate evidence)
Intellectual disability v4.44 TMEM147 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.44 TMEM147 Sarah Leigh Gene: tmem147 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.43 TMEM147 Sarah Leigh gene: TMEM147 was added
gene: TMEM147 was added to Intellectual disability. Sources: Literature
Q1_23_promote_green tags were added to gene: TMEM147.
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, OMIM:620075
Review for gene: TMEM147 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. PMID: 36044892 reports 12 variants in at least 15 unrelated derived from GeneMatcher. Supportive functional evidence is also presented.
Sources: Literature
Fetal anomalies v2.8 KIF21A Hannah Robinson gene: KIF21A was added
gene: KIF21A was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to 34740919
Phenotypes for gene: KIF21A were set to Arthrogryposis; fetal akinesia
Penetrance for gene: KIF21A were set to unknown
Review for gene: KIF21A was set to GREEN
gene: KIF21A was marked as current diagnostic
Added comment: Falb et al 2023 (PMID: 34740919) describe two unrelated families in which biallelic loss of function variants segregated with a severe form of fetal akinesia characterised by arthrogryposis multiplex, pulmonary hypoplasia and variable facial dysmorphisms.

Exeter Genomics Laboratory has identified an unrelated third case homozygous for a nonsense variant in KIF21A. The patient had an antenatal diagnosis of talipes, arthrogryposis, polyhydramnios and lack of fetal movements. At birth, all joints displayed fixed flexion deformities, no primitive reflexes, poor muscle bulk and care was re-oriented shortly after birth.

Taken together, three unrelated cases including segregation evidence in the published families provides sufficient evidence for the gene-disease association.
Sources: Literature, NHS GMS
Arthrogryposis v4.3 KIF21A Hannah Robinson gene: KIF21A was added
gene: KIF21A was added to Arthrogryposis. Sources: Literature,NHS GMS
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to 34740919
Phenotypes for gene: KIF21A were set to Arthrogryposis; fetal akinesia
Penetrance for gene: KIF21A were set to unknown
Review for gene: KIF21A was set to GREEN
gene: KIF21A was marked as current diagnostic
Added comment: Falb et al 2023 (PMID: 34740919) describe two unrelated families in which biallelic loss of function variants segregated with a severe form of fetal akinesia characterised by arthrogryposis multiplex, pulmonary hypoplasia and variable facial dysmorphisms.

Exeter Genomics Laboratory has identified an unrelated third case homozygous for a nonsense variant in KIF21A. The patient had an antenatal diagnosis of talipes, arthrogryposis, polyhydramnios and lack of fetal movements. At birth, all joints displayed fixed flexion deformities, no primitive reflexes, poor muscle bulk and care was re-oriented shortly after birth.

Taken together, three unrelated cases including segregation evidence in the published families provides sufficient evidence for the gene-disease association.
Sources: Literature, NHS GMS
Ataxia and cerebellar anomalies - childhood onset v3.23 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209
Hereditary ataxia, adult onset v3.8 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209
Hereditary spastic paraplegia, adult onset v2.5 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209
Ataxia and cerebellar anomalies - childhood onset v3.22 UCHL1 Sarah Leigh reviewed gene: UCHL1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, adult onset v2.5 UCHL1 Sarah Leigh reviewed gene: UCHL1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v3.7 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Added comment: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v2.4 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Added comment: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.314 UCHL1 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous UCHL1 variants have been reported, including 13 heterozygous loss-of-function variants (15 families) and a heterozygous inframe insertion (3 families) in PMID: 35986737. These affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous UCHL1 variants have been reported, including 13 heterozygous loss-of-function variants (15 families) and a heterozygous inframe insertion (3 families) in PMID: 35986737. The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).
Hereditary ataxia v1.314 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous UCHL1 variants have been reported, including 13 heterozygous loss-of-function variants (15 families) and a heterozygous inframe insertion (3 families) in PMID: 35986737. These affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.314 UCHL1 Sarah Leigh Added comment: Comment on mode of inheritance: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous loss of function UCHL1 variants.
Hereditary ataxia v1.314 UCHL1 Sarah Leigh Mode of inheritance for gene: UCHL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.22 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641; 11555633; 33159930
Dystonia, chorea or related movement disorder, adult onset v2.5 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from {?Parkinson disease 5, susceptibility to}, OMIM:613643 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; ?{Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to' MONDO:0013340
Dystonia, chorea or related movement disorder, adult onset v2.4 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 28007905; 23359680; 29735986; 10048490
Hereditary ataxia, adult onset v3.7 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641
Hereditary spastic paraplegia, adult onset v2.4 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 BCL11B Helen Lord changed review comment from: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list; to: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

31067316 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 BCL11B Helen Lord gene: BCL11B was added
gene: BCL11B was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: BCL11B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BCL11B were set to 36275064; 310673176; 34900871; 36512050; 36470856
Phenotypes for gene: BCL11B were set to Craniosynostosis and global developmental delay
Review for gene: BCL11B was set to GREEN
Added comment: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list
Li Fraumeni Syndrome v0.4 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Hereditary diffuse gastric cancer v0.4 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.4 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Ataxia telangiectasia - mutation testing v0.5 Eleanor Williams Panel status changed from internal to public
Ataxia telangiectasia - mutation testing v0.4 Eleanor Williams Panel types changed to
APC associated Polyposis v0.6 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.4 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Alstrom syndrome v0.4 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.5 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Agammaglobulinaemia with absent BTK expression v0.5 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Acute intermittent porphyria v0.5 Eleanor Williams Panel status changed from internal to public
Panel types changed to
Li Fraumeni Syndrome v0.3 TP53 Eleanor Williams reviewed gene: TP53: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Li Fraumeni Syndrome v0.2 TP53 Eleanor Williams gene: TP53 was added
gene: TP53 was added to Li Fraumeni Syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Li Fraumeni Syndrome v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Hereditary diffuse gastric cancer v0.3 CDH1 Eleanor Williams reviewed gene: CDH1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary diffuse gastric cancer v0.2 CDH1 Eleanor Williams gene: CDH1 was added
gene: CDH1 was added to CDH1-related cancer syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CDH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary diffuse gastric cancer v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.3 FAS Eleanor Williams reviewed gene: FAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.2 FAS Eleanor Williams gene: FAS was added
gene: FAS was added to Autoimmune lymphoproliferative syndrome with defective apoptosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FAS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
APC associated Polyposis v0.5 APC Eleanor Williams changed review comment from: APC has been added to the panel for R414 APC associated Polyposis with a green rating as agreed with the NHS Genomic Medicine Service.; to: APC has been added to the panel for the clinical indication 'R414 APC associated Polyposis' with a green rating as agreed with the NHS Genomic Medicine Service.
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.3 FOXF1 Eleanor Williams changed review comment from: FOXF1 has been added to the panel for R330 Alveolar capillary dysplasia with misalignment of pulmonary veins with a green rating as agreed with the NHS Genomic Medicine Service.; to: FOXF1 has been added to the panel for the clinical indication 'R330 Alveolar capillary dysplasia with misalignment of pulmonary veins' with a green rating as agreed with the NHS Genomic Medicine Service.
Alstrom syndrome v0.3 ALMS1 Eleanor Williams changed review comment from: ALMS1 has been added to the panel for R106 Alstrom syndrome with a green rating as agreed with the NHS Genomic Medicine Service.; to: ALMS1 has been added to the panel for the clinical indication 'R106 Alstrom syndrome' with a green rating as agreed with the NHS Genomic Medicine Service.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.4 PRKAR1A Eleanor Williams changed review comment from: PRKAR1A has been added to the panel for R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis with a green rating as agreed with the NHS Genomic Medicine Service.; to: PRKAR1A has been added to the panel for the clinical indication 'R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis' with a green rating as agreed with the NHS Genomic Medicine Service.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.4 PDE4D Eleanor Williams changed review comment from: PDE4D has been added to the panel for R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis with a green rating as agreed with the NHS Genomic Medicine Service.; to: PDE4D has been added to the panel for the clinical indication 'R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis' with a green rating as agreed with the NHS Genomic Medicine Service.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.4 GNAS Eleanor Williams changed review comment from: GNAS has been added to the panel for R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis with a green rating as agreed with the NHS Genomic Medicine Service.; to: GNAS has been added to the panel for the clinical indication 'R293 Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis' with a green rating as agreed with the NHS Genomic Medicine Service.
Agammaglobulinaemia with absent BTK expression v0.4 BTK Eleanor Williams changed review comment from: BTK has been added to the panel for R233 Agammaglobulinaemia with absent BTK expression with a green rating as agreed with the NHS Genomic Medicine Service.; to: BTK has been added to the panel for the clinical indication 'R233 Agammaglobulinaemia with absent BTK expression' with a green rating as agreed with the NHS Genomic Medicine Service.
Ataxia telangiectasia - mutation testing v0.3 ATM Eleanor Williams reviewed gene: ATM: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia telangiectasia - mutation testing v0.2 ATM Eleanor Williams gene: ATM was added
gene: ATM was added to Ataxia telangiectasia - mutation testing. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ATM was set to BIALLELIC, autosomal or pseudoautosomal
Ataxia telangiectasia - mutation testing v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
APC associated Polyposis v0.5 APC Eleanor Williams reviewed gene: APC: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
APC associated Polyposis v0.4 APC Eleanor Williams gene: APC was added
gene: APC was added to APC associated Polyposis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: APC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
APC associated Polyposis v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.3 FOXF1 Eleanor Williams reviewed gene: FOXF1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.2 FOXF1 Eleanor Williams gene: FOXF1 was added
gene: FOXF1 was added to Alveolar capillary dysplasia with misalignment of pulmonary veins. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FOXF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Alstrom syndrome v0.3 ALMS1 Eleanor Williams reviewed gene: ALMS1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Alstrom syndrome v0.2 ALMS1 Eleanor Williams gene: ALMS1 was added
gene: ALMS1 was added to Alstrom syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ALMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Alstrom syndrome v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.3 PRKAR1A Eleanor Williams reviewed gene: PRKAR1A: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.3 PDE4D Eleanor Williams reviewed gene: PDE4D: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.3 GNAS Eleanor Williams reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.2 PRKAR1A Eleanor Williams gene: PRKAR1A was added
gene: PRKAR1A was added to Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.2 PDE4D Eleanor Williams gene: PDE4D was added
gene: PDE4D was added to Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PDE4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.2 GNAS Eleanor Williams gene: GNAS was added
gene: GNAS was added to Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: GNAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Acute intermittent porphyria v0.4 HMBS Eleanor Williams edited their review of gene: HMBS: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Acute intermittent porphyria v0.4 HMBS Eleanor Williams changed review comment from: This gene has been added to the panel for R169 Acute intermittent porphyria with a green rating as agreed with the NHS Genomic Medicine Service.; to: HMBS has been added to the panel for R169 Acute intermittent porphyria with a green rating as agreed with the NHS Genomic Medicine Service.
Agammaglobulinaemia with absent BTK expression v0.4 BTK Eleanor Williams reviewed gene: BTK: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Agammaglobulinaemia with absent BTK expression v0.3 BTK Eleanor Williams gene: BTK was added
gene: BTK was added to Agammaglobulinaemia with absent BTK expression. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: BTK was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Agammaglobulinaemia with absent BTK expression v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Acute intermittent porphyria v0.4 HMBS Eleanor Williams commented on gene: HMBS
Acute intermittent porphyria v0.3 HMBS Eleanor Williams gene: HMBS was added
gene: HMBS was added to Acute intermittent porphyria. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: HMBS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia v1.313 UCHL1 Samuel McCall reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35986737; Phenotypes: spasticity, ataxia, neuropathy, optic atrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Congenital disorders of glycosylation v3.2 ST3GAL3 Arina Puzriakova Classified gene: ST3GAL3 as Amber List (moderate evidence)
Congenital disorders of glycosylation v3.2 ST3GAL3 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Sufficient cases (>3) to support a gene-disease association (PMID: 21907012; 23252400; 31584066). This gene is also green on the IEM panel (v3.0) and as such should be reflected on this panel.

ST3GAL3 encodes the β-galactoside-α2,3-sialyltransferase-III (ST3Gal-III), which in humans predominantly forms the sialyl Lewis a (sLe a) epitope on glycoproteins.
Congenital disorders of glycosylation v3.2 ST3GAL3 Arina Puzriakova Gene: st3gal3 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v3.1 ST3GAL3 Arina Puzriakova Tag Q1_23_promote_green tag was added to gene: ST3GAL3.
Acute intermittent porphyria v0.1 Eleanor Williams Panel types changed to GMS Rare Disease
Li Fraumeni Syndrome v0.0 Eleanor Williams Added Panel Li Fraumeni Syndrome
Set list of related panels to R216
Hereditary diffuse gastric cancer v0.0 Eleanor Williams Added Panel CDH1-related cancer syndrome
Set list of related panels to R215
Neurodegenerative disorders, adult onset v3.47 CST3 Achchuthan Shanmugasundram changed review comment from: There are >3 unrelated cases with relevant phenotype (cerebral amyloid angiopathy) and age of onset is third or fourth decade of life. However, all these cases were identified with the same heterozygous variant in the CST3 gene (p.L68Q) and was from the same Icelandic population. This gene should be rated AMBER in the absence of functional studies on this specific variant, de novo cases with this variant from other populations or existence of other variants causing the same phenotype.; to: There are >3 unrelated cases with relevant phenotype (cerebral amyloid angiopathy) and age of onset is third or fourth decade of life. However, all these cases were identified with the same heterozygous variant in the CST3 gene (p.L68Q) and was from the same Icelandic population. There should be functional studies on this specific variant, de novo cases with this variant from other populations or existence of other variants causing the same phenotype for it to be rated green. Hence, this gene is rated AMBER.
Neurodegenerative disorders, adult onset v3.47 CST3 Achchuthan Shanmugasundram Deleted their comment
Neurodegenerative disorders, adult onset v3.47 CST3 Achchuthan Shanmugasundram edited their review of gene: CST3: Added comment: There are >3 unrelated cases with relevant phenotype (cerebral amyloid angiopathy) and age of onset is third or fourth decade of life. However, all these cases were identified with the same heterozygous variant in the CST3 gene (p.L68Q) and was from the same Icelandic population. This gene should be rated AMBER in the absence of functional studies on this specific variant, de novo cases with this variant from other populations or existence of other variants causing the same phenotype.; Changed rating: AMBER
Neurodegenerative disorders, adult onset v3.47 CST3 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: CST3.
Leukodystrophy, adult onset v2.44 LAMB1 Sarah Leigh edited their review of gene: LAMB1: Added comment: PMID: 34606115 reports heterozygous end-truncated LAMB1 in a hippocampal memory defect and a leukoencephalopathy. Other publications (PMID: 32548278; 25925986;23472759;29888467),
OMIM (https://www.omim.org/entry/150240?search=LAMB1&highlight=lamb1#geneMap), Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=1439) and ClinGen (https://search.clinicalgenome.org/kb/genes/HGNC:6486) all report the a bialleic mode inheritance between LAMB1 variants and disease. Based on this discrepancy, the suggested mode of inheritance has been changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Leukodystrophy, adult onset v2.44 LAMB1 Sarah Leigh Tag Q1_23_MOI tag was added to gene: LAMB1.
Intellectual disability v4.42 PAN2 Sarah Leigh edited their review of gene: PAN2: Added comment: PAN2 is not associated with a phenotype in OMIM, but has a moderate association with PAN2-related neurodevelopmental disorder with multiple congenital anomalies in Gen2Phen. PMID: 29620724 reports one homozygous variant in one case and PMID: 35304602 reports a further three homozygous variants in three unrelated cases. It would appear that the syndrome associated with PAN2 variants has multiple congenital anomalies (PMID: 35304602, table 1), including intellectual disabilty ranging from mild to global developmental delay.; Changed rating: GREEN
Intellectual disability v4.42 PAN2 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: PAN2.
Intellectual disability v4.42 PAN2 Sarah Leigh Classified gene: PAN2 as Amber List (moderate evidence)
Intellectual disability v4.42 PAN2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.42 PAN2 Sarah Leigh Gene: pan2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.41 PAN2 Sarah Leigh Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Intellectual disability v4.40 HIST1H4D Sarah Leigh commented on gene: HIST1H4D: HIST1H4D is the previous symbol for H4 clustered histone 4 with the approved symbol: H4C4 (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4782).
Intellectual disability v4.40 HIST1H4D Sarah Leigh Classified gene: HIST1H4D as Red List (low evidence)
Intellectual disability v4.40 HIST1H4D Sarah Leigh Gene: hist1h4d has been classified as Red List (Low Evidence).
Intellectual disability v4.39 HIST1H4D Sarah Leigh Tag new-gene-name tag was added to gene: HIST1H4D.
Intellectual disability v4.39 HIST1H4D Sarah Leigh reviewed gene: HIST1H4D: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v4.39 HIST1H4F Sarah Leigh Classified gene: HIST1H4F as Red List (low evidence)
Intellectual disability v4.39 HIST1H4F Sarah Leigh Gene: hist1h4f has been classified as Red List (Low Evidence).
Intellectual disability v4.38 HIST1H4F Sarah Leigh edited their review of gene: HIST1H4F: Added comment: H4C6 is not associated with a phenotype in OMIM or Gen2Phen. PMID: 35202563 reports single H4C6 variant in a case with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variant does not have a loss of function action.; Changed rating: RED
Intellectual disability v4.38 HIST1H4F Sarah Leigh commented on gene: HIST1H4F
Intellectual disability v4.38 HIST1H4F Sarah Leigh Tag new-gene-name tag was added to gene: HIST1H4F.
Intellectual disability v4.38 HIST1H4I Sarah Leigh commented on gene: HIST1H4I: Associated with Tessadori-van Haaften neurodevelopmental syndrome 4, (OMIM:619951), but not with a phenotype in Gen2Phen. PMID: 35202563 reports two H4C9 variants in two patients with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variants do not have a loss of function action.
Intellectual disability v4.38 HIST1H4I Sarah Leigh Classified gene: HIST1H4I as Amber List (moderate evidence)
Intellectual disability v4.38 HIST1H4I Sarah Leigh Gene: hist1h4i has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.37 HIST1H4I Sarah Leigh Phenotypes for gene: HIST1H4I were changed from Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face to Tessadori-van Haaften neurodevelopmental syndrome 4, OMIM:619951; Tessadori-Van Haaften neurodevelopmental syndrome 4, MONDO:0031000
Intellectual disability v4.36 HIST1H4I Sarah Leigh commented on gene: HIST1H4I
Intellectual disability v4.36 HIST1H4I Sarah Leigh Tag new-gene-name tag was added to gene: HIST1H4I.
Intellectual disability v4.36 HIST1H4E Sarah Leigh Tag Q1_23_promote_green tag was added to gene: HIST1H4E.
Intellectual disability v4.36 HIST1H4E Sarah Leigh edited their review of gene: HIST1H4E: Added comment: Associated with in Tessadori-van Haaften neurodevelopmental syndrome 3 (OMIM:619950), but not with a phenotype in Gen2Phen. PMID: 35202563 reports seven H4C5 variants in 17 patients with a neurodevelopmental syndrome, based on functional studies, the authors suggest that the variants do not have a loss of function action.; Changed rating: GREEN
Intellectual disability v4.36 HIST1H4E Sarah Leigh Classified gene: HIST1H4E as Amber List (moderate evidence)
Intellectual disability v4.36 HIST1H4E Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.36 HIST1H4E Sarah Leigh Gene: hist1h4e has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.35 HIST1H4E Sarah Leigh commented on gene: HIST1H4E
Intellectual disability v4.35 HIST1H4E Sarah Leigh Tag new-gene-name tag was added to gene: HIST1H4E.
Intellectual disability v4.35 HIST1H4E Sarah Leigh Phenotypes for gene: HIST1H4E were changed from Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face to Tessadori-van Haaften neurodevelopmental syndrome 3, OMIM:619950; Tessadori-Van Haaften neurodevelopmental syndrome 3 MONDO:0030993
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh Tag Q1_23_MOI tag was added to gene: CUX2.
Tag Q1_23_NHS_review tag was added to gene: CUX2.
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh edited their review of gene: CUX2: Added comment: It is recommended that the mode of inheritance of CUX2 is changed from:
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, based on the review by Tracy Lester (Genetics laboratory, Oxford UK)(14 Nov 2022).; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v4.34 ZNF292 Sarah Leigh edited their review of gene: ZNF292: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least seven autosomal dominant or de novo ZNF292 variants have been reported in at least eleven unrelated cases of Intellectual developmental disorder, autosomal dominant 64 (OMIM: 619188)(PMID: 31723249).; Changed rating: GREEN
Intellectual disability v4.34 ZNF292 Sarah Leigh Classified gene: ZNF292 as Amber List (moderate evidence)
Intellectual disability v4.34 ZNF292 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.34 ZNF292 Sarah Leigh Gene: znf292 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.33 ZNF292 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: ZNF292.
Tag Q1_23_NHS_review tag was added to gene: ZNF292.
Intellectual disability v4.33 ZNF292 Sarah Leigh Phenotypes for gene: ZNF292 were changed from Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures to Intellectual developmental disorder, autosomal dominant 64, OMIM:619188; intellectual developmental disorder, autosomal dominant 64, MONDO:0030934
Intellectual disability v4.32 PAX6 Sarah Leigh Tag Q1_23_demote_red tag was added to gene: PAX6.
Tag Q1_23_NHS_review tag was added to gene: PAX6.
Intellectual disability v4.32 PAX6 Sarah Leigh reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v3.12 KY Sarah Leigh Classified gene: KY as Amber List (moderate evidence)
Congenital myopathy v3.12 KY Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital myopathy v3.12 KY Sarah Leigh Gene: ky has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.11 KY Sarah Leigh Tag Q1_23_promote_green tag was added to gene: KY.
Tag Q1_23_NHS_review tag was added to gene: KY.
Congenital muscular dystrophy v3.20 DPM3 Sarah Leigh Deleted their comment
Congenital muscular dystrophy v3.20 DPM3 Sarah Leigh Classified gene: DPM3 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.20 DPM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.20 DPM3 Sarah Leigh Gene: dpm3 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.19 DPM3 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: DPM3.
Tag Q1_23_NHS_review tag was added to gene: DPM3.
Congenital muscular dystrophy v3.19 DPM3 Sarah Leigh edited their review of gene: DPM3: Added comment: A green rating has been recommended based on the review from Anna Sarkozy (Great Ormond Street Hospital)(10 Nov 2022) and consultation with Helen Brittain (Clinical Fellow, Genomics England).; Changed rating: GREEN
Congenital muscular dystrophy v3.19 DPM3 Sarah Leigh Classified gene: DPM3 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.19 DPM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.19 DPM3 Sarah Leigh Gene: dpm3 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.4 DPM3 Sarah Leigh Phenotypes for gene: DPM3 were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937; limb-girdle muscular dystrophy; dystroglycanopathy to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, OMIM:612937; DPM3-congenital disorder of glycosylation, MONDO:0013049; ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, OMIM:618992; muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type b, 15, MONDO:0033556
Congenital muscular dystrophy v3.18 DPM3 Sarah Leigh Phenotypes for gene: DPM3 were changed from congenital muscular dystrophies; Congenital disorder of glycosylation, type Io, 612937'Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, OMIM:612937; DPM3-congenital disorder of glycosylation, MONDO:0013049; ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, OMIM:618992; muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type b, 15, MONDO:0033556
Intellectual disability v4.32 ZNF292 Ian Berry reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, mild, ASD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Retinal disorders v3.24 POMGNT2 Achchuthan Shanmugasundram Phenotypes for gene: POMGNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830
Retinal disorders v3.23 POMGNT2 Achchuthan Shanmugasundram Publications for gene: POMGNT2 were set to
Retinal disorders v3.22 POMGNT2 Achchuthan Shanmugasundram Mode of inheritance for gene: POMGNT2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.21 POMGNT2 Achchuthan Shanmugasundram Classified gene: POMGNT2 as Amber List (moderate evidence)
Retinal disorders v3.21 POMGNT2 Achchuthan Shanmugasundram Gene: pomgnt2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v3.20 POMGNT2 Achchuthan Shanmugasundram reviewed gene: POMGNT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 22958903, 27066570; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.20 STN1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: STN1.
Retinal disorders v3.20 STN1 Achchuthan Shanmugasundram Phenotypes for gene: STN1 were changed from to Cerebroretinal microangiopathy with calcifications and cysts 2, OMIM:617341
Retinal disorders v3.19 STN1 Achchuthan Shanmugasundram Publications for gene: STN1 were set to
Retinal disorders v3.18 STN1 Achchuthan Shanmugasundram Mode of inheritance for gene: STN1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.17 STN1 Achchuthan Shanmugasundram Classified gene: STN1 as Amber List (moderate evidence)
Retinal disorders v3.17 STN1 Achchuthan Shanmugasundram Gene: stn1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v3.16 STN1 Achchuthan Shanmugasundram changed review comment from: Comment on classification: Four unrelated patients identified with biallelic variants (homozygous or compound heterozygous) have been reported with retinal telangiectasia/ retinal lesions (PMID:27432940, PMID:34110109). hence, this gene can be rated GREEN.; to: Comment on classification: Four unrelated patients identified with biallelic variants (homozygous or compound heterozygous) have been reported with retinal telangiectasia/ retinal lesions (PMID:27432940, PMID:34110109). I would therefore recommend this gene to be rated GREEN at the next GMS review.
Retinal disorders v3.16 STN1 Achchuthan Shanmugasundram reviewed gene: STN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27432940, 34110109; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts 2, OMIM:617341; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.16 COL11A1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL11A1.
Tag Q1_23_expert_review tag was added to gene: COL11A1.
Retinal disorders v3.16 COL11A1 Achchuthan Shanmugasundram Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, OMIM:604841 to Stickler syndrome, type II, OMIM:604841; Marshall syndrome, OMIM:154780
Retinal disorders v3.15 COL11A1 Achchuthan Shanmugasundram Publications for gene: COL11A1 were set to
Retinal disorders v3.14 COL11A1 Achchuthan Shanmugasundram Mode of inheritance for gene: COL11A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v3.13 COL11A1 Achchuthan Shanmugasundram reviewed gene: COL11A1: Rating: ; Mode of pathogenicity: None; Publications: 10486316, 17318849; Phenotypes: Marshall syndrome, OMIM:154780, Stickler syndrome, type II, OMIM:604841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v3.13 COL9A3 Achchuthan Shanmugasundram Tag Q1_23_expert_review tag was added to gene: COL9A3.
Retinal disorders v3.13 COL9A3 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL9A3.
Retinal disorders v3.13 COL9A3 Achchuthan Shanmugasundram Phenotypes for gene: COL9A3 were changed from to Stickler syndrome, type VI, OMIM:620022
Retinal disorders v3.12 COL9A3 Achchuthan Shanmugasundram Publications for gene: COL9A3 were set to
Retinal disorders v3.11 COL9A3 Achchuthan Shanmugasundram Mode of inheritance for gene: COL9A3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.10 COL9A3 Achchuthan Shanmugasundram edited their review of gene: COL9A3: Changed publications to: 30450842, 33570243, 33633367
Retinal disorders v3.10 COL9A3 Achchuthan Shanmugasundram reviewed gene: COL9A3: Rating: ; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: Stickler syndrome, type VI, OMIM:620022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v3.2 IKZF2 Dmitrijs Rots reviewed gene: IKZF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34826260, 34920454; Phenotypes: Immunodeficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v3.21 DMXL2 Dmitrijs Rots reviewed gene: DMXL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.313 DMXL2 Dmitrijs Rots reviewed gene: DMXL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v2.7 MYH14 Dmitrijs Rots reviewed gene: MYH14: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31231018; Phenotypes: Neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy v1.457 MYH14 Dmitrijs Rots reviewed gene: MYH14: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31231018; Phenotypes: Neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v3.10 COL9A2 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL9A2.
Tag Q1_23_expert_review tag was added to gene: COL9A2.
Retinal disorders v3.10 COL9A2 Achchuthan Shanmugasundram Publications for gene: COL9A2 were set to
Retinal disorders v3.9 COL9A2 Achchuthan Shanmugasundram reviewed gene: COL9A2: Rating: ; Mode of pathogenicity: None; Publications: 21671392, 31090205, 33356723; Phenotypes: Stickler syndrome, type V, OMIM:614284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.9 COL9A1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL9A1.
Tag Q1_23_expert_review tag was added to gene: COL9A1.
Retinal disorders v3.9 COL9A1 Achchuthan Shanmugasundram Publications for gene: COL9A1 were set to
Retinal disorders v3.8 COL9A1 Achchuthan Shanmugasundram reviewed gene: COL9A1: Rating: ; Mode of pathogenicity: None; Publications: 16909383, 21421862; Phenotypes: Stickler syndrome, type IV, OMIM:614134; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.8 COL2A1 Achchuthan Shanmugasundram changed review comment from: There is sufficient evidence linking COL2A1 with retinal disorders (retinal thinning, lattice retinopathy, retinal detachment, vitreoretinal degeneration, blindness etc). However, these phenotypes overlap with that of Stickler syndrome and this gene is green on Stickler syndrome panel. It has previously been decided (2019) in consultation with Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital) that this gene can stay red in this panel. Given this gene has recently been proposed for this panel by an expert, I am recommending that the Test Evaluation Working Group review and define the panel scope, and reach consensus as to whether this gene is appropriate for inclusion.; to: There is sufficient evidence linking COL2A1 with retinal disorders (retinal thinning, lattice retinopathy, retinal detachment, vitreoretinal degeneration, blindness etc). However, these phenotypes overlap with that of Stickler syndrome and this gene is green on Stickler syndrome panel (https://panelapp.genomicsengland.co.uk/panels/3/gene/COL2A1/). It has previously been decided (2019) in consultation with Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital) that this gene can stay red in this panel. Given this gene has recently been proposed for this panel by an expert, I am recommending that the Test Evaluation Working Group review and define the panel scope, and reach consensus as to whether this gene is appropriate for inclusion.
Retinal disorders v3.8 COL2A1 Achchuthan Shanmugasundram Phenotypes for gene: COL2A1 were changed from Eye Disorders to Epiphyseal dysplasia, multiple, with myopia and deafness, OMIM:132450; Vitreoretinopathy with phalangeal epiphyseal dysplasia, OMIM:619248; Kniest dysplasia, OMIM:156550; SED congenita, OMIM:183900; Stickler syndrome, type I, OMIM:108300; Stickler syndrome, type I, nonsyndromic ocular, OMIM:609508
Retinal disorders v3.7 COL2A1 Achchuthan Shanmugasundram Mode of inheritance for gene: COL2A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v3.6 COL2A1 Achchuthan Shanmugasundram reviewed gene: COL2A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Epiphyseal dysplasia, multiple, with myopia and deafness, OMIM:132450, Vitreoretinopathy with phalangeal epiphyseal dysplasia, OMIM:619248, Kniest dysplasia, OMIM:156550, SED congenita, OMIM:183900, Stickler syndrome, type I, OMIM:108300, Stickler syndrome, type I, nonsyndromic ocular, OMIM:609508; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v4.32 KDM6A Arina Puzriakova Phenotypes for gene: KDM6A were changed from Kabuki syndrome 2, 300867; Kabuki syndrome; KABUKI SYNDROME 2; KABUK2 to Kabuki syndrome 2, OMIM:300867
Leukodystrophy, adult onset v2.44 TTR Sarah Leigh edited their review of gene: TTR: Added comment: Associated with Amyloidosis, hereditary, transthyretin-related (OMIM:105210), but not associated with a phenotype in Gen2Phen. Numerous TTR variants have been reported in cases from different populations.; Changed rating: GREEN
Leukodystrophy, adult onset v2.44 TTR Sarah Leigh Classified gene: TTR as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.44 TTR Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.44 TTR Sarah Leigh Gene: ttr has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.43 TTR Sarah Leigh Tag Q1_23_promote_green tag was added to gene: TTR.
Tag Q1_23_NHS_review tag was added to gene: TTR.
Leukodystrophy, adult onset v2.43 TTR Sarah Leigh Mode of inheritance for gene: TTR was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.42 TTR Sarah Leigh Phenotypes for gene: TTR were changed from to Amyloidosis, hereditary, transthyretin-related, OMIM:105210; familial amyloid neuropathy, MONDO:0007100
Leukodystrophy, adult onset v2.41 TTR Sarah Leigh Publications for gene: TTR were set to
Neurodegenerative disorders, adult onset v3.47 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to 32548278; 34606115
Leukodystrophy, adult onset v2.40 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to 32548278; 34606115; 23472759; 25925986
Inherited white matter disorders v1.169 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to 23472759; 25925986; 29888467
Leukodystrophy, adult onset v2.39 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to 32548278; 34606115
Leukodystrophy, adult onset v2.38 LAMB1 Sarah Leigh edited their review of gene: LAMB1: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least four variants have been reported in three unrelated cases of Lissencephaly 5, (OMIM:615191).; Changed rating: GREEN
Leukodystrophy, adult onset v2.38 LAMB1 Sarah Leigh Classified gene: LAMB1 as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.38 LAMB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.38 LAMB1 Sarah Leigh Gene: lamb1 has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.37 LAMB1 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: LAMB1.
Tag Q1_23_NHS_review tag was added to gene: LAMB1.
Neurodegenerative disorders, adult onset v3.46 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to
Leukodystrophy, adult onset v2.37 LAMB1 Sarah Leigh Phenotypes for gene: LAMB1 were changed from Retinal Vascular Abnormality; mild intellectual disability; white matter lesions; lower limb spasticity to Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077
Neurodegenerative disorders, adult onset v3.45 LAMB1 Sarah Leigh Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, OMIM:615191 to Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077
Inherited white matter disorders v1.168 LAMB1 Sarah Leigh Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, OMIM:615191 to Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077
Leukodystrophy, adult onset v2.36 LAMB1 Sarah Leigh Publications for gene: LAMB1 were set to 32548278
Leukodystrophy, adult onset v2.35 PSEN2 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: PSEN2.
Tag Q1_23_NHS_review tag was added to gene: PSEN2.
Leukodystrophy, adult onset v2.35 PSEN2 Sarah Leigh reviewed gene: PSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Leukodystrophy, adult onset v2.35 PSEN2 Sarah Leigh Classified gene: PSEN2 as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.35 PSEN2 Sarah Leigh Gene: psen2 has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.34 PSEN2 Sarah Leigh Publications for gene: PSEN2 were set to 9450781
Leukodystrophy, adult onset v2.33 PSEN2 Sarah Leigh Mode of inheritance for gene: PSEN2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric disorders - additional genes v2.5 PAPPA2 Arina Puzriakova Classified gene: PAPPA2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v2.5 PAPPA2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Paediatric disorders - additional genes v2.5 PAPPA2 Arina Puzriakova Gene: pappa2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v2.4 PAPPA2 Arina Puzriakova gene: PAPPA2 was added
gene: PAPPA2 was added to Paediatric disorders - additional genes. Sources: Expert list
Q1_23_promote_green tags were added to gene: PAPPA2.
Mode of inheritance for gene: PAPPA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAPPA2 were set to 26902202; 33875846; 34272725
Phenotypes for gene: PAPPA2 were set to Short stature, Dauber-Argente type, OMIM:619489
Added comment: At least 9 individuals from 5 unrelated families reported in literature with biallelic variants in this gene (PMID: 26902202; 33875846; 34272725). Clinical presentation is most notable for short stature, mild/moderate microcephaly, and dysmorphic features. Growth restriction typically becomes apparent with age.
Sources: Expert list
Neurodegenerative disorders, adult onset v3.44 PSEN2 Sarah Leigh Phenotypes for gene: PSEN2 were changed from Alzheimer disease-4, OMIM:606889; Alzheimer disease 4MONDO:0011743 to Alzheimer disease-4, OMIM:606889; Alzheimer disease 4, MONDO:0011743
Leukodystrophy, adult onset v2.32 PSEN2 Sarah Leigh Phenotypes for gene: PSEN2 were changed from to Alzheimer disease-4, OMIM:606889; Alzheimer disease 4, MONDO:0011743
Neurodegenerative disorders, adult onset v3.43 PSEN2 Sarah Leigh Phenotypes for gene: PSEN2 were changed from Alzheimer disease-4, OMIM:606889 to Alzheimer disease-4, OMIM:606889; Alzheimer disease 4MONDO:0011743
Leukodystrophy, adult onset v2.31 PSEN2 Sarah Leigh Publications for gene: PSEN2 were set to
Leukodystrophy, adult onset v2.30 PSEN1 Sarah Leigh edited their review of gene: PSEN1: Added comment: PSEN1 variants are sssociated with OMIM:607822 & OMIM:600274, but not with a phenotype in Gen2Phen. Numerous PSEN1 variants have been reported in these conditions and PSEN1 related cerebral amyloid angiopathy is seen within a number of cases of Alzheimer disease, type 3 (OMIM:607822)(PMID: 26888304,11489138, 11395394, 34319632).; Changed rating: GREEN
Leukodystrophy, adult onset v2.30 PSEN1 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: PSEN1.
Tag Q1_23_NHS_review tag was added to gene: PSEN1.
Leukodystrophy, adult onset v2.30 PSEN1 Sarah Leigh Classified gene: PSEN1 as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.30 PSEN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.30 PSEN1 Sarah Leigh Gene: psen1 has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.29 PSEN1 Sarah Leigh Mode of inheritance for gene: PSEN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.28 PSEN1 Sarah Leigh Phenotypes for gene: PSEN1 were changed from to Alzheimer disease, type 3, OMIM:607822; Alzheimer disease 3, MONDO:0011913; Dementia, frontotemporal, OMIM:600274; semantic dementia, MONDO:0010857
Leukodystrophy, adult onset v2.27 PSEN1 Sarah Leigh Publications for gene: PSEN1 were set to
Leukodystrophy, adult onset v2.26 PRNP Sarah Leigh edited their review of gene: PRNP: Added comment: Associated with relevant phenotype in OMIM (OMIM:137440), but not associated with a phenotype in Gen2Phen. Numberous PRNP variants have been reported for OMIM:137440.; Changed rating: GREEN
Leukodystrophy, adult onset v2.26 PRNP Sarah Leigh Tag Q1_23_promote_green tag was added to gene: PRNP.
Tag Q1_23_NHS_review tag was added to gene: PRNP.
Leukodystrophy, adult onset v2.26 PRNP Sarah Leigh Mode of inheritance for gene: PRNP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.25 PRNP Sarah Leigh Classified gene: PRNP as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.25 PRNP Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.25 PRNP Sarah Leigh Gene: prnp has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.24 PRNP Sarah Leigh Phenotypes for gene: PRNP were changed from to Cerebral amyloid angiopathy, PRNP-related, OMIM:137440; Gerstmann-Straussler disease, OMIM:137440; Gerstmann-Straussler-Scheinker syndrome, MONDO:0007656
Leukodystrophy, adult onset v2.23 GSN Sarah Leigh edited their review of gene: GSN: Added comment: Associated with Amyloidosis, Finnish type, in OMIM and as definitive gene for this phenotype in Gen2Phen. At least 4 variants have been reported (PMID: 25097823; 33973672; 33499149).; Changed rating: GREEN
Leukodystrophy, adult onset v2.23 GSN Sarah Leigh Tag Q1_23_promote_green tag was added to gene: GSN.
Tag Q1_23_NHS_review tag was added to gene: GSN.
Leukodystrophy, adult onset v2.23 GSN Sarah Leigh Classified gene: GSN as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.23 GSN Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.23 GSN Sarah Leigh Gene: gsn has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.42 GSN Sarah Leigh Publications for gene: GSN were set to 25097823
Leukodystrophy, adult onset v2.22 GSN Sarah Leigh Publications for gene: GSN were set to 25097823; 7550233
Leukodystrophy, adult onset v2.21 GSN Sarah Leigh Mode of inheritance for gene: GSN was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Leukodystrophy, adult onset v2.20 GSN Sarah Leigh Publications for gene: GSN were set to 25097823
Neurodegenerative disorders, adult onset v3.41 GSN Sarah Leigh Publications for gene: GSN were set to
Leukodystrophy, adult onset v2.19 GSN Sarah Leigh Publications for gene: GSN were set to
Leukodystrophy, adult onset v2.18 GSN Sarah Leigh Phenotypes for gene: GSN were changed from to Amyloidosis, Finnish type, OMIM:105120; Finnish type amyloidosis, MONDO:0007097
Neurodegenerative disorders, adult onset v3.40 GSN Sarah Leigh Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type, OMIM:105120 to Amyloidosis, Finnish type, OMIM:105120; Finnish type amyloidosis, MONDO:0007097
Leukodystrophy, adult onset v2.17 ITM2B Sarah Leigh Mode of inheritance for gene: ITM2B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Leukodystrophy, adult onset v2.16 ITM2B Sarah Leigh edited their review of gene: ITM2B: Added comment: Associated with relevant phenotypes in OMIM (OMIM:176500 & OMIM:117300), but not associated with these phenotypes in Gen2Phen. Two terminating variants have been reported, one for each of the above phenotypes (PMID: 10391242, 10781099).; Changed rating: GREEN
Leukodystrophy, adult onset v2.16 ITM2B Sarah Leigh Tag Q1_23_promote_green tag was added to gene: ITM2B.
Tag Q1_23_NHS_review tag was added to gene: ITM2B.
Leukodystrophy, adult onset v2.16 ITM2B Sarah Leigh Classified gene: ITM2B as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.16 ITM2B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Leukodystrophy, adult onset v2.16 ITM2B Sarah Leigh Gene: itm2b has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.15 ITM2B Sarah Leigh Phenotypes for gene: ITM2B were changed from to Dementia, familial British, OMIM:176500; ABri amyloidosis, MONDO:0008306; Dementia, familial Danish, OMIM:117300; ADan amyloidosis, MONDO:0007297
Neurodegenerative disorders, adult onset v3.39 ITM2B Sarah Leigh Phenotypes for gene: ITM2B were changed from Dementia, familial British, OMIM:176500 to Dementia, familial British, OMIM:176500; ABri amyloidosis, MONDO:0008306; Dementia, familial Danish, OMIM:117300; ADan amyloidosis, MONDO:0007297
Neurodegenerative disorders, adult onset v3.38 ITM2B Sarah Leigh Publications for gene: ITM2B were set to 29525180; 10391242; 10781099
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.83 ITM2B Sarah Leigh Phenotypes for gene: ITM2B were changed from Dementia, familial British, 176500 to Dementia, familial British, OMIM:176500; ABri amyloidosis, MONDO:0008306; Dementia, familial Danish, OMIM:117300; ADan amyloidosis, MONDO:0007297
Leukodystrophy, adult onset v2.14 ITM2B Sarah Leigh Publications for gene: ITM2B were set to
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.82 ITM2B Sarah Leigh Publications for gene: ITM2B were set to 10391242; 10781099
Neurodegenerative disorders, adult onset v3.37 ITM2B Sarah Leigh Publications for gene: ITM2B were set to 29525180; 10391242; 210391242; 10781099
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.81 ITM2B Sarah Leigh Publications for gene: ITM2B were set to
Leukodystrophy, adult onset v2.13 CST3 Sarah Leigh reviewed gene: CST3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Leukodystrophy, adult onset v2.13 CST3 Sarah Leigh Publications for gene: CST3 were set to 2900981; 3495457; 1352269; 3673496; 7482672
Hereditary systemic amyloidosis v1.16 CST3 Sarah Leigh Publications for gene: CST3 were set to 2900981; 3495457; 1352269; 3673496; 7482672
Neurodegenerative disorders, adult onset v3.36 TTR Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: TTR.
Neurodegenerative disorders, adult onset v3.36 LAMB1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: LAMB1.
Leukodystrophy, adult onset v2.12 CST3 Sarah Leigh Tag founder-effect tag was added to gene: CST3.
Neurodegenerative disorders, adult onset v3.36 GSN Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: GSN.
Leukodystrophy, adult onset v2.12 CST3 Sarah Leigh Classified gene: CST3 as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.12 CST3 Sarah Leigh Gene: cst3 has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.11 CST3 Sarah Leigh Publications for gene: CST3 were set to
Neurodegenerative disorders, adult onset v3.36 CST3 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: CST3.
Hereditary systemic amyloidosis v1.15 CST3 Sarah Leigh Publications for gene: CST3 were set to 2900981; 3495457; 1352269; 367349; 7482672
Leukodystrophy, adult onset v2.10 CST3 Sarah Leigh Mode of inheritance for gene: CST3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.9 CST3 Sarah Leigh Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy, OMIM:105150; ACys amyloidosis, MONDO:0007098 to Cerebral amyloid angiopathy, OMIM:105150; ACys amyloidosis, MONDO:0007098
Leukodystrophy, adult onset v2.9 CST3 Sarah Leigh Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy, OMIM:105150 to Cerebral amyloid angiopathy, OMIM:105150; ACys amyloidosis, MONDO:0007098
Neurodegenerative disorders, adult onset v3.36 TREX1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: TREX1.
Neurodegenerative disorders, adult onset v3.36 GLA Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: GLA.
Neurodegenerative disorders, adult onset v3.36 COL4A2 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL4A2.
Neurodegenerative disorders, adult onset v3.36 COL4A1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: COL4A1.
Neurodegenerative disorders, adult onset v3.36 CTSA Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: CTSA.
Neurodegenerative disorders, adult onset v3.36 CTSA Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be promoted to GREEN at the next GMS panel update as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P.; to: Comment on classification: This gene should be promoted to GREEN at the next GMS panel update as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) in both OMIM and G2P.
Leukodystrophy, adult onset v2.8 APP Arina Puzriakova Tag Q1_23_promote_green tag was added to gene: APP.
Neurodegenerative disorders, adult onset v3.36 CTSA Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be promoted to GREEN at the next GMS panel update as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P; to: Comment on classification: This gene should be promoted to GREEN at the next GMS panel update as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P.
Neurodegenerative disorders, adult onset v3.36 CTSA Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be promoted to GREEN for adult-onset neurodegenerative disorders as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P; to: Comment on classification: This gene should be promoted to GREEN at the next GMS panel update as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P
Neurodegenerative disorders, adult onset v3.36 TTR Achchuthan Shanmugasundram Publications for gene: TTR were set to
Neurodegenerative disorders, adult onset v3.35 TTR Achchuthan Shanmugasundram Phenotypes for gene: TTR were changed from to Amyloidosis, hereditary, transthyretin-related, OMIM:105210; Carpal tunnel syndrome, familial, OMIM:115430
Neurodegenerative disorders, adult onset v3.34 TTR Achchuthan Shanmugasundram Mode of inheritance for gene: TTR was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.33 TTR Achchuthan Shanmugasundram Classified gene: TTR as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.33 TTR Achchuthan Shanmugasundram Gene: ttr has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.32 TTR Achchuthan Shanmugasundram edited their review of gene: TTR: Added comment: Comment on classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and with adult-onset reported in patients.

This gene has been associated with relevant phenotypes in OMIM, but not in G2P.; Changed phenotypes to: Amyloidosis, hereditary, transthyretin-related, OMIM:105210, Carpal tunnel syndrome, familial, OMIM:115430
Neurodegenerative disorders, adult onset v3.32 TTR Achchuthan Shanmugasundram reviewed gene: TTR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyloidosis, hereditary, transthyretin-related, OMIM: 105210; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.32 LAMB1 Achchuthan Shanmugasundram Phenotypes for gene: LAMB1 were changed from to Lissencephaly 5, OMIM:615191
Neurodegenerative disorders, adult onset v3.31 LAMB1 Achchuthan Shanmugasundram Mode of inheritance for gene: LAMB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.30 LAMB1 Achchuthan Shanmugasundram Mode of inheritance for gene: LAMB1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.29 LAMB1 Achchuthan Shanmugasundram Classified gene: LAMB1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.29 LAMB1 Achchuthan Shanmugasundram Gene: lamb1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.28 LAMB1 Achchuthan Shanmugasundram reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lissencephaly 5, OMIM:615191; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.28 GSN Achchuthan Shanmugasundram Phenotypes for gene: GSN were changed from to Amyloidosis, Finnish type, OMIM:105120
Neurodegenerative disorders, adult onset v3.27 GSN Achchuthan Shanmugasundram Mode of inheritance for gene: GSN was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.26 GSN Achchuthan Shanmugasundram Classified gene: GSN as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.26 GSN Achchuthan Shanmugasundram Gene: gsn has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.25 GSN Achchuthan Shanmugasundram reviewed gene: GSN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyloidosis, Finnish type, OMIM:105120; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.25 CST3 Achchuthan Shanmugasundram Mode of inheritance for gene: CST3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.24 CST3 Achchuthan Shanmugasundram Classified gene: CST3 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.24 CST3 Achchuthan Shanmugasundram Gene: cst3 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.23 CST3 Achchuthan Shanmugasundram Classified gene: CST3 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.23 CST3 Achchuthan Shanmugasundram Gene: cst3 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.22 CST3 Achchuthan Shanmugasundram reviewed gene: CST3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral amyloid angiopathy, OMIM:105150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.22 TREX1 Achchuthan Shanmugasundram Phenotypes for gene: TREX1 were changed from Dystonia to Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations, OMIM:192315
Neurodegenerative disorders, adult onset v3.21 TREX1 Achchuthan Shanmugasundram Mode of inheritance for gene: TREX1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.20 TREX1 Achchuthan Shanmugasundram Classified gene: TREX1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.20 TREX1 Achchuthan Shanmugasundram Gene: trex1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.19 TREX1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and with confirmed cases of adult-onset.

TREX1 has also been associated with relevant phenotypes in both OMIM and G2P.; to: Comment on classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and with confirmed cases of adult-onset.

TREX1 has also been associated with relevant phenotypes in both OMIM and G2P.
Neurodegenerative disorders, adult onset v3.19 TREX1 Achchuthan Shanmugasundram Deleted their comment
Neurodegenerative disorders, adult onset v3.19 TREX1 Achchuthan Shanmugasundram commented on gene: TREX1: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and with confirmed cases of adult-onset.

TREX1 has also been associated with relevant phenotypes in both OMIM and G2P.
Neurodegenerative disorders, adult onset v3.19 TREX1 Achchuthan Shanmugasundram reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750, Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations, OMIM:192315; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.19 GLA Achchuthan Shanmugasundram Phenotypes for gene: GLA were changed from to Fabry disease, OMIM:301500
Neurodegenerative disorders, adult onset v3.18 GLA Achchuthan Shanmugasundram Mode of inheritance for gene: GLA was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Neurodegenerative disorders, adult onset v3.17 GLA Achchuthan Shanmugasundram Classified gene: GLA as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.17 GLA Achchuthan Shanmugasundram Gene: gla has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.16 GLA Achchuthan Shanmugasundram reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fabry disease, OMIM:301500; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Neurodegenerative disorders, adult onset v3.16 COL4A2 Achchuthan Shanmugasundram Phenotypes for gene: COL4A2 were changed from to Brain small vessel disease 2, OMIM:614483; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519
Neurodegenerative disorders, adult onset v3.15 COL4A2 Achchuthan Shanmugasundram Mode of inheritance for gene: COL4A2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.14 COL4A2 Achchuthan Shanmugasundram Classified gene: COL4A2 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.14 COL4A2 Achchuthan Shanmugasundram Gene: col4a2 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.13 COL4A2 Achchuthan Shanmugasundram reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 2, OMIM:614483, {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.13 COL4A1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and most patients had adult-onset of disorder.; to: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotypes and most patients had adult-onset of disorder.

Relevant phenotypes have already been reported in both OMIM and G2P.
Neurodegenerative disorders, adult onset v3.13 COL4A1 Achchuthan Shanmugasundram Phenotypes for gene: COL4A1 were changed from to Brain small vessel disease with or without ocular anomalies, OMIM:175780; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519
Neurodegenerative disorders, adult onset v3.12 COL4A1 Achchuthan Shanmugasundram Mode of inheritance for gene: COL4A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.11 COL4A1 Achchuthan Shanmugasundram Classified gene: COL4A1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.11 COL4A1 Achchuthan Shanmugasundram Gene: col4a1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.10 COL4A1 Achchuthan Shanmugasundram reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease with or without ocular anomalies, OMIM:175780, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564, {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v3.10 COL4A1 Achchuthan Shanmugasundram Deleted their review
Neurodegenerative disorders, adult onset v3.10 COL4A1 Achchuthan Shanmugasundram reviewed gene: COL4A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease with or without ocular anomalies, OMIM:175780, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:v; Mode of inheritance: None
IUGR and IGF abnormalities v1.56 IGFALS Arina Puzriakova Phenotypes for gene: IGFALS were changed from Short stature; delayed puberty; very low IGF-I levels to Acid-labile subunit, deficiency of, OMIM:615961; Short stature; Delayed puberty; Very low IGF-I levels
COVID-19 research v1.135 STAT5B Arina Puzriakova Phenotypes for gene: STAT5B were changed from Combined immunodeficiency; T-B+ SCID; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Growth hormone insensitivity with immunodeficiency 245590; Combined immunodeficiencies with associated or syndromic features to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, OMIM:618985; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features
Intellectual disability v4.31 STAT5B Arina Puzriakova Mode of inheritance for gene: STAT5B was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v3.2 STAT5B Arina Puzriakova Phenotypes for gene: STAT5B were changed from Growth hormone insensitivity with immunodeficiency 245590; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, OMIM:618985; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features
Intellectual disability v4.30 STAT5B Arina Puzriakova Phenotypes for gene: STAT5B were changed from to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, OMIM:618985
Intellectual disability v4.29 GHR Arina Puzriakova Phenotypes for gene: GHR were changed from Laron dwarfism, 262500; Short stature, 604271; {Hypercholesterolemia, familial, modifier of}, 143890; Increased responsiveness to growth hormone to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271
Skeletal dysplasia v3.3 GHR Arina Puzriakova Phenotypes for gene: GHR were changed from {Hypercholesterolemia, familial, modification of}, 143890; Growth hormone insensitivity; Short stature, 604271; increased responsiveness to growth hormone 604271; Increased responsiveness to growth hormone; Laron dwarfism, 262500; Proportionate Short Stature/Small for Gestational Age to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271
Pituitary hormone deficiency v2.104 GHR Arina Puzriakova changed review comment from: Review submitted on behalf of Helen Storr - "This gene is currently on panel R159.1 Pituitary hormone deficiency. It should be removed from this panel as it does not cause GH deficiency - it is causes defective GH signalling."

Variants in this gene confer dysfunction of the growth hormone receptor resulting in altered signalling. GH levels are typically normal or increased and therefore inclusion of GHR on this panel should be re-evaluated by the GMS Endocrinology Specialist Test Group.

This gene may possibly be more appropriate for R147 Growth failure in early childhood, but this is currently also pending expert review (https://panelapp.genomicsengland.co.uk/panels/473/gene/GHR/); to: Review submitted on behalf of Helen Storr - "This gene is currently on panel R159.1 Pituitary hormone deficiency. It should be removed from this panel as it does not cause GH deficiency - it is causes defective GH signalling."

Variants in this gene confer dysfunction of the growth hormone receptor resulting in altered signalling. GH levels are typically normal or increased and therefore inclusion of GHR on this panel should be re-evaluated by the GMS Endocrinology Specialist Test Group.

GHR may possibly be more appropriate for R147 Growth failure in early childhood, but relevance is currently also pending expert review (https://panelapp.genomicsengland.co.uk/panels/473/gene/GHR/)
Pituitary hormone deficiency v2.104 GHR Arina Puzriakova changed review comment from: Review submitted on behalf of Helen Storr - "This gene is currently on panel R159.1 Pituitary hormone deficiency. It should be removed from this panel as it does not cause GH deficiency - it is causes defective GH signalling."

Variants in this gene confer dysfunction of the growth hormone receptor resulting in altered signalling. GH levels are typically normal or increased and therefore inclusion of GHR on this panel should be re-evaluated by the GMS Endocrinology Specialist Test Group.; to: Review submitted on behalf of Helen Storr - "This gene is currently on panel R159.1 Pituitary hormone deficiency. It should be removed from this panel as it does not cause GH deficiency - it is causes defective GH signalling."

Variants in this gene confer dysfunction of the growth hormone receptor resulting in altered signalling. GH levels are typically normal or increased and therefore inclusion of GHR on this panel should be re-evaluated by the GMS Endocrinology Specialist Test Group.

This gene may possibly be more appropriate for R147 Growth failure in early childhood, but this is currently also pending expert review (https://panelapp.genomicsengland.co.uk/panels/473/gene/GHR/)
Pituitary hormone deficiency v2.104 GHR Arina Puzriakova Tag Q1_23_demote_red tag was added to gene: GHR.
Tag Q1_23_expert_review tag was added to gene: GHR.
Pituitary hormone deficiency v2.104 GHR Arina Puzriakova commented on gene: GHR
Pituitary hormone deficiency v2.104 GHR Arina Puzriakova Phenotypes for gene: GHR were changed from Laron dwarfism (262500); Increased responsiveness to growth hormone (604271); Growth hormone insensitivity, partial (604271) to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271
Paediatric pseudo-obstruction syndrome v0.213 PHOX2B Arina Puzriakova Tag STR tag was added to gene: PHOX2B.
Paediatric pseudo-obstruction syndrome v0.213 TPM3 Arina Puzriakova Phenotypes for gene: TPM3 were changed from to Megacolon
Paediatric pseudo-obstruction syndrome v0.212 TPM3 Arina Puzriakova Mode of inheritance for gene: TPM3 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.211 SURF1 Arina Puzriakova Mode of inheritance for gene: SURF1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.210 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011
Paediatric pseudo-obstruction syndrome v0.209 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.208 SCN10A Arina Puzriakova Phenotypes for gene: SCN10A were changed from to Colon sensory neurons activation
Paediatric pseudo-obstruction syndrome v0.207 SCN10A Arina Puzriakova Mode of inheritance for gene: SCN10A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.206 NRTN Arina Puzriakova Publications for gene: NRTN were set to
Paediatric pseudo-obstruction syndrome v0.205 NRTN Arina Puzriakova Phenotypes for gene: NRTN were changed from to susceptibility to Hirschsprung disease
Paediatric pseudo-obstruction syndrome v0.204 NRTN Arina Puzriakova Mode of inheritance for gene: NRTN was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.203 NKX2-1 Arina Puzriakova Publications for gene: NKX2-1 were set to
Paediatric pseudo-obstruction syndrome v0.202 NKX2-1 Arina Puzriakova Phenotypes for gene: NKX2-1 were changed from to Megacolon, oesophageal atresia
Paediatric pseudo-obstruction syndrome v0.201 NKX2-1 Arina Puzriakova Mode of inheritance for gene: NKX2-1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.200 NDUFS1 Arina Puzriakova Phenotypes for gene: NDUFS1 were changed from to Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226
Paediatric pseudo-obstruction syndrome v0.199 NDUFS1 Arina Puzriakova Mode of inheritance for gene: NDUFS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.198 KIF26A Arina Puzriakova Phenotypes for gene: KIF26A were changed from to GDNF-Ret in ENS development
Paediatric pseudo-obstruction syndrome v0.197 KIF26A Arina Puzriakova Mode of inheritance for gene: KIF26A was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.196 FOCAD Arina Puzriakova Mode of inheritance for gene: FOCAD was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.195 MPV17 Arina Puzriakova Mode of inheritance for gene: MPV17 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v3.10 CTSA Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be promoted to GREEN for adult-onset neurodegenerative disorders as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P; to: Comment on classification: This gene should be promoted to GREEN for adult-onset neurodegenerative disorders as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese. The evidence from literature also confirms the adult-onset nature of this disorder.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P
Neurodegenerative disorders, adult onset v3.10 CTSA Achchuthan Shanmugasundram Phenotypes for gene: CTSA were changed from Cathepsin a-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551 to Cathepsin A-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551
Neurodegenerative disorders, adult onset v3.9 CTSA Achchuthan Shanmugasundram Phenotypes for gene: CTSA were changed from to Cathepsin a-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551
Neurodegenerative disorders, adult onset v3.8 CTSA Achchuthan Shanmugasundram Publications for gene: CTSA were set to
Neurodegenerative disorders, adult onset v3.7 CTSA Achchuthan Shanmugasundram Mode of inheritance for gene: CTSA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.6 CTSA Achchuthan Shanmugasundram Classified gene: CTSA as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v3.6 CTSA Achchuthan Shanmugasundram Gene: ctsa has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v3.5 CTSA Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be rated GREEN for adult-onset neurodegenerative disorders as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P; to: Comment on classification: This gene should be promoted to GREEN for adult-onset neurodegenerative disorders as this gene has been implicated in >10 unrelated patients of multiple ancestry including Europeans and Chinese.

This gene has not yet been associated with this disorder caused by autosomal dominant inheritance in OMIM. However, it has already been associated with galactosialidosis (autosomal recessive disorder) ion both OMIM and G2P
Neurodegenerative disorders, adult onset v3.5 CTSA Achchuthan Shanmugasundram reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 27664989, 28702507, 35904593; Phenotypes: cathepsin a-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial cerebral small vessel disease v1.16 CST3 Arina Puzriakova Phenotypes for gene: CST3 were changed from Stroke; haemorrhagic stroke; dementia; Cerebral amyloid angiopathy 105150 to Cerebral amyloid angiopathy, OMIM:105150
Periodic fever syndromes v1.33 CST3 Arina Puzriakova Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy 105150 to Cerebral amyloid angiopathy, OMIM:105150
Neurodegenerative disorders, adult onset v3.5 CST3 Arina Puzriakova Phenotypes for gene: CST3 were changed from to Cerebral amyloid angiopathy, OMIM:105150
Leukodystrophy, adult onset v2.8 CST3 Arina Puzriakova Phenotypes for gene: CST3 were changed from to Cerebral amyloid angiopathy, OMIM:105150
Leukodystrophy, adult onset v2.7 APP Arina Puzriakova Classified gene: APP as Amber List (moderate evidence)
Leukodystrophy, adult onset v2.7 APP Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated cases including relevant phenotype (leukoencephalopathy) and age of onset (~44 to 60 years).
Leukodystrophy, adult onset v2.7 APP Arina Puzriakova Gene: app has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v2.6 APP Arina Puzriakova Publications for gene: APP were set to
Familial cerebral small vessel disease v1.15 APP Arina Puzriakova Phenotypes for gene: APP were changed from Haemorrhagic stroke; stroke; ischaemic stroke; leukoencephalopathy; seizures; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants 605714 to Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, OMIM:605714; Haemorrhagic stroke; Ischaemic stroke; Leukoencephalopathy; Seizures
Periodic fever syndromes v1.32 APP Arina Puzriakova Phenotypes for gene: APP were changed from Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants 605714 to Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, OMIM:605714
Leukodystrophy, adult onset v2.5 APP Arina Puzriakova Mode of inheritance for gene: APP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.4 APP Arina Puzriakova Phenotypes for gene: APP were changed from to Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, OMIM:605714
Familial Hirschsprung Disease v1.10 EDNRB Arina Puzriakova Phenotypes for gene: EDNRB were changed from susceptibility to Hirschsprung disease 2, 600155; Waardenburg syndrome, type 4A, 277580; {Hirschsprung disease, susceptibility to, 2}, 600155; Waardenburg syndrome, type 4A, 277580; Hirschsprung Disease, Recessive; Waardenburg; HSCR (short-segment type); colonic aganglionosis; Shah-Waardenburg syndrome; long-segment Hirschsprung's disease; short-segment Hirschsprung's disease to Waardenburg syndrome, type 4A, OMIM:277580; {Hirschsprung disease, susceptibility to, 2}, OMIM:600155; ?ABCD syndrome, OMIM:600501; Colonic aganglionosis; Shah-Waardenburg syndrome; Long-segment Hirschsprung's disease; Short-segment Hirschsprung's disease
Paediatric pseudo-obstruction syndrome v0.194 EDNRB Arina Puzriakova Publications for gene: EDNRB were set to
Paediatric pseudo-obstruction syndrome v0.193 EDNRB Arina Puzriakova Classified gene: EDNRB as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.193 EDNRB Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to rate this gene as Green. Mouse model of colonic aganglionosis plus >3 unrelated cases supporting gene:disease association (e.g. PMID:20009762, 10528251, 25852447, 16618617).
Paediatric pseudo-obstruction syndrome v0.193 EDNRB Arina Puzriakova Gene: ednrb has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.192 EDNRB Arina Puzriakova Tag monogenic-polygenic tag was added to gene: EDNRB.
Paediatric pseudo-obstruction syndrome v0.192 EDNRB Arina Puzriakova commented on gene: EDNRB
Paediatric pseudo-obstruction syndrome v0.192 EDNRB Arina Puzriakova Mode of inheritance for gene: EDNRB was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.191 EDNRB Arina Puzriakova Phenotypes for gene: EDNRB were changed from to Waardenburg syndrome, type 4A, OMIM:277580; {Hirschsprung disease, susceptibility to, 2}, OMIM:600155; ?ABCD syndrome, OMIM:600501
Paediatric pseudo-obstruction syndrome v0.190 EDN3 Arina Puzriakova Classified gene: EDN3 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.190 EDN3 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to rate this gene as Green. >3 unrelated cases of EDN3 variants causing Waardenburg syndrome, type 4 (WS4). Note that WS4 is diagnosed when WS2 is accompanied by Hirschsprung disease. Hirschsprung's disease also occurs in ~16% of patients with congenital central hypoventilation syndrome/CCHS, which is also caused by EDN3 variants.
Paediatric pseudo-obstruction syndrome v0.190 EDN3 Arina Puzriakova Gene: edn3 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.189 EDN3 Arina Puzriakova commented on gene: EDN3
Paediatric pseudo-obstruction syndrome v0.189 EDN3 Arina Puzriakova Tag monogenic-polygenic tag was added to gene: EDN3.
Paediatric pseudo-obstruction syndrome v0.189 EDN3 Arina Puzriakova Mode of inheritance for gene: EDN3 was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.188 EDN3 Arina Puzriakova Publications for gene: EDN3 were set to
Paediatric pseudo-obstruction syndrome v0.187 EDN3 Arina Puzriakova Phenotypes for gene: EDN3 were changed from to Waardenburg syndrome, type 4B, OMIM:613265; {Hirschsprung disease, susceptibility to, 4}, OMIM:613712
Paediatric pseudo-obstruction syndrome v0.186 ECE1 Arina Puzriakova Publications for gene: ECE1 were set to
Paediatric pseudo-obstruction syndrome v0.185 ECE1 Arina Puzriakova Classified gene: ECE1 as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v0.185 ECE1 Arina Puzriakova Added comment: Comment on list classification: Only a single human patient discovered to date - Hofstra et al. (1999, PMID:9915973) identified heterozygosity an R742C mutation in the ECE1 gene in a patient with skip-lesions Hirschsprung disease, cardiac defects, craniofacial abnormalities and other dysmorphic features, and autonomic dysfunction (HCAD, MIM:613870). Given mouse model displays distal intestinal aganglionosis (PMID: 9449665; 17131407) have rated Amber but additional human cases are required to meet diagnostic-grade criteria.
Paediatric pseudo-obstruction syndrome v0.185 ECE1 Arina Puzriakova Gene: ece1 has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v0.184 ECE1 Arina Puzriakova Mode of inheritance for gene: ECE1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.183 ECE1 Arina Puzriakova Phenotypes for gene: ECE1 were changed from to ?Hirschsprung disease, cardiac defects, and autonomic dysfunction, OMIM:613870
Paediatric pseudo-obstruction syndrome v0.182 DLX2 Arina Puzriakova Phenotypes for gene: DLX2 were changed from to Abnormal bowel motility in mice
Paediatric pseudo-obstruction syndrome v0.181 DLX2 Arina Puzriakova Publications for gene: DLX2 were set to
Paediatric pseudo-obstruction syndrome v0.180 DLX2 Arina Puzriakova Mode of inheritance for gene: DLX2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.179 DLX2 Arina Puzriakova Classified gene: DLX2 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.179 DLX2 Arina Puzriakova Added comment: Comment on list classification: No human cases with pathogenic DLX2 variants reported to date and therefore this gene should be rated Red.

Mice lacking DLX1 and DLX2 had slower small bowel transit and reduced or absent neurally-mediated contraction complexes, and have reduced vasoactive intestinal peptide (VIP) expression and fewer VIP-lineage neurons in their enteric nervous system. Small bowel motility seemed normal in adult mice lacking only DLX1 (PMID: 32017713).
Paediatric pseudo-obstruction syndrome v0.179 DLX2 Arina Puzriakova Gene: dlx2 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.178 DLX1 Arina Puzriakova changed review comment from: Comment on list classification: No human cases with pathogenic DLX1 variants reported to date and therefore this gene should be rated Red.

Mice lacking DLX1 and DLX2 had slower small bowel transit and reduced or absent neurally-mediated contraction complexes, and have reduced vasoactive intestinal peptide (VIP) expression and fewer VIP-lineage neurons in their enteric nervous system. Small bowel motility seemed normal in adult mice lacking only DLX1.; to: Comment on list classification: No human cases with pathogenic DLX1 variants reported to date and therefore this gene should be rated Red.

Mice lacking DLX1 and DLX2 had slower small bowel transit and reduced or absent neurally-mediated contraction complexes, and have reduced vasoactive intestinal peptide (VIP) expression and fewer VIP-lineage neurons in their enteric nervous system. Small bowel motility seemed normal in adult mice lacking only DLX1 (PMID: 32017713).
Paediatric pseudo-obstruction syndrome v0.178 DLX1 Arina Puzriakova Classified gene: DLX1 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.178 DLX1 Arina Puzriakova Added comment: Comment on list classification: No human cases with pathogenic DLX1 variants reported to date and therefore this gene should be rated Red.

Mice lacking DLX1 and DLX2 had slower small bowel transit and reduced or absent neurally-mediated contraction complexes, and have reduced vasoactive intestinal peptide (VIP) expression and fewer VIP-lineage neurons in their enteric nervous system. Small bowel motility seemed normal in adult mice lacking only DLX1.
Paediatric pseudo-obstruction syndrome v0.178 DLX1 Arina Puzriakova Gene: dlx1 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.177 DLX1 Arina Puzriakova Mode of inheritance for gene: DLX1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.176 DLX1 Arina Puzriakova Publications for gene: DLX1 were set to
Paediatric pseudo-obstruction syndrome v0.175 DLX1 Arina Puzriakova Phenotypes for gene: DLX1 were changed from to Abnormal bowel motility in mice
Paediatric pseudo-obstruction syndrome v0.174 DGUOK Arina Puzriakova Classified gene: DGUOK as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.174 DGUOK Arina Puzriakova Added comment: Comment on list classification: Could not find clear evidence linking this gene with intestinal pseudo-obstruction and therefore recommending Red gene rating at this time. DGUOK causes a hepatocerebral mitochondrial depletion disorder characterised by hepatic dysfunction, psychomotor delay, hypotonia, nystagmus/opsoclonus, lactic acidosis, hypoglycemia.
Paediatric pseudo-obstruction syndrome v0.174 DGUOK Arina Puzriakova Gene: dguok has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.173 DGUOK Arina Puzriakova Publications for gene: DGUOK were set to
Paediatric pseudo-obstruction syndrome v0.172 DGUOK Arina Puzriakova Phenotypes for gene: DGUOK were changed from to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), OMIM:251880
Paediatric pseudo-obstruction syndrome v0.171 ZEB2 Achchuthan Shanmugasundram Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome, OMIM:235730
Paediatric pseudo-obstruction syndrome v0.170 ZEB2 Achchuthan Shanmugasundram Publications for gene: ZEB2 were set to
Paediatric pseudo-obstruction syndrome v0.169 ZEB2 Achchuthan Shanmugasundram Mode of inheritance for gene: ZEB2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v0.168 ZEB2 Achchuthan Shanmugasundram Classified gene: ZEB2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.168 ZEB2 Achchuthan Shanmugasundram Gene: zeb2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.167 ZEB2 Achchuthan Shanmugasundram reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11279515; Phenotypes: Mowat-Wilson syndrome, OMIM:235730; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v0.167 TYMP Achchuthan Shanmugasundram Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), OMIM:603041
Paediatric pseudo-obstruction syndrome v0.166 TYMP Achchuthan Shanmugasundram Publications for gene: TYMP were set to
Paediatric pseudo-obstruction syndrome v0.165 TYMP Achchuthan Shanmugasundram Mode of inheritance for gene: TYMP was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.164 TYMP Achchuthan Shanmugasundram Classified gene: TYMP as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.164 TYMP Achchuthan Shanmugasundram Gene: tymp has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.163 TYMP Achchuthan Shanmugasundram reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31848803, 32898308, 33825174; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), OMIM:603041; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.163 TWNK Achchuthan Shanmugasundram Phenotypes for gene: TWNK were changed from to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Perrault syndrome 5, OMIM:616138
Paediatric pseudo-obstruction syndrome v0.162 TWNK Achchuthan Shanmugasundram Mode of inheritance for gene: TWNK was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.161 TWNK Achchuthan Shanmugasundram Publications for gene: TWNK were set to
Paediatric pseudo-obstruction syndrome v0.160 TWNK Achchuthan Shanmugasundram reviewed gene: TWNK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245, Perrault syndrome 5, OMIM:616138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.160 TTC7A Achchuthan Shanmugasundram Phenotypes for gene: TTC7A were changed from to Gastrointestinal defects and immunodeficiency syndrome, OMIM:243150
Paediatric pseudo-obstruction syndrome v0.159 TTC7A Achchuthan Shanmugasundram Publications for gene: TTC7A were set to
Paediatric pseudo-obstruction syndrome v0.158 TTC7A Achchuthan Shanmugasundram Mode of inheritance for gene: TTC7A was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.157 TTC7A Achchuthan Shanmugasundram Classified gene: TTC7A as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.157 TTC7A Achchuthan Shanmugasundram Gene: ttc7a has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.156 TTC7A Achchuthan Shanmugasundram reviewed gene: TTC7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31787977, 34975848, 34985046, 35627206; Phenotypes: Gastrointestinal defects and immunodeficiency syndrome, OMIM:243150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.156 TK2 Achchuthan Shanmugasundram Classified gene: TK2 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.156 TK2 Achchuthan Shanmugasundram Gene: tk2 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.155 TK2 Achchuthan Shanmugasundram edited their review of gene: TK2: Added comment: Comment on list classification: This gene should be rated RED as I do not see any association of this gene with intestinal dysmotility and pseudo-obstruction.

This gene has been associated with mitochondrial DNA depletion syndrome 2 (myopathic type) (MIM #609560) in OMIM. However, this disorder is characterised by hypotonia and muscle weakness, facial weakness, bulbar weakness (dysarthria and dysphagia) and elevated serum creatine phosphokinase. I do not see any clear indication of links of this disorder with either pseudo-obstruction or intestinal dysmotility.; Changed rating: RED
Paediatric pseudo-obstruction syndrome v0.155 TK2 Achchuthan Shanmugasundram Deleted their comment
Paediatric pseudo-obstruction syndrome v0.155 SUCLG1 Achchuthan Shanmugasundram Classified gene: SUCLG1 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.155 SUCLG1 Achchuthan Shanmugasundram Gene: suclg1 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.154 SUCLG1 Achchuthan Shanmugasundram edited their review of gene: SUCLG1: Added comment: Comment on list classification: This gene should be rated RED as I do not see any association of this gene with intestinal dysmotility and pseudo-obstruction.

This gene has been associated with mitochondrial DNA depletion syndrome 9 (encephalomyopathic with or without methylmalonic aciduria) (MIM #245400) in OMIM. However, this disorder is characterised by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Although other frequent manifestations include feeding difficulty and gastroesophageal reflux, there is no clear indication of any links of this disorder with either pseudo-obstruction or intestinal dysmotility.; Changed rating: RED
Paediatric pseudo-obstruction syndrome v0.154 SUCLG1 Achchuthan Shanmugasundram Deleted their comment
Paediatric pseudo-obstruction syndrome v0.154 SUCLA2 Achchuthan Shanmugasundram Classified gene: SUCLA2 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.154 SUCLA2 Achchuthan Shanmugasundram Gene: sucla2 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.153 SUCLA2 Achchuthan Shanmugasundram edited their review of gene: SUCLA2: Added comment: Comment on list classification: This gene should be rated RED as I do not see any association of this gene with intestinal dysmotility and pseudo-obstruction.

This gene has been associated with mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) (MIM #612073) in OMIM. However, this disorder is characterised by infantile onset of hypotonia, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, variable renal tubular dysfunction, and mild methylmalonic aciduria. Although other frequent manifestations include feeding difficulty and gastroesophageal reflux, there is no clear indication of any links of this disorder with either pseudo-obstruction or intestinal dysmotility.; Changed rating: RED
Paediatric pseudo-obstruction syndrome v0.153 SUCLA2 Achchuthan Shanmugasundram Deleted their comment
Paediatric pseudo-obstruction syndrome v0.153 MPV17 Achchuthan Shanmugasundram Phenotypes for gene: MPV17 were changed from Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); OMIM:256810 to Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), OMIM:256810
Paediatric pseudo-obstruction syndrome v0.152 MPV17 Achchuthan Shanmugasundram edited their review of gene: MPV17: Changed phenotypes to: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), OMIM:256810
Paediatric pseudo-obstruction syndrome v0.152 MPV17 Achchuthan Shanmugasundram changed review comment from: Comment on rating: The rating should be GREEN as this gene has been implicated in Navajo neurohepatopathy (MIM #256810) from multiple (>3) unrelated cases, and supported by functional studies.

PMID:35750291 recently reported two patients from unrelated families with different variants from MPV17 gene.

PMID:29282788 summarised the clinical features of 100 affected individuals with a total of 48 pathogenic variants in MPV17 gene, of which 25 new individuals with nine novel variants were reported in this publication.

This gene-disease association was already reported in both OMIM and G2P.; to: Comment on rating: The rating should be GREEN as this gene has been implicated in Navajo neurohepatopathy (MIM #256810) from multiple (>3) unrelated cases, and supported by functional studies.

PMID:35750291 recently reported two patients from unrelated families with different variants from MPV17 gene.

PMID:29282788 summarised the clinical features of 100 affected individuals with a total of 48 pathogenic variants in MPV17 gene, of which 25 new individuals with nine novel variants were reported in this publication. About a third of these individuals have feeding difficulties and gastrointestinal dysmotility manifesting as gastroesophagal reflux, recurrent vomiting, and diarrhoea.

This gene-disease association was already reported in both OMIM and G2P.
Paediatric pseudo-obstruction syndrome v0.152 TPM3 Achchuthan Shanmugasundram reviewed gene: TPM3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.152 TK2 Achchuthan Shanmugasundram Phenotypes for gene: TK2 were changed from to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Paediatric pseudo-obstruction syndrome v0.151 TK2 Achchuthan Shanmugasundram Publications for gene: TK2 were set to
Paediatric pseudo-obstruction syndrome v0.150 TK2 Achchuthan Shanmugasundram Mode of inheritance for gene: TK2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.149 TK2 Achchuthan Shanmugasundram Classified gene: TK2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.149 TK2 Achchuthan Shanmugasundram Gene: tk2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.148 TK2 Achchuthan Shanmugasundram reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23385875; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.148 SURF1 Achchuthan Shanmugasundram Phenotypes for gene: SURF1 were changed from to Mitochondrial complex IV deficiency, nuclear type 1, OMIM:220110
Paediatric pseudo-obstruction syndrome v0.147 SURF1 Achchuthan Shanmugasundram edited their review of gene: SURF1: Changed phenotypes to: Mitochondrial complex IV deficiency, nuclear type 1, OMIM:220110
Paediatric pseudo-obstruction syndrome v0.147 SURF1 Achchuthan Shanmugasundram reviewed gene: SURF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.147 SUCLG1 Achchuthan Shanmugasundram Phenotypes for gene: SUCLG1 were changed from to Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria), OMIM:245400
Paediatric pseudo-obstruction syndrome v0.146 SUCLG1 Achchuthan Shanmugasundram Publications for gene: SUCLG1 were set to
Paediatric pseudo-obstruction syndrome v0.145 SUCLG1 Achchuthan Shanmugasundram Mode of inheritance for gene: SUCLG1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.144 SUCLG1 Achchuthan Shanmugasundram Classified gene: SUCLG1 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.144 SUCLG1 Achchuthan Shanmugasundram Gene: suclg1 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.143 SUCLG1 Achchuthan Shanmugasundram edited their review of gene: SUCLG1: Changed rating: GREEN
Paediatric pseudo-obstruction syndrome v0.143 SUCLG1 Achchuthan Shanmugasundram reviewed gene: SUCLG1: Rating: ; Mode of pathogenicity: None; Publications: 19526370, 20453710, 23385875, 26028457, 33230783, 35762302; Phenotypes: Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria), OMIM:245400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.143 SUCLA2 Achchuthan Shanmugasundram Phenotypes for gene: SUCLA2 were changed from to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), OMIM:612073
Paediatric pseudo-obstruction syndrome v0.142 SUCLA2 Achchuthan Shanmugasundram Publications for gene: SUCLA2 were set to
Paediatric pseudo-obstruction syndrome v0.141 SUCLA2 Achchuthan Shanmugasundram Mode of inheritance for gene: SUCLA2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.140 SUCLA2 Achchuthan Shanmugasundram Classified gene: SUCLA2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.140 SUCLA2 Achchuthan Shanmugasundram Gene: sucla2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.139 SUCLA2 Achchuthan Shanmugasundram reviewed gene: SUCLA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23385875; Phenotypes: Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), OMIM:612073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.139 SOX10 Achchuthan Shanmugasundram Phenotypes for gene: SOX10 were changed from to PCWH syndrome, OMIM:609136; Waardenburg syndrome, type 4C, OMIM:613266
Paediatric pseudo-obstruction syndrome v0.138 SOX10 Achchuthan Shanmugasundram Publications for gene: SOX10 were set to
Paediatric pseudo-obstruction syndrome v0.137 SOX10 Achchuthan Shanmugasundram Mode of inheritance for gene: SOX10 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.136 SOX10 Achchuthan Shanmugasundram Classified gene: SOX10 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.136 SOX10 Achchuthan Shanmugasundram Gene: sox10 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.135 SOX10 Achchuthan Shanmugasundram reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 12189494; Phenotypes: PCWH syndrome, OMIM:609136, Waardenburg syndrome, type 4C, OMIM:613266; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.135 SGO1 Achchuthan Shanmugasundram Phenotypes for gene: SGO1 were changed from to Chronic atrial and intestinal dysrhythmia, OMIM:616201
Paediatric pseudo-obstruction syndrome v0.134 SGO1 Achchuthan Shanmugasundram Publications for gene: SGO1 were set to
Paediatric pseudo-obstruction syndrome v0.133 SGO1 Achchuthan Shanmugasundram Mode of inheritance for gene: SGO1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.132 SGO1 Achchuthan Shanmugasundram Classified gene: SGO1 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.132 SGO1 Achchuthan Shanmugasundram Gene: sgo1 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.131 SGO1 Achchuthan Shanmugasundram reviewed gene: SGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25282101, 31848803; Phenotypes: Chronic atrial and intestinal dysrhythmia, OMIM:616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.131 SEMA3F Achchuthan Shanmugasundram Publications for gene: SEMA3F were set to
Paediatric pseudo-obstruction syndrome v0.130 SEMA3F Achchuthan Shanmugasundram Phenotypes for gene: SEMA3F were changed from to megacolon, MONDO:0001273
Paediatric pseudo-obstruction syndrome v0.129 SEMA3F Achchuthan Shanmugasundram Mode of inheritance for gene: SEMA3F was changed from to Unknown
Paediatric pseudo-obstruction syndrome v0.128 SEMA3F Achchuthan Shanmugasundram reviewed gene: SEMA3F: Rating: RED; Mode of pathogenicity: None; Publications: 30663199; Phenotypes: megacolon, MONDO:0001273; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.128 SDHA Achchuthan Shanmugasundram edited their review of gene: SDHA: Changed rating: RED
Paediatric pseudo-obstruction syndrome v0.128 SDHA Achchuthan Shanmugasundram commented on gene: SDHA
Paediatric pseudo-obstruction syndrome v0.128 SCN10A Achchuthan Shanmugasundram reviewed gene: SCN10A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.128 RRM2B Achchuthan Shanmugasundram Phenotypes for gene: RRM2B were changed from to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), OMIM:612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type), OMIM:612075
Paediatric pseudo-obstruction syndrome v0.127 RRM2B Achchuthan Shanmugasundram Publications for gene: RRM2B were set to
Paediatric pseudo-obstruction syndrome v0.126 RRM2B Achchuthan Shanmugasundram Mode of inheritance for gene: RRM2B was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.125 RRM2B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene should be rated RED as this gene was associated with mitochondrial DNA depletion syndrome 8B (MNGIE type) (#612075) from only one patient from PMID:19667227.

This adult patient exhibited clinical findings strongly suggestive for MNGIE such as gastrointestinal dysmotility, cachexia and peripheral neuropathy. This patient also showed severe mtDNA depletion in muscle tissue and was identified with two variants in the RRM2B gene.

Although gastrointestinal phenotypes are found in some of the patients with mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) (10 out of 31), these are limited to recurrent vomiting, feed intolerance, chronic diarrhea and cachexia and none of them had gastrointestinal dysmotility or pseudo-obstruction.

This gene is associated with relevant phenotypes in both OMIM and G2P.; to: Comment on list classification: This gene should be rated RED as this gene was associated with mitochondrial DNA depletion syndrome 8B (MNGIE type) (#612075) from only one patient from PMID:19667227.

This adult patient exhibited clinical findings strongly suggestive for MNGIE such as gastrointestinal dysmotility, cachexia and peripheral neuropathy. This patient also showed severe mtDNA depletion in muscle tissue and was identified with two variants in the RRM2B gene.

Although gastrointestinal phenotypes are found in some of the patients with mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) (10 out of 31), these are limited to recurrent vomiting, feed intolerance, chronic diarrhea and cachexia and none of them had gastrointestinal dysmotility or pseudo-obstruction (PMID:24741716).

This gene is associated with relevant phenotypes in both OMIM and G2P.
Paediatric pseudo-obstruction syndrome v0.125 RRM2B Achchuthan Shanmugasundram edited their review of gene: RRM2B: Changed publications to: 19667227, 23385875, 24741716
Paediatric pseudo-obstruction syndrome v0.125 RRM2B Achchuthan Shanmugasundram reviewed gene: RRM2B: Rating: RED; Mode of pathogenicity: None; Publications: 19667227, 23385875; Phenotypes: Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), OMIM:612075, Mitochondrial DNA depletion syndrome 8B (MNGIE type), OMIM:612075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.125 RET Achchuthan Shanmugasundram Phenotypes for gene: RET were changed from to {Hirschsprung disease, susceptibility to, 1}, 142623; {Hirschsprung disease, protection against}, 142623
Paediatric pseudo-obstruction syndrome v0.124 RET Achchuthan Shanmugasundram Publications for gene: RET were set to
Paediatric pseudo-obstruction syndrome v0.123 RET Achchuthan Shanmugasundram Mode of inheritance for gene: RET was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.122 RET Achchuthan Shanmugasundram Classified gene: RET as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.122 RET Achchuthan Shanmugasundram Gene: ret has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.121 RET Achchuthan Shanmugasundram reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: 21960833, 31848803, 34092334, 36521661; Phenotypes: {Hirschsprung disease, susceptibility to, 1}, 142623, {Hirschsprung disease, protection against}, 142623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.121 RAD21 Achchuthan Shanmugasundram Phenotypes for gene: RAD21 were changed from to Mungan syndrome, OMIM:611376
Paediatric pseudo-obstruction syndrome v0.120 RAD21 Achchuthan Shanmugasundram Publications for gene: RAD21 were set to
Paediatric pseudo-obstruction syndrome v0.119 RAD21 Achchuthan Shanmugasundram Mode of inheritance for gene: RAD21 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.118 RAD21 Achchuthan Shanmugasundram Classified gene: RAD21 as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v0.118 RAD21 Achchuthan Shanmugasundram Gene: rad21 has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v0.117 RAD21 Achchuthan Shanmugasundram Classified gene: RAD21 as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v0.117 RAD21 Achchuthan Shanmugasundram Gene: rad21 has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v0.116 RAD21 Achchuthan Shanmugasundram reviewed gene: RAD21: Rating: AMBER; Mode of pathogenicity: None; Publications: 14638363, 21832993, 25575569, 31848803, 32687945; Phenotypes: Mungan syndrome, OMIM:611376; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.116 PROKR2 Achchuthan Shanmugasundram Phenotypes for gene: PROKR2 were changed from to Hirschsprung disease, MONDO:0018309
Paediatric pseudo-obstruction syndrome v0.115 PROKR2 Achchuthan Shanmugasundram Publications for gene: PROKR2 were set to
Paediatric pseudo-obstruction syndrome v0.114 PROKR2 Achchuthan Shanmugasundram Mode of inheritance for gene: PROKR2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.113 PROKR2 Achchuthan Shanmugasundram Classified gene: PROKR2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.113 PROKR2 Achchuthan Shanmugasundram Gene: prokr2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.112 PROKR2 Achchuthan Shanmugasundram reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21858136; Phenotypes: Hirschsprung disease, MONDO:0018309; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.112 PROKR1 Achchuthan Shanmugasundram Phenotypes for gene: PROKR1 were changed from to Hirschsprung disease, MONDO:0018309
Paediatric pseudo-obstruction syndrome v0.111 PROKR1 Achchuthan Shanmugasundram Publications for gene: PROKR1 were set to
Paediatric pseudo-obstruction syndrome v0.110 PROKR1 Achchuthan Shanmugasundram Mode of inheritance for gene: PROKR1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.109 PROKR1 Achchuthan Shanmugasundram Classified gene: PROKR1 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.109 PROKR1 Achchuthan Shanmugasundram Gene: prokr1 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.108 PROKR1 Achchuthan Shanmugasundram reviewed gene: PROKR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21858136; Phenotypes: Hirschsprung disease, MONDO:0018309; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.108 PROK1 Achchuthan Shanmugasundram Phenotypes for gene: PROK1 were changed from to Hirschsprung disease, MONDO:0018309
Paediatric pseudo-obstruction syndrome v0.107 PROK1 Achchuthan Shanmugasundram Publications for gene: PROK1 were set to
Paediatric pseudo-obstruction syndrome v0.106 PROK1 Achchuthan Shanmugasundram Mode of inheritance for gene: PROK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.105 PROK1 Achchuthan Shanmugasundram Classified gene: PROK1 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.105 PROK1 Achchuthan Shanmugasundram Gene: prok1 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.104 PROK1 Achchuthan Shanmugasundram reviewed gene: PROK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21858136; Phenotypes: Hirschsprung disease, MONDO:0018309; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.104 POLG Achchuthan Shanmugasundram Phenotypes for gene: POLG were changed from to Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662
Paediatric pseudo-obstruction syndrome v0.103 POLG Achchuthan Shanmugasundram Publications for gene: POLG were set to
Paediatric pseudo-obstruction syndrome v0.102 POLG Achchuthan Shanmugasundram Mode of inheritance for gene: POLG was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.101 POLG Achchuthan Shanmugasundram Classified gene: POLG as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.101 POLG Achchuthan Shanmugasundram Gene: polg has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.100 POLG Achchuthan Shanmugasundram reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 12825077, 19307547, 21993618, 23385875, 31848803; Phenotypes: Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.100 PDCL3 Achchuthan Shanmugasundram Phenotypes for gene: PDCL3 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome, MONDO:0025986
Paediatric pseudo-obstruction syndrome v0.99 PDCL3 Achchuthan Shanmugasundram Publications for gene: PDCL3 were set to
Paediatric pseudo-obstruction syndrome v0.98 PDCL3 Achchuthan Shanmugasundram Mode of inheritance for gene: PDCL3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.97 PDCL3 Achchuthan Shanmugasundram reviewed gene: PDCL3: Rating: RED; Mode of pathogenicity: None; Publications: 32621347; Phenotypes: megacystis-microcolon-intestinal hypoperistalsis syndrome, MONDO:0025986; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.97 NKX2-1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Not associated with any relevant phenotype in OMIM or G2P. PMID:30663199 does not report any cases associated with NKX2-1 and a quick literature search did not find any literature making an association. So, this gene should be rated as RED.; to: Comment on list classification: The phenotypes that are reported in OMIM or G2P are not relevant to this panel. PMID:30663199 does not report any cases associated with NKX2-1 and a quick literature search did not find any literature making an association. So, this gene should be rated as RED.
Paediatric pseudo-obstruction syndrome v0.97 NRTN Achchuthan Shanmugasundram reviewed gene: NRTN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.97 NKX2-1 Achchuthan Shanmugasundram reviewed gene: NKX2-1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.97 NDUFS1 Achchuthan Shanmugasundram reviewed gene: NDUFS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.97 MYLK Achchuthan Shanmugasundram Phenotypes for gene: MYLK were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 1, OMIM:249210
Paediatric pseudo-obstruction syndrome v0.96 MYLK Achchuthan Shanmugasundram Publications for gene: MYLK were set to
Paediatric pseudo-obstruction syndrome v0.95 MYLK Achchuthan Shanmugasundram Mode of inheritance for gene: MYLK was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.94 MYLK Achchuthan Shanmugasundram Classified gene: MYLK as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.94 MYLK Achchuthan Shanmugasundram Gene: mylk has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.93 MYLK Achchuthan Shanmugasundram reviewed gene: MYLK: Rating: GREEN; Mode of pathogenicity: None; Publications: 28602422, 31848803, 33729000; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 1, OMIM:249210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.93 MYL9 Achchuthan Shanmugasundram Phenotypes for gene: MYL9 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 4, OMIM:619365
Paediatric pseudo-obstruction syndrome v0.92 MYL9 Achchuthan Shanmugasundram Publications for gene: MYL9 were set to
Paediatric pseudo-obstruction syndrome v0.91 MYL9 Achchuthan Shanmugasundram Mode of inheritance for gene: MYL9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.90 MYL9 Achchuthan Shanmugasundram Classified gene: MYL9 as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v0.90 MYL9 Achchuthan Shanmugasundram Gene: myl9 has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v0.89 MYL9 Achchuthan Shanmugasundram reviewed gene: MYL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 27481187, 31848803, 33031641, 33729000; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 4, OMIM:619365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.89 MYH11 Achchuthan Shanmugasundram Phenotypes for gene: MYH11 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 2, OMIM:619351; Visceral myopathy 2, OMIM:619350
Paediatric pseudo-obstruction syndrome v0.88 MYH11 Achchuthan Shanmugasundram Publications for gene: MYH11 were set to
Paediatric pseudo-obstruction syndrome v0.87 MYH11 Achchuthan Shanmugasundram Mode of inheritance for gene: MYH11 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.86 MYH11 Achchuthan Shanmugasundram edited their review of gene: MYH11: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.86 MYH11 Achchuthan Shanmugasundram Classified gene: MYH11 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.86 MYH11 Achchuthan Shanmugasundram Gene: myh11 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.85 MYH11 Achchuthan Shanmugasundram reviewed gene: MYH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 25407000, 29575632, 31044419, 31389005, 31427716, 31848803, 31944481, 33729000; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 2, OMIM:619351, Visceral myopathy 2, OMIM:619350; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.85 MPV17 Achchuthan Shanmugasundram Phenotypes for gene: MPV17 were changed from to Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); OMIM:256810
Paediatric pseudo-obstruction syndrome v0.84 MPV17 Achchuthan Shanmugasundram Publications for gene: MPV17 were set to
Paediatric pseudo-obstruction syndrome v0.83 MPV17 Achchuthan Shanmugasundram Classified gene: MPV17 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.83 MPV17 Achchuthan Shanmugasundram Gene: mpv17 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.82 MPV17 Achchuthan Shanmugasundram reviewed gene: MPV17: Rating: GREEN; Mode of pathogenicity: None; Publications: 23385875, 29282788, 35750291; Phenotypes: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), OMIM:256810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.28 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from Polymicrogyria, symmetric or asymmetric, 610031; POLYMICROGYRIA ASYMMETRIC (PMGA) to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Hereditary ataxia, adult onset v3.6 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from Complex cortical dysplasia with other brain abnormalities 7, 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Early onset or syndromic epilepsy v3.19 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from Cortical dysplasia, complex, with other brain malformations 7, 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Fetal anomalies v2.8 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from POLYMICROGYRIA ASYMMETRIC to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Cerebellar hypoplasia v1.72 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from complex cortical dysplasia with other brain malformations-7 , 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Malformations of cortical development v3.9 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from Polymicrogyria, symmetric or asymmetric 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Ataxia and cerebellar anomalies - childhood onset v3.21 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from complex cortical dysplasia with other brain malformations-7 , 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Leukodystrophy, adult onset v2.3 PRNP Eleanor Williams changed review comment from: Review submitted on behalf of David Lynch, James Polke, Henry Houlden, Lucy Jenkins. Mode of inheritance: AD. Phenotype: Cerebral amyloid angiopathy,PRNP-related. Evidence: MIM: 137440.; to: Review submitted on behalf of David Lynch, James Polke, Henry Houlden, Lucy Jenkins. Mode of inheritance: AD. Phenotype: Cerebral amyloid angiopathy, PRNP-related. Evidence: MIM: 137440.
Leukodystrophy, adult onset v2.3 TTR Eleanor Williams reviewed gene: TTR: Rating: ; Mode of pathogenicity: ; Publications: 25802113, 31257920, 27466465, 34663645, 28991667, 35040071, 29779881, 34390072; Phenotypes: Cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 LAMB1 Eleanor Williams reviewed gene: LAMB1: Rating: ; Mode of pathogenicity: ; Publications: 34606115; Phenotypes: Cerebral small vessel disease, with leukoencephalopathy and hippocampal memory impairment; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 PSEN2 Eleanor Williams reviewed gene: PSEN2: Rating: ; Mode of pathogenicity: ; Publications: 9450781; Phenotypes: PSEN2 related cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 PSEN1 Eleanor Williams reviewed gene: PSEN1: Rating: ; Mode of pathogenicity: ; Publications: 34319632, 26888304, 11489138, 11395394; Phenotypes: PSEN1 related cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 PRNP Eleanor Williams reviewed gene: PRNP: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebral amyloid angiopathy,PRNP-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 GSN Eleanor Williams reviewed gene: GSN: Rating: ; Mode of pathogenicity: ; Publications: 25097823; Phenotypes: Hereditary gelsolin amyloidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 ITM2B Eleanor Williams reviewed gene: ITM2B: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Familial British Dementia/Familial Danish Dementia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 CST3 Eleanor Williams reviewed gene: CST3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.3 APP Eleanor Williams reviewed gene: APP: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: CEREBRAL AMYLOID ANGIOPATHY,APP-RELATED; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Leukodystrophy, adult onset v2.2 TTR Eleanor Williams gene: TTR was added
gene: TTR was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: TTR was set to
Leukodystrophy, adult onset v2.2 PSEN2 Eleanor Williams gene: PSEN2 was added
gene: PSEN2 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: PSEN2 was set to
Leukodystrophy, adult onset v2.2 PSEN1 Eleanor Williams gene: PSEN1 was added
gene: PSEN1 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: PSEN1 was set to
Leukodystrophy, adult onset v2.2 PRNP Eleanor Williams gene: PRNP was added
gene: PRNP was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: PRNP was set to
Leukodystrophy, adult onset v2.2 GSN Eleanor Williams gene: GSN was added
gene: GSN was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GSN was set to
Leukodystrophy, adult onset v2.2 ITM2B Eleanor Williams gene: ITM2B was added
gene: ITM2B was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: ITM2B was set to
Leukodystrophy, adult onset v2.2 CST3 Eleanor Williams gene: CST3 was added
gene: CST3 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: CST3 was set to
Leukodystrophy, adult onset v2.2 APP Eleanor Williams gene: APP was added
gene: APP was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: APP was set to
Neurological segmental overgrowth v2.2 TBC1D7 Arina Puzriakova Phenotypes for gene: TBC1D7 were changed from MGCPH; Macrocephaly/megalencephaly syndrome, autosomal recessive, 248000 to Macrocephaly/megalencephaly syndrome, autosomal recessive, OMIM:248000
Intellectual disability v4.27 TBC1D7 Arina Puzriakova Phenotypes for gene: TBC1D7 were changed from intellectual disability; macrocephaly; megalencephaly to Macrocephaly/megalencephaly syndrome, autosomal recessive, OMIM:248000
Malformations of cortical development v3.8 SLC35A2 Arina Puzriakova Tag Q4_22_expert_review was removed from gene: SLC35A2.
Tag mosaicism tag was added to gene: SLC35A2.
Tag somatic tag was added to gene: SLC35A2.
Malformations of cortical development v3.8 SLC35A2 Arina Puzriakova Phenotypes for gene: SLC35A2 were changed from Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) to Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE); Congenital disorder of glycosylation, type IIm, OMIM:300896
Malformations of cortical development v3.7 SLC35A2 Arina Puzriakova Publications for gene: SLC35A2 were set to 33407896
Malformations of cortical development v3.6 SLC35A2 Arina Puzriakova Classified gene: SLC35A2 as Amber List (moderate evidence)
Malformations of cortical development v3.6 SLC35A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene-disease association and regardless of ability to detect somatic variants via this panel, there are enough cases with germline variants to warrant inclusion with a Green classification. Somatic cases should be picked up via other routes such as R429 'Mosaic brain disorders - deep sequencing' which is catered to somatic variant detection.
Malformations of cortical development v3.6 SLC35A2 Arina Puzriakova Gene: slc35a2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v3.5 SLC35A2 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: SLC35A2.
Tag Q4_22_expert_review tag was added to gene: SLC35A2.
Neurodegenerative disorders, adult onset v3.4 TTR Eleanor Williams reviewed gene: TTR: Rating: ; Mode of pathogenicity: ; Publications: 29779881, 31257920, 34390072, 27466465, 35040071, 25802113, 34663645, 28991667; Phenotypes: Cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 LAMB1 Eleanor Williams reviewed gene: LAMB1: Rating: ; Mode of pathogenicity: ; Publications: 34606115; Phenotypes: Cerebral small vessel disease, with leukoencephalopathy and hippocampal memory impairment; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 GSN Eleanor Williams reviewed gene: GSN: Rating: ; Mode of pathogenicity: ; Publications: 25097823; Phenotypes: Hereditary gelsolin amyloidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 CST3 Eleanor Williams reviewed gene: CST3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebral amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 TREX1 Eleanor Williams reviewed gene: TREX1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 GLA Eleanor Williams reviewed gene: GLA: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Fabry disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Neurodegenerative disorders, adult onset v3.4 COL4A2 Eleanor Williams reviewed gene: COL4A2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Brain small vessel disease 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 COL4A1 Eleanor Williams reviewed gene: COL4A1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Brain small vessel disease with or without ocular anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.4 CTSA Eleanor Williams reviewed gene: CTSA: Rating: ; Mode of pathogenicity: ; Publications: 35904593, 28702507, 27664989; Phenotypes: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v3.3 TTR Eleanor Williams gene: TTR was added
gene: TTR was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: TTR was set to
Neurodegenerative disorders, adult onset v3.3 LAMB1 Eleanor Williams gene: LAMB1 was added
gene: LAMB1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: LAMB1 was set to
Neurodegenerative disorders, adult onset v3.3 GSN Eleanor Williams gene: GSN was added
gene: GSN was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GSN was set to
Neurodegenerative disorders, adult onset v3.3 CST3 Eleanor Williams gene: CST3 was added
gene: CST3 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: CST3 was set to
Neurodegenerative disorders, adult onset v3.3 GLA Eleanor Williams gene: GLA was added
gene: GLA was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GLA was set to
Neurodegenerative disorders, adult onset v3.3 COL4A2 Eleanor Williams gene: COL4A2 was added
gene: COL4A2 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: COL4A2 was set to
Neurodegenerative disorders, adult onset v3.3 COL4A1 Eleanor Williams gene: COL4A1 was added
gene: COL4A1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: COL4A1 was set to
Neurodegenerative disorders, adult onset v3.3 CTSA Eleanor Williams gene: CTSA was added
gene: CTSA was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: CTSA was set to
Paediatric pseudo-obstruction syndrome v0.82 PHOX2B Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance of both monoalleic and biallelic has been selected as PubMed: 30672101 reports a family where monoallelic family members are unaffected, but the compound heterozygous patient is affected.
Paediatric pseudo-obstruction syndrome v0.82 PHOX2B Sarah Leigh Mode of inheritance for gene: PHOX2B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.81 PHOX2B Sarah Leigh Classified gene: PHOX2B as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.81 PHOX2B Sarah Leigh Gene: phox2b has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.80 PHOX2B Sarah Leigh reviewed gene: PHOX2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.80 PHOX2B Sarah Leigh Publications for gene: PHOX2B were set to 30672101; 29543228; 12438263
Paediatric pseudo-obstruction syndrome v0.79 PHOX2B Sarah Leigh Publications for gene: PHOX2B were set to 30672101
Paediatric pseudo-obstruction syndrome v0.78 PHOX2B Sarah Leigh Phenotypes for gene: PHOX2B were changed from Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880; central hypoventilation syndrome, congenital, MONDO:0800031 to Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880; central hypoventilation syndrome, congenital, MONDO:0800031; Neuroblastoma with Hirschsprung disease, OMIM:613013; neuroblastoma, susceptibility to, 2, MONDO:0700041
Paediatric pseudo-obstruction syndrome v0.77 PHOX2B Sarah Leigh Mode of inheritance for gene: PHOX2B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.76 PHOX2B Sarah Leigh Publications for gene: PHOX2B were set to
Paediatric pseudo-obstruction syndrome v0.75 PHOX2B Sarah Leigh Phenotypes for gene: PHOX2B were changed from to Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880; central hypoventilation syndrome, congenital, MONDO:0800031
Paediatric pseudo-obstruction syndrome v0.74 PHOX2B Sarah Leigh Mode of inheritance for gene: PHOX2B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v3.6 POMGNT2 Eleanor Williams reviewed gene: POMGNT2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Muscle Eye Brain disease, Walker Warburg disease, limb girdle muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.6 POMGNT1 Eleanor Williams reviewed gene: POMGNT1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: non-syndromic Retinitis Pigmentosa, Walker Warburg syndrome, Muscle-eye-brain disease, dystroglycanopathy, retinal detachment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.6 STN1 Eleanor Williams reviewed gene: STN1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Coats plus syndrome, cerebroretinal microangiopathy with calcifications and cysts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.6 COL11A1 Eleanor Williams reviewed gene: COL11A1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Stickler syndrome, Marshall syndrome,, beaded vitreous, early onset hearing loss, retinal detachment; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v3.6 COL9A3 Eleanor Williams reviewed gene: COL9A3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: stickler syndrome, retinal degeneration, retinal detachment; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v3.6 COL9A2 Eleanor Williams reviewed gene: COL9A2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Stickler Syndrome, high myopia, retinal detachment,; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.6 COL9A1 Eleanor Williams reviewed gene: COL9A1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Stickler Syndrome, high myopia, retinal detachment, sensorineural hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v3.6 COL2A1 Eleanor Williams reviewed gene: COL2A1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: retinal detachment, Stickler syndrome, cleft palate, hearing impairment, cataract,; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v3.5 POMGNT2 Eleanor Williams gene: POMGNT2 was added
gene: POMGNT2 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: POMGNT2 was set to
Retinal disorders v3.5 STN1 Eleanor Williams gene: STN1 was added
gene: STN1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: STN1 was set to
Retinal disorders v3.5 COL9A3 Eleanor Williams gene: COL9A3 was added
gene: COL9A3 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: COL9A3 was set to
Intellectual disability v4.26 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia; LISSENCEPHALY TYPE 1 (LIS1) to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Early onset or syndromic epilepsy v3.18 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Lissencephaly 1 607432 to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Fetal anomalies v2.7 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from LISSENCEPHALY TYPE 1; SUBCORTICAL BAND HETEROTOPIA to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Inherited white matter disorders v1.167 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Cerebral Malformation Disorders; Lissencephaly 1; Lissencephaly/Subcortical Band Heterotopia to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Malformations of cortical development v3.5 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Lissencephaly 1 607432; Subcortical laminar heterotopia 607432 to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
White matter disorders and cerebral calcification - childhood onset v2.7 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Lissencephaly 1; Cerebral Malformation Disorders; Lissencephaly/Subcortical Band Heterotopia to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Cerebral vascular malformations v2.66 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Cerebral Malformation Disorders to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Early onset or syndromic epilepsy v3.17 NPRL2 Arina Puzriakova Phenotypes for gene: NPRL2 were changed from Epilepsy, familial focal, with variable foci 2, 617116 to Epilepsy, familial focal, with variable foci 2, OMIM:617116
Unexplained death in infancy and sudden unexplained death in childhood v3.0 Eleanor Williams Added Panel Unexplained death in infancy and childhood
Set child panels to: Genetic epilepsy syndromes; Inborn errors of metabolism; Long QT syndrome; Cardiomyopathies - including childhood onset
Set panel types to: Super Panel
Paediatric pseudo-obstruction syndrome v0.73 LMOD1 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: This gene should be rated GREEN, as this gene has been implicated in megacystis microcolon intestinal hypoperistalsis syndrome in two unrelated patients and is supported by evidence from mouse model.

A dutch female infant identified with homozygous nonsense variant (p.R370X) died at 5 days of life. Both her parents were heterozygous for the same variant. The clinical presentations include distended and lax abdominal wall, with palpable intestines, bladder distention, bilateral distention of the proximal ureters, and hydronephrosis (PMID:28292896).

A male infant with compound heterozygous missense variants (p.T369M; p.R421H) was also presented with typical symptoms of pediatric intestinal pseudo-obstruction (PIPO) but without megacystis and microcolon (PMID:35170814).

A mouse model with a similar Lmod1 mutation, engineered with CRISPR-Cas9 genome editing, exhibited the same gastrointestinal and urinary bladder phenotypes as seen in the dutch female infant (PMID:28292896).; to: Comment on classification of this gene: This gene should be rated GREEN, as this gene has been implicated in megacystis microcolon intestinal hypoperistalsis syndrome in two unrelated patients and is supported by evidence from mouse model.

A dutch female infant identified with homozygous nonsense variant (p.R370X) died at 5 days of life. Both her parents were heterozygous for the same variant. The clinical presentations include distended and lax abdominal wall, with palpable intestines, bladder distention, bilateral distention of the proximal ureters, and hydronephrosis (PMID:28292896).

A male infant with compound heterozygous missense variants (p.T369M; p.R421H) was also presented with typical symptoms of pediatric intestinal pseudo-obstruction (PIPO) but without megacystis and microcolon (PMID:35170814).

A mouse model with a similar Lmod1 mutation, engineered with CRISPR-Cas9 genome editing, exhibited the same gastrointestinal and urinary bladder phenotypes as seen in the dutch female infant (PMID:28292896).

This gene-disease association has already been reported in OMIM.
Paediatric pseudo-obstruction syndrome v0.73 LMOD1 Achchuthan Shanmugasundram Publications for gene: LMOD1 were set to
Paediatric pseudo-obstruction syndrome v0.72 LMOD1 Achchuthan Shanmugasundram Phenotypes for gene: LMOD1 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, OMIM:619362
Paediatric pseudo-obstruction syndrome v0.71 LMOD1 Achchuthan Shanmugasundram Mode of inheritance for gene: LMOD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.70 LMOD1 Achchuthan Shanmugasundram Classified gene: LMOD1 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.70 LMOD1 Achchuthan Shanmugasundram Gene: lmod1 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.69 LMOD1 Achchuthan Shanmugasundram reviewed gene: LMOD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28292896, 35170814; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, OMIM:619362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.25 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-linked, 300067Subcortical laminal heteropia, X-linked, 300067; SUBCORTICAL BAND HETEROTOPIA X-LINKED (SBHX) to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Early onset or syndromic epilepsy v3.16 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-linked 300067; Subcortical laminal heterotopia, X-linked 300067 to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Fetal anomalies v2.6 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from SUBCORTICAL BAND HETEROTOPIA X-LINKED; LISSENCEPHALY X-LINKED TYPE 1 to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Inherited white matter disorders v1.166 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Cerebral Malformation Disorders; Lissencephaly, X-Linked, 1; Classic Lissencephaly/Subcortical Band Heterotopia; Lissencephaly, X-linked, 300067; Subcortical laminal heteropia, X-linked, 300067 to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Malformations of cortical development v3.4 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-linked 300067; Subcortical laminal heteropia, X-linked 300067; Classic Lissencephaly/Subcortical Band Heterotopia to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
White matter disorders and cerebral calcification - childhood onset v2.6 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-Linked, 1; Subcortical laminal heteropia, X-linked, 300067; Cerebral Malformation Disorders; Lissencephaly, X-linked, 300067; Classic Lissencephaly/Subcortical Band Heterotopia to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Cerebral vascular malformations v2.65 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Cerebral Malformation Disorders to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Cerebral vascular malformations v2.64 DCX Arina Puzriakova Mode of inheritance for gene: DCX was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric pseudo-obstruction syndrome v0.69 DGUOK Arina Puzriakova Mode of inheritance for gene: DGUOK was changed from to BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v3.5 DDX3X Arina Puzriakova Classified gene: DDX3X as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v3.5 DDX3X Arina Puzriakova Gene: ddx3x has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v3.4 DDX3X Arina Puzriakova Publications for gene: DDX3X were set to
Hereditary spastic paraplegia, childhood onset v3.3 DDX3X Arina Puzriakova Classified gene: DDX3X as Red List (low evidence)
Hereditary spastic paraplegia, childhood onset v3.3 DDX3X Arina Puzriakova Gene: ddx3x has been classified as Red List (Low Evidence).
Hereditary spastic paraplegia, childhood onset v3.2 DDX3X Arina Puzriakova changed review comment from: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop movement disorders. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature; to: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop a movement disorder. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v3.2 DDX3X Arina Puzriakova edited their review of gene: DDX3X: Changed publications to: 26235985, 29490693, 30936465, 32852922
Hereditary spastic paraplegia, childhood onset v3.2 DDX3X Arina Puzriakova gene: DDX3X was added
gene: DDX3X was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q4_22_promote_green tags were added to gene: DDX3X.
Mode of inheritance for gene: DDX3X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: DDX3X were set to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Review for gene: DDX3X was set to GREEN
Added comment: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop movement disorders. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature
Paediatric pseudo-obstruction syndrome v0.68 DDX3X Arina Puzriakova Publications for gene: DDX3X were set to
Paediatric pseudo-obstruction syndrome v0.67 DDX3X Arina Puzriakova Classified gene: DDX3X as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.67 DDX3X Arina Puzriakova Added comment: Comment on list classification: This gene is associated with a syndromic ID phenotype. Gastrointestinal disturbances were exhibited by one patient with severe constipation and a recurrent paralytic ileus (PMID: 32896648), and another patient with persistent gastro-oesophageal reflux (PMID: 30734472) although the latter isn't within the scope of this panel. Based on only one individual found displaying a phenotype that is relevant to this panel, recommending this gene is rated Red until further cases are reported. Cases are more likely to be picked up via other routes such as the ID panel.
Paediatric pseudo-obstruction syndrome v0.67 DDX3X Arina Puzriakova Gene: ddx3x has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.66 LIG3 Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
Paediatric pseudo-obstruction syndrome v0.65 LIG3 Achchuthan Shanmugasundram Publications for gene: LIG3 were set to
Paediatric pseudo-obstruction syndrome v0.64 LIG3 Achchuthan Shanmugasundram Mode of inheritance for gene: LIG3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.63 LIG3 Achchuthan Shanmugasundram Classified gene: LIG3 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.63 LIG3 Achchuthan Shanmugasundram Gene: lig3 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.62 LIG3 Achchuthan Shanmugasundram changed review comment from: Comment on rating: The rating should be GREEN as this gene has been implicated in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MIM #619780) from seven patients from three unrelated families, and supported by functional studies.

These patients harboured compound heterozygous variants (family 1: p.K537N & p.G964R; family 2: p.C999Y & p.R267Ter; family 3: p.P609L & p.R811Ter) and their clinical phenotypes resembled the mitochondrial MINGE disease in many aspects. Severe dysmotility of the gut was present in all patients and most patients fulfilled the diagnostic criteria for CIPO.

Evidence from skeletal muscle biopsies from patients from all three families showed mitochondrial dysfunction. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. In addition, LIG3 gene defects result in mitochondrial DNA depletion.

In vivo modelling of LIG3 mutations in zebrafish model also reproduced the brain alterations and impaired gut transit.; to: Comment on rating: The rating should be GREEN as this gene has been implicated in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MIM #619780) from seven patients from three unrelated families, and supported by functional studies.

These patients harboured compound heterozygous variants (family 1: p.K537N & p.G964R; family 2: p.C999Y & p.R267Ter; family 3: p.P609L & p.R811Ter) and their clinical phenotypes resembled the mitochondrial MINGE disease in many aspects. Severe dysmotility of the gut was present in all patients and most patients fulfilled the diagnostic criteria for CIPO.

Evidence from skeletal muscle biopsies from patients from all three families showed mitochondrial dysfunction. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. In addition, LIG3 gene defects result in mitochondrial DNA depletion.

In vivo modelling of LIG3 mutations in zebrafish model also reproduced the brain alterations and impaired gut transit.

This gene has already been reported in OMIM.
Paediatric pseudo-obstruction syndrome v0.62 LIG3 Achchuthan Shanmugasundram reviewed gene: LIG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33855352; Phenotypes: Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.24 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from Intellectual disability, Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Clefting v3.3 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from MENTAL RETARDATION, X-LINKED 102; MRX102 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Fetal anomalies v2.5 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from INTELLECTUAL DIABILITY; Intellectual disability; Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Early onset or syndromic epilepsy v3.15 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Paediatric pseudo-obstruction syndrome v0.62 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from Intellectual developmental disorder, X-linked syndromic, Snijders Blok type 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Paediatric pseudo-obstruction syndrome v0.61 DDX3X Arina Puzriakova Mode of inheritance for gene: DDX3X was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric pseudo-obstruction syndrome v0.60 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type 300958
Paediatric pseudo-obstruction syndrome v0.59 COX15 Arina Puzriakova Classified gene: COX15 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.59 COX15 Arina Puzriakova Added comment: Comment on list classification: Could not find clear evidence linking this gene with intestinal pseudo-obstruction and therefore recommending Red gene rating at this time.
Paediatric pseudo-obstruction syndrome v0.59 COX15 Arina Puzriakova Gene: cox15 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.58 L1CAM Achchuthan Shanmugasundram commented on gene: L1CAM: Added a 'monogenic-polygenic' tag based on patient in PMID:22344793 who carried both L1CAM and RET variants.
Paediatric pseudo-obstruction syndrome v0.58 L1CAM Achchuthan Shanmugasundram Tag monogenic-polygenic tag was added to gene: L1CAM.
Paediatric pseudo-obstruction syndrome v0.58 L1CAM Achchuthan Shanmugasundram Classified gene: L1CAM as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.58 L1CAM Achchuthan Shanmugasundram Gene: l1cam has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.57 L1CAM Achchuthan Shanmugasundram Mode of inheritance for gene: L1CAM was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Paediatric pseudo-obstruction syndrome v0.56 L1CAM Achchuthan Shanmugasundram Phenotypes for gene: L1CAM were changed from to Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, OMIM:307000
Paediatric pseudo-obstruction syndrome v0.55 L1CAM Achchuthan Shanmugasundram Publications for gene: L1CAM were set to
Paediatric pseudo-obstruction syndrome v0.54 L1CAM Achchuthan Shanmugasundram reviewed gene: L1CAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 28543993, 20860806, 22344793, 11857550, 15148591, 19641926, 9279760; Phenotypes: Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, OMIM:307000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Paediatric pseudo-obstruction syndrome v0.54 KIF26A Achchuthan Shanmugasundram Publications for gene: KIF26A were set to
Paediatric pseudo-obstruction syndrome v0.53 KIF26A Achchuthan Shanmugasundram reviewed gene: KIF26A: Rating: RED; Mode of pathogenicity: None; Publications: 19914172, 33542431; Phenotypes: ; Mode of inheritance: None
Paediatric pseudo-obstruction syndrome v0.53 COX15 Arina Puzriakova Mode of inheritance for gene: COX15 was changed from to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.571 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Leigh syndrome due to cytochrome c oxidase deficiency, 256000Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Dystonia, chorea or related movement disorder, childhood onset v2.3 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Intellectual disability v4.23 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Leigh syndrome due to cytochrome c oxidase deficiency, 256000Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Paediatric or syndromic cardiomyopathy v2.4 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; Leigh syndrome due to cytochrome c oxidase deficiency, 256000 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Mitochondrial disorders v3.4 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Isolated complex IV deficiency; Leigh syndrome due to cytochrome c oxidase deficiency, 256000; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Dystonia, chorea or related movement disorder, adult onset v2.3 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Early onset or syndromic epilepsy v3.14 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 615119; Leigh syndrome 256000 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Likely inborn error of metabolism v3.4 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Leigh syndrome due to cytochrome c oxidase deficiency, 256000; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Possible mitochondrial disorder, nuclear genes v2.3 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Leigh syndrome due to cytochrome c oxidase deficiency, 256000; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Structural basal ganglia disorders v1.35 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Mitochondrial disorder with complex IV deficiency v2.3 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Leigh syndrome due to cytochrome c oxidase deficiency, 256000; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Inherited white matter disorders v1.165 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Mitochondrial Leukoencephalopathy; Mitochondrial complex IV disorders to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119; Mitochondrial Leukoencephalopathy
White matter disorders and cerebral calcification - childhood onset v2.5 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Mitochondrial complex IV disorders; Mitochondrial Leukoencephalopathy to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119; Mitochondrial Leukoencephalopathy
Paediatric pseudo-obstruction syndrome v0.52 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Likely inborn error of metabolism v3.3 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency
Undiagnosed metabolic disorders v1.570 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency
Dystonia, chorea or related movement disorder, childhood onset v2.2 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Mitochondrial complex IV deficiency, 220110; Leigh syndrome due to mitochondrial COX4 deficiency, 256000 to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Paediatric or syndromic cardiomyopathy v2.3 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Dystonia, chorea or related movement disorder, adult onset v2.2 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Leigh syndrome due to mitochondrial COX4 deficiency, 256000; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Mitochondrial disorders v3.3 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Isolated complex IV deficiency; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Intellectual disability v4.22 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from LEIGH SYNDROME (LS) to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Early onset or syndromic epilepsy v3.13 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Early onset or syndromic epilepsy v3.12 COX10 Arina Puzriakova Mode of inheritance for gene: COX10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v2.4 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY; LEIGH SYNDROME to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Possible mitochondrial disorder, nuclear genes v2.2 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Mitochondrial disorder with complex IV deficiency v2.2 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Structural basal ganglia disorders v1.34 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Unexplained young onset end-stage renal disease v2.4 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency
CAKUT v1.173 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency
Unexplained kidney failure in young people v1.117 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due tocytochrome c oxidase deficiency
Inherited white matter disorders v1.164 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Mitochondrial complex IV disorder; Mitochondrial Leukoencephalopathy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Paediatric pseudo-obstruction syndrome v0.51 GFRA1 Achchuthan Shanmugasundram Phenotypes for gene: GFRA1 were changed from to Susceptibility to Hirschsprung disease, MONDO:0100179
Paediatric pseudo-obstruction syndrome v0.50 GFRA1 Achchuthan Shanmugasundram Publications for gene: GFRA1 were set to
White matter disorders and cerebral calcification - childhood onset v2.4 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitochondrial Leukoencephalopathy; Mitochondrial complex IV disorder to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Paediatric pseudo-obstruction syndrome v0.49 GFRA1 Achchuthan Shanmugasundram Mode of inheritance for gene: GFRA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v0.48 GFRA1 Achchuthan Shanmugasundram Classified gene: GFRA1 as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v0.48 GFRA1 Achchuthan Shanmugasundram Gene: gfra1 has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v0.47 GFRA1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: GFRA1.
Paediatric pseudo-obstruction syndrome v0.47 GFRA1 Achchuthan Shanmugasundram changed review comment from: Added watchlist tag as panel 63 to be notified of additional cases.; to: Added watchlist tag as in panel 63 to be notified of additional cases.
Paediatric pseudo-obstruction syndrome v0.47 GFRA1 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: Tis gene should be rated AMBER as curated in Familial Hirschsprung Disease panel (https://panelapp.genomicsengland.co.uk/panels/63/gene/GFRA1/). There is only limited literature evidence to support a causation role in Hirschsprung disease.

This gene is not associated with Susceptibility to Hirschsprung disease in OMIM yet.; to: Comment on classification of this gene: This gene should be rated AMBER as curated in Familial Hirschsprung Disease panel (https://panelapp.genomicsengland.co.uk/panels/63/gene/GFRA1/). There is only limited literature evidence to support a causation role in Hirschsprung disease.

This gene has not yet been associated with Susceptibility to Hirschsprung disease in OMIM.
Familial Hirschsprung Disease v1.9 GFRA1 Achchuthan Shanmugasundram Deleted their review
Paediatric pseudo-obstruction syndrome v0.47 GFRA1 Achchuthan Shanmugasundram commented on gene: GFRA1: Added watchlist tag as panel 63 to be notified of additional cases.
Paediatric pseudo-obstruction syndrome v0.47 COX10 Arina Puzriakova Classified gene: COX10 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.47 COX10 Arina Puzriakova Added comment: Comment on list classification: Could not find clear evidence linking this gene with intestinal pseudo-obstruction and therefore recommending Red gene rating at this time.
Paediatric pseudo-obstruction syndrome v0.47 COX10 Arina Puzriakova Gene: cox10 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.46 GFRA1 Achchuthan Shanmugasundram reviewed gene: GFRA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28543993, 27370713, 9545641, 17507417, 12624147; Phenotypes: Susceptibility to Hirschsprung disease, MONDO:0100179; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial Hirschsprung Disease v1.9 GFRA1 Achchuthan Shanmugasundram commented on gene: GFRA1: Added watchlist tag as panel 63 to be notified of additional cases.
Familial Hirschsprung Disease v1.9 GFRA1 Achchuthan Shanmugasundram reviewed gene: GFRA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28543993, 27370713, 9545641, 17507417, 12624147; Phenotypes: Susceptibility to Hirschsprung disease, MONDO:0100179; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v0.46 CHRNE Arina Puzriakova Publications for gene: CHRNE were set to
Paediatric pseudo-obstruction syndrome v0.45 C17orf107 Arina Puzriakova Publications for gene: C17orf107 were set to
Fetal anomalies v2.3 CHRNE Arina Puzriakova Phenotypes for gene: CHRNE were changed from Myasthenic syndrome, congenital, 4A, slow-channel, 605809; Myasthenic syndrome, congenital, 4B, fast-channel, 616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, 608931 to Myasthenic syndrome, congenital, 4A, slow-channel, OMIM:605809; Myasthenic syndrome, congenital, 4B, fast-channel, OMIM:616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, OMIM:608931
Arthrogryposis v4.3 CHRNE Arina Puzriakova Phenotypes for gene: CHRNE were changed from Myasthenic syndrome, congenital, 4A, slow-channel 605809; Myasthenic syndrome, congenital, 4B, fast-channel 616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency 608931 to Myasthenic syndrome, congenital, 4A, slow-channel, OMIM:605809; Myasthenic syndrome, congenital, 4B, fast-channel, OMIM:616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, OMIM:608931
Paediatric pseudo-obstruction syndrome v0.44 C17orf107 Arina Puzriakova Phenotypes for gene: C17orf107 were changed from to Myasthenic syndrome, congenital, 4A, slow-channel, OMIM:605809; Myasthenic syndrome, congenital, 4B, fast-channel, OMIM:616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, OMIM:608931
Paediatric pseudo-obstruction syndrome v0.43 CHRNE Arina Puzriakova Phenotypes for gene: CHRNE were changed from to Myasthenic syndrome, congenital, 4A, slow-channel, OMIM:605809; Myasthenic syndrome, congenital, 4B, fast-channel, OMIM:616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, OMIM:608931
Paediatric pseudo-obstruction syndrome v0.42 CHRNE Arina Puzriakova Mode of inheritance for gene: CHRNE was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.41 CHRNE Arina Puzriakova Classified gene: CHRNE as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.41 CHRNE Arina Puzriakova Added comment: Comment on list classification: C17orf107 [CHRNE] is associated with congenital myasthenic syndromes, however I could not find clear evidence of intestinal disturbance and therefore recommending a Red gene rating at this time.
Paediatric pseudo-obstruction syndrome v0.41 CHRNE Arina Puzriakova Gene: chrne has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.40 C17orf107 Arina Puzriakova Classified gene: C17orf107 as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.40 C17orf107 Arina Puzriakova Added comment: Comment on list classification: C17orf107 [CHRNE] is associated with congenital myasthenic syndromes, however I could not find clear evidence of intestinal disturbance and therefore recommending a Red gene rating at this time.
Paediatric pseudo-obstruction syndrome v0.40 C17orf107 Arina Puzriakova Gene: c17orf107 has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.39 C17orf107 Arina Puzriakova Mode of inheritance for gene: C17orf107 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.38 GDNF Achchuthan Shanmugasundram Phenotypes for gene: GDNF were changed from to {Hirschsprung disease, susceptibility to, 3}, OMIM:613711
Paediatric pseudo-obstruction syndrome v0.37 GDNF Achchuthan Shanmugasundram Mode of inheritance for gene: GDNF was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.36 GDNF Achchuthan Shanmugasundram reviewed gene: GDNF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hirschsprung disease, susceptibility to, 3}, OMIM:613711; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.36 FLNA Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be GREEN as this gene has been implicated in intestinal pseudo-obstruction, as identified from five unrelated families.

Four patients from family 1 reported with intestinal pseudo-obstruction in PMID:20871226 had diffuse abnormal layering of small intestinal smooth muscle (DAL). At least five males were affected in this family and they were all maternally-related. Both the mother and sister of patient 1 have normal intestinal motility and cranial magnetic resonance imaging, but the sister had a PDA and bifid uvula. Patient 5 from a second family was also reported with variant in FLNA gene (c.7021C>T; p.Gln2341Ter) and the parents also gave birth to a healthy female. Bot these cases suggest biallelic mode of inheritance in females.

2-bp deletion in exon 2 of the FLNA gene was found in the male proband and his second cousin and the variant was present in heterozygous state in the carrier females of the family (PMID:17357080). Similarly, a 4-bp deletion in exon 40 was identified in PMID:26059841, which results in translation of a mutant FLNA missing an internal region of 41 amino acids.

In another family, three males and four females were identified with a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). This variant causes classical X-linked periventricular nodular heterotopia (XL-PNH) in females and an unusual multi-organ phenotype in males (PMID:23873601).

This gene is associated to Intestinal pseudoobstruction, neuronal and Congenital short bowel syndrome in OMIM.; to: Comment on classification of this gene: The rating for this gene should be GREEN as this gene has been implicated in intestinal pseudo-obstruction, as identified from five unrelated families.

Four patients from family 1 reported with intestinal pseudo-obstruction in PMID:20871226 had diffuse abnormal layering of small intestinal smooth muscle (DAL). At least five males were affected in this family and they were all maternally-related. Both the mother and sister of patient 1 have normal intestinal motility and cranial magnetic resonance imaging, but the sister had a PDA and bifid uvula. Patient 5 from a second family was also reported with variant in FLNA gene (c.7021C>T; p.Gln2341Ter) and the parents also gave birth to a healthy female. Bot these cases suggest biallelic mode of inheritance in females.

2-bp deletion in exon 2 of the FLNA gene was found in the male proband and his second cousin and the variant was present in heterozygous state in the carrier females of the family (PMID:17357080). Similarly, a 4-bp deletion in exon 40 was identified in PMID:26059841, which results in translation of a mutant FLNA missing an internal region of 41 amino acids.

In another family, three males and four females were identified with a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). This variant causes classical X-linked periventricular nodular heterotopia (XL-PNH) in females and an unusual multi-organ phenotype in males (PMID:23873601).

This gene is associated with relevant phenotypes in both OMIM and Gene2Phenotype.
Paediatric pseudo-obstruction syndrome v0.36 FLNA Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be GREEN as this gene has been implicated in intestinal pseudo-obstruction, as identified from five unrelated families.

Four patients from family 1 reported with intestinal pseudo-obstruction in PMID:20871226 had diffuse abnormal layering of small intestinal smooth muscle (DAL). At least five males were affected in this family and they were all maternally-related. Both the mother and sister of patient 1 have normal intestinal motility and cranial magnetic resonance imaging, but the sister had a PDA and bifid uvula. Patient 5 from a second family was also reported with variant in FLNA gene (c.7021C>T; p.Gln2341Ter) and the parents also gave birth to a healthy female. Bot these cases suggest biallelic mode of inheritance in females.

2-bp deletion in exon 2 of the FLNA gene was found in the male proband and his second cousin and the variant was present in heterozygous state in the carrier females of the family (PMID:17357080). Similarly, a 4-bp deletion in exon 40 was identified in PMID:26059841, which results in translation of a mutant FLNA missing an internal region of 41 amino acids.

In another family, three males and four females were identified with a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). This variant causes classical X-linked periventricular nodular heterotopia (XL-PNH) in females and an unusual multi-organ phenotype in males (PMID:23873601).; to: Comment on classification of this gene: The rating for this gene should be GREEN as this gene has been implicated in intestinal pseudo-obstruction, as identified from five unrelated families.

Four patients from family 1 reported with intestinal pseudo-obstruction in PMID:20871226 had diffuse abnormal layering of small intestinal smooth muscle (DAL). At least five males were affected in this family and they were all maternally-related. Both the mother and sister of patient 1 have normal intestinal motility and cranial magnetic resonance imaging, but the sister had a PDA and bifid uvula. Patient 5 from a second family was also reported with variant in FLNA gene (c.7021C>T; p.Gln2341Ter) and the parents also gave birth to a healthy female. Bot these cases suggest biallelic mode of inheritance in females.

2-bp deletion in exon 2 of the FLNA gene was found in the male proband and his second cousin and the variant was present in heterozygous state in the carrier females of the family (PMID:17357080). Similarly, a 4-bp deletion in exon 40 was identified in PMID:26059841, which results in translation of a mutant FLNA missing an internal region of 41 amino acids.

In another family, three males and four females were identified with a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). This variant causes classical X-linked periventricular nodular heterotopia (XL-PNH) in females and an unusual multi-organ phenotype in males (PMID:23873601).

This gene is associated to Intestinal pseudoobstruction, neuronal and Congenital short bowel syndrome in OMIM.
Paediatric pseudo-obstruction syndrome v0.36 FOCAD Achchuthan Shanmugasundram Phenotypes for gene: FOCAD were changed from to Chronic intestinal pseudoobstruction, MONDO:0017574
Paediatric pseudo-obstruction syndrome v0.35 FOCAD Achchuthan Shanmugasundram Publications for gene: FOCAD were set to
Paediatric pseudo-obstruction syndrome v0.34 FOCAD Achchuthan Shanmugasundram reviewed gene: FOCAD: Rating: RED; Mode of pathogenicity: None; Publications: 31814461; Phenotypes: Chronic intestinal pseudoobstruction, MONDO:0017574; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.34 FLNA Achchuthan Shanmugasundram Phenotypes for gene: FLNA were changed from to Congenital short bowel syndrome, OMIM:300048; Intestinal pseudoobstruction, neuronal, OMIM:300048
Paediatric pseudo-obstruction syndrome v0.33 FLNA Achchuthan Shanmugasundram Publications for gene: FLNA were set to
Paediatric pseudo-obstruction syndrome v0.32 FLNA Achchuthan Shanmugasundram Mode of inheritance for gene: FLNA was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Paediatric pseudo-obstruction syndrome v0.31 FLNA Achchuthan Shanmugasundram Classified gene: FLNA as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.31 FLNA Achchuthan Shanmugasundram Gene: flna has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.30 FLNA Achchuthan Shanmugasundram reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 17357080, 20871226, 23873601, 26059841, 31848803, 33729000; Phenotypes: Congenital short bowel syndrome, OMIM:300048, Intestinal pseudoobstruction, neuronal, OMIM:300048; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Paediatric pseudo-obstruction syndrome v0.30 ERBB2 Achchuthan Shanmugasundram Publications for gene: ERBB2 were set to 33497358
Paediatric pseudo-obstruction syndrome v0.29 ERBB2 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be RED, as the disease association was identified from only one family.

A Turkish female proband identified with biallelic variants (c.2129C>T/ p.Ala710Val) was reported with arthrogryposis, peripheral neuropathy, hearing loss and ptosis. Her brother with the same variant had similar clinical presentation with short-segment Hirschsprung disease (HSCR). In addition, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen of the brother.

This gene-disease association is reported in OMIM, but not in Gene2Phenotype.; to: Comment on classification of this gene: The rating for this gene should be RED, as the disease association was identified from only one family.

A Turkish female proband identified with biallelic variants (c.2129C>T/ p.Ala710Val) was reported with arthrogryposis, peripheral neuropathy, hearing loss and ptosis. Her brother with the same variant had similar clinical presentation with short-segment Hirschsprung disease (HSCR). In addition, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen of the brother.

This gene-disease association is reported in OMIM, but not in Gene2Phenotype.
Paediatric pseudo-obstruction syndrome v0.29 ERBB2 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be RED, as the disease association was identified from only one family.

A Turkish female proband identified with biallelic variants (c.2129C>T/ p.Ala710Val) was reported with arthrogryposis, peripheral neuropathy, hearing loss and ptosis. Her brother with the same variant had similar clinical presentation with short-segment Hirschsprung disease (HSCR). In addition, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen of the brother.; to: Comment on classification of this gene: The rating for this gene should be RED, as the disease association was identified from only one family.

A Turkish female proband identified with biallelic variants (c.2129C>T/ p.Ala710Val) was reported with arthrogryposis, peripheral neuropathy, hearing loss and ptosis. Her brother with the same variant had similar clinical presentation with short-segment Hirschsprung disease (HSCR). In addition, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen of the brother.

This gene-disease association is reported in OMIM, but not in Gene2Phenotype.
Paediatric pseudo-obstruction syndrome v0.29 ERBB3 Achchuthan Shanmugasundram Publications for gene: ERBB3 were set to
Paediatric pseudo-obstruction syndrome v0.28 ERBB3 Achchuthan Shanmugasundram Phenotypes for gene: ERBB3 were changed from to Visceral neuropathy, familial, 1, autosomal recessive, OMIM:243180
Paediatric pseudo-obstruction syndrome v0.27 ERBB3 Achchuthan Shanmugasundram Mode of inheritance for gene: ERBB3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.26 ERBB3 Achchuthan Shanmugasundram Classified gene: ERBB3 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.26 ERBB3 Achchuthan Shanmugasundram Gene: erbb3 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.25 ERBB3 Achchuthan Shanmugasundram reviewed gene: ERBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33497358; Phenotypes: Visceral neuropathy, familial, 1, autosomal recessive, OMIM:243180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.25 COX10 Arina Puzriakova Mode of inheritance for gene: COX10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.24 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Paediatric pseudo-obstruction syndrome v0.23 BCS1L Arina Puzriakova Classified gene: BCS1L as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.23 BCS1L Arina Puzriakova Added comment: Comment on list classification: Could not find clear evidence linking this gene with intestinal pseudo-obstruction and therefore recommending Red gene rating at this time.
Paediatric pseudo-obstruction syndrome v0.23 BCS1L Arina Puzriakova Gene: bcs1l has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.22 BCS1L Arina Puzriakova Mode of inheritance for gene: BCS1L was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.21 BCS1L Arina Puzriakova Phenotypes for gene: BCS1L were changed from to Mitochondrial complex III deficiency, nuclear type 1, OMIM:124000
Paediatric pseudo-obstruction syndrome v0.20 ERBB2 Achchuthan Shanmugasundram Publications for gene: ERBB2 were set to
Paediatric pseudo-obstruction syndrome v0.19 ERBB2 Achchuthan Shanmugasundram Phenotypes for gene: ERBB2 were changed from to Visceral neuropathy, familial, 2, autosomal recessive, OMIM:619465
Paediatric pseudo-obstruction syndrome v0.18 ERBB2 Achchuthan Shanmugasundram Mode of inheritance for gene: ERBB2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.17 ERBB2 Achchuthan Shanmugasundram reviewed gene: ERBB2: Rating: RED; Mode of pathogenicity: None; Publications: 33497358; Phenotypes: Visceral neuropathy, familial, 2, autosomal recessive, OMIM:619465; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.17 BCR Arina Puzriakova Classified gene: BCR as Red List (low evidence)
Paediatric pseudo-obstruction syndrome v0.17 BCR Arina Puzriakova Added comment: Comment on list classification: Not associated with any relevant phenotype in OMIM or G2P. Only a single patient has been reported in literature (PMID: 34190380) with paediatric intestinal pseudo-obstruction and a heterozygous de novo variant (c.3072+1G>A). Bcr null mice did display growth retardation and impaired gastrointestinal motility but additional patients required prior to adding as diagnostic-grade.
Paediatric pseudo-obstruction syndrome v0.17 BCR Arina Puzriakova Gene: bcr has been classified as Red List (Low Evidence).
Paediatric pseudo-obstruction syndrome v0.16 BCR Arina Puzriakova Phenotypes for gene: BCR were changed from to Paediatric intestinal pseudo-obstruction
Paediatric pseudo-obstruction syndrome v0.15 BCR Arina Puzriakova Mode of inheritance for gene: BCR was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.14 BCR Arina Puzriakova Publications for gene: BCR were set to
Paediatric pseudo-obstruction syndrome v0.13 ACTG2 Arina Puzriakova Publications for gene: ACTG2 were set to 24676022; 24337657; 33729000
Paediatric pseudo-obstruction syndrome v0.12 ACTG2 Arina Puzriakova Publications for gene: ACTG2 were set to 24676022; 24337657; 33729000; 31848803
Paediatric pseudo-obstruction syndrome v0.11 ACTG2 Arina Puzriakova Publications for gene: ACTG2 were set to
Paediatric pseudo-obstruction syndrome v0.10 ACTG2 Arina Puzriakova Classified gene: ACTG2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.10 ACTG2 Arina Puzriakova Gene: actg2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.9 ACTG2 Arina Puzriakova Mode of inheritance for gene: ACTG2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.8 ACTG2 Arina Puzriakova Phenotypes for gene: ACTG2 were changed from Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, OMIM:619431 to Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, OMIM:619431; Visceral myopathy 1, OMIM:155310
Paediatric pseudo-obstruction syndrome v0.7 ACTG2 Arina Puzriakova Phenotypes for gene: ACTG2 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, OMIM:619431
Paediatric pseudo-obstruction syndrome v0.6 ACTA2 Arina Puzriakova Classified gene: ACTA2 as Green List (high evidence)
Paediatric pseudo-obstruction syndrome v0.6 ACTA2 Arina Puzriakova Gene: acta2 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disorders v1.23 ACTA2 Arina Puzriakova Phenotypes for gene: ACTA2 were changed from Multisystemic smooth muscle dysfunction syndrome, MIM# 613834 to Multisystemic smooth muscle dysfunction syndrome, OMIM:613834
Paediatric pseudo-obstruction syndrome v0.5 ACTA2 Arina Puzriakova Publications for gene: ACTA2 were set to
Gastrointestinal neuromuscular disorders v1.22 ACTA2 Arina Puzriakova Classified gene: ACTA2 as Green List (high evidence)
Gastrointestinal neuromuscular disorders v1.22 ACTA2 Arina Puzriakova Gene: acta2 has been classified as Green List (High Evidence).
Paediatric pseudo-obstruction syndrome v0.4 ACTA2 Arina Puzriakova commented on gene: ACTA2
Paediatric pseudo-obstruction syndrome v0.4 ACTA2 Arina Puzriakova Phenotypes for gene: ACTA2 were changed from to Multisystemic smooth muscle dysfunction syndrome, OMIM:613834
Paediatric pseudo-obstruction syndrome v0.3 ACTA2 Arina Puzriakova Mode of inheritance for gene: ACTA2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v2.2 SCN5A Arina Puzriakova Publications for gene: SCN5A were set to 20186049; 27532257
Paediatric or syndromic cardiomyopathy v2.2 SCN5A Arina Puzriakova Publications for gene: SCN5A were set to 24317018; doi:10. 1007/ s12265-016-9673-5
Retinal disorders v3.4 EYS Arina Puzriakova Phenotypes for gene: EYS were changed from Retinitis pigmentosa 25; Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa 25, 602772 to Retinitis pigmentosa 25, OMIM:602772
Retinal disorders v3.3 EYS Arina Puzriakova Publications for gene: EYS were set to
Paediatric pseudo-obstruction syndrome v0.2 ZEB2 Eleanor Williams reviewed gene: ZEB2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Mowat-Wilson syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 TYMP Eleanor Williams reviewed gene: TYMP: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Accumulation of thymidine in mitochondrial DNA leads to impaired function. Multi-system mitochondrial disease with progressive gastrointestinal dysmotility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 TWNK Eleanor Williams reviewed gene: TWNK: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Feeding intolerance, irregular rhythm of respiration, hypoglycemia, lactic acidosis, liver cytolysis and neurological abnormalities.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 TTC7A Eleanor Williams reviewed gene: TTC7A: Rating: ; Mode of pathogenicity: ; Publications: 31787977; Phenotypes: Lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 TPM3 Eleanor Williams reviewed gene: TPM3: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Megacolon; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 TK2 Eleanor Williams reviewed gene: TK2: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: myopathic changes on EMG, Loss of motor function, progressive external ophthalmoplegia, respiratory failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 SURF1 Eleanor Williams reviewed gene: SURF1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 SUCLG1 Eleanor Williams reviewed gene: SUCLG1: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: motor neuron changes on EMG, Decreased muscle tone, failure to thrive, microcephaly, GI dysmotility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 SUCLA2 Eleanor Williams reviewed gene: SUCLA2: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: motor neuron changes on EMG, Decreased muscle tone, failure to thrive, microcephaly, GI dysmotility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 SOX10 Eleanor Williams reviewed gene: SOX10: Rating: ; Mode of pathogenicity: ; Publications: 29570554, 31848803; Phenotypes: Peripheral neuropathy with hypomyelination, sensorineural deafness and pseudo-obstruction; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 SGO1 Eleanor Williams reviewed gene: SGO1: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Accelerated cell cycle progression and enhanced activation of TGF-B signaling leading to changes in both the enteric nervous system and smooth muscle. ChronicAtrial andIntestinalDysrhythmia (CAID) syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 SEMA3F Eleanor Williams reviewed gene: SEMA3F: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Megacolon; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 SDHA Eleanor Williams reviewed gene: SDHA: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 SCN10A Eleanor Williams reviewed gene: SCN10A: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Colon sensory neurons activation; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 RRM2B Eleanor Williams reviewed gene: RRM2B: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Issues in maintenance of mtDNA dNTP pools; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 RET Eleanor Williams reviewed gene: RET: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Gain in function mutation associated with intestinal ganglioneuromas leading to increased cell number in the myenteric plexus and dysmotility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 RAD21 Eleanor Williams reviewed gene: RAD21: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Pseudo-obstruction, megaduodenum, long segment Barretts esophagus and cardiac abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 PROKR2 Eleanor Williams reviewed gene: PROKR2: Rating: ; Mode of pathogenicity: ; Publications: 21858136; Phenotypes: Long segment megacolon, HSCR; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 PROKR1 Eleanor Williams reviewed gene: PROKR1: Rating: ; Mode of pathogenicity: ; Publications: 21858136; Phenotypes: Long segment megacolon, HSCR; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 PROK1 Eleanor Williams reviewed gene: PROK1: Rating: ; Mode of pathogenicity: ; Publications: 21858136; Phenotypes: Long segment megacolon, HSCR; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 POLG Eleanor Williams reviewed gene: POLG: Rating: ; Mode of pathogenicity: ; Publications: 23385875, 31848803; Phenotypes: Associated with mitochondrial depletion and deletions. Severe hypotonia and generalized muscle weakness, severe abdominal distension and hypoactive bowel; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 PHOX2B Eleanor Williams reviewed gene: PHOX2B: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 PDCL3 Eleanor Williams reviewed gene: PDCL3: Rating: ; Mode of pathogenicity: ; Publications: 32621347; Phenotypes: Loss-of-function of this protein affects the contractility of smooth muscle tissues; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 NRTN Eleanor Williams reviewed gene: NRTN: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: 1 case reported.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 NKX2-1 Eleanor Williams reviewed gene: NKX2-1: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Megacolon, oesophageal atresia; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 NDUFS1 Eleanor Williams reviewed gene: NDUFS1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 MYLK Eleanor Williams reviewed gene: MYLK: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYLK leads to impaired smooth muscle cell contraction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MYL9 Eleanor Williams reviewed gene: MYL9: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYL9 leads to impaired intestinal smooth muscle contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MYH11 Eleanor Williams reviewed gene: MYH11: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYH11 in smooth muscle myosin leads to impaired contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MPV17 Eleanor Williams reviewed gene: MPV17: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Elevated transaminases, GGT, hyperbilirubinemia, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 LMOD1 Eleanor Williams reviewed gene: LMOD1: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal LMOD1 leads to impaired intestinal smooth muscle contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 LIG3 Eleanor Williams reviewed gene: LIG3: Rating: ; Mode of pathogenicity: ; Publications: 33855352; Phenotypes: ; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 L1CAM Eleanor Williams reviewed gene: L1CAM: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Defect in the differentiation of the interstitial cells of Cajal leading to progressive distension and intermittent episodes of obstruction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 KIF26A Eleanor Williams reviewed gene: KIF26A: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: GDNF-Ret in ENS development; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 GFRA1 Eleanor Williams reviewed gene: GFRA1: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Effect on ENS development; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 GDNF Eleanor Williams reviewed gene: GDNF: Rating: ; Mode of pathogenicity: ; Publications: 21858136; Phenotypes: Long segment megacolon, HSCR; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 FOCAD Eleanor Williams reviewed gene: FOCAD: Rating: ; Mode of pathogenicity: ; Publications: 31814461; Phenotypes: familial intestinal degenerative neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 FLNA Eleanor Williams reviewed gene: FLNA: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Cytoskeletal abnormalities and potentially disrupts enteric-neuron structure and function. Seizures and progressive abdominal distension and obstruction; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric pseudo-obstruction syndrome v0.2 ERBB3 Eleanor Williams reviewed gene: ERBB3: Rating: ; Mode of pathogenicity: ; Publications: 33720042; Phenotypes: Aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ERBB2 Eleanor Williams reviewed gene: ERBB2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 EDNRB Eleanor Williams reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 EDN3 Eleanor Williams reviewed gene: EDN3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ECE1 Eleanor Williams reviewed gene: ECE1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Short segment megacolon, craniofacial defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 DLX2 Eleanor Williams reviewed gene: DLX2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: massive proximal bowel distention attributed to abnormal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 DLX1 Eleanor Williams reviewed gene: DLX1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: massive proximal bowel distention attributed to abnormal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 DGUOK Eleanor Williams reviewed gene: DGUOK: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Elevated serum concentration of tyrosine/phenylalanine, elevation of liver enzymes, increased serum concentration of ferritin, deficiency in complexes I, III, IV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 DDX3X Eleanor Williams reviewed gene: DDX3X: Rating: ; Mode of pathogenicity: ; Publications: 32896648; Phenotypes: Psychomotor retardation, severe constipation, and a recurrent paralytic ileus.; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 COX15 Eleanor Williams reviewed gene: COX15: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 COX10 Eleanor Williams reviewed gene: COX10: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 CHRNE Eleanor Williams reviewed gene: CHRNE: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Congenital myasthenia, cholinergic receptors; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 C17orf107 Eleanor Williams reviewed gene: C17orf107: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Congenital myasthenia, cholinergic receptors; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 BCS1L Eleanor Williams reviewed gene: BCS1L: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 BCR Eleanor Williams reviewed gene: BCR: Rating: ; Mode of pathogenicity: ; Publications: 34190380; Phenotypes: Growth retardation and impaired gastrointestinal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ACTG2 Eleanor Williams reviewed gene: ACTG2: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Altered ACTG2 protein in the muscularis propria leads to impaired contractility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 ACTA2 Eleanor Williams reviewed gene: ACTA2: Rating: ; Mode of pathogenicity: ; Publications: 33729000; Phenotypes: Dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.1 ZEB2 Eleanor Williams gene: ZEB2 was added
gene: ZEB2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ZEB2 was set to
Paediatric pseudo-obstruction syndrome v0.1 TYMP Eleanor Williams gene: TYMP was added
gene: TYMP was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TYMP was set to
Paediatric pseudo-obstruction syndrome v0.1 TWNK Eleanor Williams gene: TWNK was added
gene: TWNK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TWNK was set to
Paediatric pseudo-obstruction syndrome v0.1 TTC7A Eleanor Williams gene: TTC7A was added
gene: TTC7A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TTC7A was set to
Paediatric pseudo-obstruction syndrome v0.1 TPM3 Eleanor Williams gene: TPM3 was added
gene: TPM3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TPM3 was set to
Paediatric pseudo-obstruction syndrome v0.1 TK2 Eleanor Williams gene: TK2 was added
gene: TK2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TK2 was set to
Paediatric pseudo-obstruction syndrome v0.1 SURF1 Eleanor Williams gene: SURF1 was added
gene: SURF1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SURF1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SUCLG1 Eleanor Williams gene: SUCLG1 was added
gene: SUCLG1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SUCLG1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SUCLA2 Eleanor Williams gene: SUCLA2 was added
gene: SUCLA2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SUCLA2 was set to
Paediatric pseudo-obstruction syndrome v0.1 SOX10 Eleanor Williams gene: SOX10 was added
gene: SOX10 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SOX10 was set to
Paediatric pseudo-obstruction syndrome v0.1 SGO1 Eleanor Williams gene: SGO1 was added
gene: SGO1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SGO1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SEMA3F Eleanor Williams gene: SEMA3F was added
gene: SEMA3F was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SEMA3F was set to
Paediatric pseudo-obstruction syndrome v0.1 SDHA Eleanor Williams gene: SDHA was added
gene: SDHA was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SDHA was set to
Paediatric pseudo-obstruction syndrome v0.1 SCN10A Eleanor Williams gene: SCN10A was added
gene: SCN10A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SCN10A was set to
Paediatric pseudo-obstruction syndrome v0.1 RRM2B Eleanor Williams gene: RRM2B was added
gene: RRM2B was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RRM2B was set to
Paediatric pseudo-obstruction syndrome v0.1 RET Eleanor Williams gene: RET was added
gene: RET was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RET was set to
Paediatric pseudo-obstruction syndrome v0.1 RAD21 Eleanor Williams gene: RAD21 was added
gene: RAD21 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RAD21 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROKR2 Eleanor Williams gene: PROKR2 was added
gene: PROKR2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROKR2 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROKR1 Eleanor Williams gene: PROKR1 was added
gene: PROKR1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROKR1 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROK1 Eleanor Williams gene: PROK1 was added
gene: PROK1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROK1 was set to
Paediatric pseudo-obstruction syndrome v0.1 POLG Eleanor Williams gene: POLG was added
gene: POLG was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: POLG was set to
Paediatric pseudo-obstruction syndrome v0.1 PHOX2B Eleanor Williams gene: PHOX2B was added
gene: PHOX2B was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PHOX2B was set to
Paediatric pseudo-obstruction syndrome v0.1 PDCL3 Eleanor Williams gene: PDCL3 was added
gene: PDCL3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PDCL3 was set to
Paediatric pseudo-obstruction syndrome v0.1 NRTN Eleanor Williams gene: NRTN was added
gene: NRTN was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NRTN was set to
Paediatric pseudo-obstruction syndrome v0.1 NKX2-1 Eleanor Williams gene: NKX2-1 was added
gene: NKX2-1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NKX2-1 was set to
Paediatric pseudo-obstruction syndrome v0.1 NDUFS1 Eleanor Williams gene: NDUFS1 was added
gene: NDUFS1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NDUFS1 was set to
Paediatric pseudo-obstruction syndrome v0.1 MYLK Eleanor Williams gene: MYLK was added
gene: MYLK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYLK was set to
Paediatric pseudo-obstruction syndrome v0.1 MYL9 Eleanor Williams gene: MYL9 was added
gene: MYL9 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYL9 was set to
Paediatric pseudo-obstruction syndrome v0.1 MYH11 Eleanor Williams gene: MYH11 was added
gene: MYH11 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYH11 was set to
Paediatric pseudo-obstruction syndrome v0.1 MPV17 Eleanor Williams gene: MPV17 was added
gene: MPV17 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MPV17 was set to
Paediatric pseudo-obstruction syndrome v0.1 LMOD1 Eleanor Williams gene: LMOD1 was added
gene: LMOD1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: LMOD1 was set to
Paediatric pseudo-obstruction syndrome v0.1 LIG3 Eleanor Williams gene: LIG3 was added
gene: LIG3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: LIG3 was set to
Paediatric pseudo-obstruction syndrome v0.1 L1CAM Eleanor Williams gene: L1CAM was added
gene: L1CAM was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: L1CAM was set to
Paediatric pseudo-obstruction syndrome v0.1 KIF26A Eleanor Williams gene: KIF26A was added
gene: KIF26A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: KIF26A was set to
Paediatric pseudo-obstruction syndrome v0.1 GFRA1 Eleanor Williams gene: GFRA1 was added
gene: GFRA1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: GFRA1 was set to
Paediatric pseudo-obstruction syndrome v0.1 GDNF Eleanor Williams gene: GDNF was added
gene: GDNF was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: GDNF was set to
Paediatric pseudo-obstruction syndrome v0.1 FOCAD Eleanor Williams gene: FOCAD was added
gene: FOCAD was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: FOCAD was set to
Paediatric pseudo-obstruction syndrome v0.1 FLNA Eleanor Williams gene: FLNA was added
gene: FLNA was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: FLNA was set to
Paediatric pseudo-obstruction syndrome v0.1 ERBB3 Eleanor Williams gene: ERBB3 was added
gene: ERBB3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ERBB3 was set to
Paediatric pseudo-obstruction syndrome v0.1 ERBB2 Eleanor Williams gene: ERBB2 was added
gene: ERBB2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ERBB2 was set to
Paediatric pseudo-obstruction syndrome v0.1 EDNRB Eleanor Williams gene: EDNRB was added
gene: EDNRB was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: EDNRB was set to
Paediatric pseudo-obstruction syndrome v0.1 EDN3 Eleanor Williams gene: EDN3 was added
gene: EDN3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: EDN3 was set to
Paediatric pseudo-obstruction syndrome v0.1 ECE1 Eleanor Williams gene: ECE1 was added
gene: ECE1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ECE1 was set to
Paediatric pseudo-obstruction syndrome v0.1 DLX2 Eleanor Williams gene: DLX2 was added
gene: DLX2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DLX2 was set to
Paediatric pseudo-obstruction syndrome v0.1 DLX1 Eleanor Williams gene: DLX1 was added
gene: DLX1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DLX1 was set to
Paediatric pseudo-obstruction syndrome v0.1 DGUOK Eleanor Williams gene: DGUOK was added
gene: DGUOK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DGUOK was set to
Paediatric pseudo-obstruction syndrome v0.1 DDX3X Eleanor Williams gene: DDX3X was added
gene: DDX3X was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DDX3X was set to
Paediatric pseudo-obstruction syndrome v0.1 COX15 Eleanor Williams gene: COX15 was added
gene: COX15 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: COX15 was set to
Paediatric pseudo-obstruction syndrome v0.1 COX10 Eleanor Williams gene: COX10 was added
gene: COX10 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: COX10 was set to
Paediatric pseudo-obstruction syndrome v0.1 CHRNE Eleanor Williams gene: CHRNE was added
gene: CHRNE was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: CHRNE was set to
Paediatric pseudo-obstruction syndrome v0.1 C17orf107 Eleanor Williams gene: C17orf107 was added
gene: C17orf107 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: C17orf107 was set to
Paediatric pseudo-obstruction syndrome v0.1 BCS1L Eleanor Williams gene: BCS1L was added
gene: BCS1L was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: BCS1L was set to
Paediatric pseudo-obstruction syndrome v0.1 BCR Eleanor Williams gene: BCR was added
gene: BCR was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: BCR was set to
Paediatric pseudo-obstruction syndrome v0.1 ACTG2 Eleanor Williams gene: ACTG2 was added
gene: ACTG2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ACTG2 was set to
Paediatric pseudo-obstruction syndrome v0.1 ACTA2 Eleanor Williams gene: ACTA2 was added
gene: ACTA2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ACTA2 was set to
Paediatric pseudo-obstruction syndrome v0.0 Eleanor Williams Added Panel Paediatric pseudo-obstruction syndrome
Congenital myopathy v3.11 FXR1 Arina Puzriakova Publications for gene: FXR1 were set to 30770808
Intellectual disability v4.21 SOX4 Arina Puzriakova Phenotypes for gene: SOX4 were changed from Coffin-Siris syndrome 10, 618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism to Coffin-Siris syndrome 10, OMIM:618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism
Intellectual disability v4.20 SOX4 Arina Puzriakova Publications for gene: SOX4 were set to 30661772
Nephrocalcinosis or nephrolithiasis v3.2 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
watchlist tags were added to gene: SLC26A6.
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Likely inborn error of metabolism v3.2 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Inborn errors of metabolism. Sources: Literature
watchlist tags were added to gene: SLC26A6.
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Intellectual disability v4.19 CASK Arina Puzriakova Publications for gene: CASK were set to
Cerebellar hypoplasia v1.71 CASK Arina Puzriakova Publications for gene: CASK were set to
Severe microcephaly v3.3 CASK Arina Puzriakova Publications for gene: CASK were set to
Ataxia and cerebellar anomalies - childhood onset v3.20 CASK Arina Puzriakova Publications for gene: CASK were set to 35149592
Malformations of cortical development v3.3 CASK Arina Puzriakova Publications for gene: CASK were set to 21954287; 20595373; 32700313; 33090494; 33272775
Ataxia and cerebellar anomalies - childhood onset v3.19 CASK Arina Puzriakova Publications for gene: CASK were set to
Intellectual disability v4.18 KLHL20 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: KLHL20.
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Classified gene: KLHL20 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
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Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Gene: klhl20 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.18 KLHL20 Arina Puzriakova Classified gene: KLHL20 as Amber List (moderate evidence)
Intellectual disability v4.18 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
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Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Intellectual disability v4.18 KLHL20 Arina Puzriakova Gene: klhl20 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.10 KLHL20 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: KLHL20.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 TGFBR2 Dmitrijs Rots reviewed gene: TGFBR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v4.2 KCNK3 Arina Puzriakova changed review comment from: Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.; to: Comment on list classification: Given the number of unrelated cases with a comparable phenotype (including arthrogryposis/flexion contractures/foot deformities), all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.
Arthrogryposis v4.2 KCNK3 Arina Puzriakova Entity copied from Intellectual disability v4.17
Arthrogryposis v4.2 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Arthrogryposis. Sources: Literature,Expert Review Amber
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v4.17 KCNK3 Arina Puzriakova Classified gene: KCNK3 as Amber List (moderate evidence)
Intellectual disability v4.17 KCNK3 Arina Puzriakova Added comment: Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.
Intellectual disability v4.17 KCNK3 Arina Puzriakova Gene: kcnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.16 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Heterozygous variant in the KCNK3 gene already have a well-established link with pulmonary arterial hypertension (OMIM:615344).

However, Sormann et al. 2022 (PMID: 36195757) identified nine unrelated individuals harbouring one of six de novo missense variants in KCNK3 who presented with developmental delay and sleep apnea among other variable features (musculoskeletal and limb anomalies, abnormalities of male genitalia/groin and digestive disturbance). The variants were shown to cause defective X-gating leading to overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways (i.e. GOF), distinct from the PAH mechanism which is caused by LOF variants.
Sources: Literature
Pulmonary arterial hypertension v3.2 KCNK3 Arina Puzriakova Phenotypes for gene: KCNK3 were changed from Idiopathic pulmonary arterial hypertension; IPAH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension; Pulmonary hypertension, primary, 4, 615344 to Pulmonary hypertension, primary, 4, OMIM:615344
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh Tag watchlist was removed from gene: POGLUT1.
Tag Q4_22_promote_green tag was added to gene: POGLUT1.
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh edited their review of gene: POGLUT1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 31897643 reports seven POGLUT1 variants in six families with Muscular dystrophy, limb-girdle, autosomal recessive 21, OMIM:617232. Supportive in vitro and in vivo functional studies were presented in PMID: 31897643.; Changed rating: GREEN
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh Publications for gene: POGLUT1 were set to 27807076; 33861953
Congenital muscular dystrophy v3.16 POGLUT1 Sarah Leigh Phenotypes for gene: POGLUT1 were changed from ?Muscular dystrophy, limb-girdle, autosomal recessive 21, 617232 to Muscular dystrophy, limb-girdle, autosomal recessive 21, OMIM:617232; autosomal recessive limb-girdle muscular dystrophy type 2R1, MONDO:0014977
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Classified gene: POGLUT1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Gene: poglut1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.14 POGLUT1 Sarah Leigh Publications for gene: POGLUT1 were set to 27807076
Congenital muscular dystrophy v3.13 GGPS1 Sarah Leigh Publications for gene: GGPS1 were set to 32403198
Early onset or syndromic epilepsy v3.10 DNM1 Sarah Leigh Publications for gene: DNM1 were set to 25262651; 27066543; 33372033; 34172529
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Tag Q4_22_promote_green tag was added to gene: DPM3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh edited their review of gene: DPM3: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least four variants have been reported in at least five cases, together with supportive functional studies (PMID: 19576565; 31469168).; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Classified gene: DPM3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Gene: dpm3 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.12 HNRNPA2B1 Sarah Leigh Tag Q4_22_promote_green tag was added to gene: HNRNPA2B1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.2 DPM3 Sarah Leigh Publications for gene: DPM3 were set to 28803818; 19576565
Congenital muscular dystrophy v3.12 DPM3 Sarah Leigh Publications for gene: DPM3 were set to 19576565
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.10 HNRNPA2B1 Sarah Leigh Added comment: Comment on phenotypes: The OMIM phenotype for HNRNPA2B1 (?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422) is based on one family. PMID: 35484142 presents further variants associated with an expanded phenotype.
Congenital muscular dystrophy v3.10 HNRNPA2B1 Sarah Leigh Phenotypes for gene: HNRNPA2B1 were changed from ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422; inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, MONDO:0014178 to early-onset oculopharyngeal muscular dystrophy, muscular dystrophy, congenital myopathy
Congenital muscular dystrophy v3.9 HNRNPA2B1 Sarah Leigh edited their review of gene: HNRNPA2B1: Added comment: PMID: 35484142 reports nine heterozygous terminating HNRNPA2B1 variants in ten unrelated cases of early onset severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD); Changed rating: GREEN; Changed publications to: 35484142; Changed phenotypes to: early-onset oculopharyngeal muscular dystrophy
Intellectual disability v4.15 RPL10 Dmitrijs Rots reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35876338; Phenotypes: ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - childhood onset v3.18 SPTAN1 Dmitrijs Rots gene: SPTAN1 was added
gene: SPTAN1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 36331550; 35150594
Phenotypes for gene: SPTAN1 were set to Ataxia; hereditary spastic paraplegia
Review for gene: SPTAN1 was set to GREEN
Added comment: Two large cohorts (36331550; 35150594) described >30 cases with hereditary ataxia and a variant in SPTAN1.
Sources: Literature
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 5 unrelated cases with seizures plus supportive fly model.
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v3.5 ATP2B3 Dmitrijs Rots reviewed gene: ATP2B3: Rating: ; Mode of pathogenicity: None; Publications: 36207321, 28807751, 25953895; Phenotypes: Ataxia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - childhood onset v3.18 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v3.18 FRMD5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 7 unrelated cases with ataxia plus supportive fly model.
Ataxia and cerebellar anomalies - childhood onset v3.18 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.15 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Intellectual disability v4.15 FRMD5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 8 unrelated cases plus supportive fly model.
Intellectual disability v4.15 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.9 HNRNPA2B1 Sarah Leigh Phenotypes for gene: HNRNPA2B1 were changed from oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy to ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422; inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, MONDO:0014178
Early onset or syndromic epilepsy v3.8 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Genetic epilepsy syndromes. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v3.17 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Intellectual disability v4.14 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Congenital muscular dystrophy v3.8 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext
Ataxia and cerebellar anomalies - childhood onset v3.16 CAPRIN1 Dmitrijs Rots gene: CAPRIN1 was added
gene: CAPRIN1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAPRIN1 were set to 36136249
Phenotypes for gene: CAPRIN1 were set to Infantile-onset ataxia
Penetrance for gene: CAPRIN1 were set to Complete
Mode of pathogenicity for gene: CAPRIN1 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: CAPRIN1 was set to GREEN
Added comment: CAPRIN1 is reported in two indepedent cases with infantile-onset ataxia and cognitive decline (reported 2 de novo in two cases + functional evidence, so enough evidence for green rating).
Sources: Literature
Intellectual disability v4.13 CAPRIN1 Dmitrijs Rots reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36136249; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v3.16 NPTX1 Dmitrijs Rots gene: NPTX1 was added
gene: NPTX1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to Ataxia
Penetrance for gene: NPTX1 were set to unknown
Mode of pathogenicity for gene: NPTX1 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: NPTX1 was set to GREEN
Added comment: Multiple individiuals with de novo or inherited (segregating with the phenotype) NPTX1 reported in the literature with both late and infantile-onset ataxia. Enough evidence for green.

The phenotype is described in 34788392 as:
"The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging."
Sources: Literature
Intellectual disability v4.13 BUB1 Sarah Leigh edited their review of gene: BUB1: Added comment: Not associated with a phenotype in OMIM, but has a moderate association with BUB1-related microcephaly and developmental disorder in Gen2Phen. PMID: 35044816 reports three BUB1 variants in two cases of developmental delay, including microcephaly, together with supportive functional studies.; Changed rating: GREEN
BAP1 associated tumour predisposition syndrome v0.0 Eleanor Williams Added Panel BAP1 associated tumour predisposition syndrome
Set list of related panels to R422
Autoimmune Polyendocrine Syndrome v0.0 Eleanor Williams Added Panel Autoimmune Polyendocrine Syndrome
Set list of related panels to R155
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.0 Eleanor Williams Added Panel Autoimmune lymphoproliferative syndrome with defective apoptosis
Set list of related panels to R19
Ataxia telangiectasia - mutation testing v0.0 Eleanor Williams Added Panel Ataxia telangiectasia - mutation testing
Set list of related panels to R295
APC associated Polyposis v0.0 Eleanor Williams Added Panel APC associated Polyposis
Set list of related panels to R414
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.0 Eleanor Williams Added Panel Alveolar capillary dysplasia with misalignment of pulmonary veins
Set list of related panels to R330
Alstrom syndrome v0.0 Eleanor Williams Added Panel Alstrom syndrome
Set list of related panels to R106
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.0 Eleanor Williams Added Panel Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis
Set list of related panels to R293
Agammaglobulinaemia with absent BTK expression v0.0 Eleanor Williams Added Panel Agammaglobulinaemia with absent BTK expression
Set list of related panels to R233
Acute intermittent porphyria v0.0 Eleanor Williams Added Panel Acute intermittent porphyria
Set list of related panels to R169
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova changed review comment from: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.; to: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei. Both variants were shown to truncate the muscle isoform (termed LAP1B) while the LAP1C isoform remained intact.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Classified gene: SLC35F1 as Red List (low evidence)
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as only a single patient with a heterozygous missense variant has been reported to date (PMID:33821533). Limited information on the SLC35F1 gene is known in general.
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Gene: slc35f1 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v2.1 KBTBD13 Dmitrijs Rots gene: KBTBD13 was added
gene: KBTBD13 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: KBTBD13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KBTBD13 were set to 36335629
Penetrance for gene: KBTBD13 were set to Incomplete
Mode of pathogenicity for gene: KBTBD13 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: KBTBD13 was set to GREEN
Added comment: 3 families with cardiomyopathy and other related cardiac phenotypes reported in 36335629 with mouse model. Enough evidence for green. All cases had p.R408C variant.
Sources: Literature
Malformations of cortical development v3.2 PAFAH1B1 Achchuthan Shanmugasundram Publications for gene: PAFAH1B1 were set to
Malformations of cortical development v3.1 PAFAH1B1 Achchuthan Shanmugasundram reviewed gene: PAFAH1B1: Rating: ; Mode of pathogenicity: None; Publications: 34635911; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v3.7 GPHN Achchuthan Shanmugasundram Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, OMIM:615501 to Molybdenum cofactor deficiency C, OMIM:615501; Developmental and epileptic encephalopathy, MONDO:0100062
Early onset or syndromic epilepsy v3.6 GPHN Achchuthan Shanmugasundram Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070; 23393157
Early onset or syndromic epilepsy v3.5 GPHN Achchuthan Shanmugasundram reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: None; Publications: 34617111; Phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: None
Intellectual disability v4.12 BUB1 Sarah Leigh Tag Q4_22_MOI tag was added to gene: BUB1.
Tag Q4_22_promote_green tag was added to gene: BUB1.
Intellectual disability v4.12 BUB1 Sarah Leigh Classified gene: BUB1 as Amber List (moderate evidence)
Intellectual disability v4.12 BUB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v4.12 BUB1 Sarah Leigh Gene: bub1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.10 KY Sarah Leigh commented on gene: KY: Associated with Myopathy, myofibrillar, 7 (OMIM: 617114) in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants have been reported in unrelated cases. PMID: 30591934 demostrates segregation of KY c.415C>T (p.R139*) in the affected homozygous members of a consanguineous family, where the parents are heterozygotes and the unaffected sister is homozygous for the wild type allele. PMID 27485408 describes the spontaneously generated murine ortholog of variant Ky with postnatally developing kyphoscoliosis, the authors note the similarities between the patient and mouse muscle fibres.
Congenital myopathy v3.10 TNNC2 Sarah Leigh reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v3.2 MYCN Achchuthan Shanmugasundram gene: MYCN was added
gene: MYCN was added to Clefting. Sources: Literature
Mode of inheritance for gene: MYCN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYCN were set to 34590686
Phenotypes for gene: MYCN were set to Cleft lip with or without cleft palate, MONDO:0016034
Review for gene: MYCN was set to RED
Added comment: Comment on classification of this gene: This gene has been added with a RED rating to this panel, as identified from one case and supported by functional studies with mouse model.

Out of the 104 multiplex families with Mendelian non-syndromic cleft lip with or without cleft palate (NSCL/P), a novel pathogenic variant (c.703G>C/ p.A235P) has been identified in MYCN gene from one family. This variant was found in the proband and his affected mother and absent in the unaffected sister, showing co-segregation with phenotype in this family.

In addition, experimental evidence from conditional knockout mouse model showed that these mice displayed cleft palate, microglossia and micrognathia, resembling the Pierre Robin sequence (PRS) in humans.

This gene has not yet been associated with clefting either in OMIM or in Gene2Phenotype.
Sources: Literature
Congenital myopathy v3.10 UNC45B Sarah Leigh Tag Q4_22_promote_green tag was added to gene: UNC45B.
Tag Q4_22_expert_review tag was added to gene: UNC45B.
Tag Q4_22_NHS_review tag was added to gene: UNC45B.
Congenital myopathy v3.10 UNC45B Sarah Leigh commented on gene: UNC45B: Associated with relevant Myofibrillar myopathy 11 in OMIM and as strong Gen2Phen gene for UNC45B-associated Progressive Myopathy with Eccentric Cores. At least 7 variants have been reported in at least 10 unrelated families. SEgregation has been observed and functional studies suggest that reduced expression of UNC45B is associated with Myofibrillar myopathy 11. This review represents further information from subsequent case reports and the update of OMIM to allow OMIM asign a phenotype tp this gene.
Congenital myopathy v3.10 UNC45B Sarah Leigh Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Myofibrillar myopathy 11, OMIM:619178; myofibrillar myopathy 11, MONDO:0030927
Congenital myopathy v3.9 UNC45B Sarah Leigh Publications for gene: UNC45B were set to 33217308
Early onset or syndromic epilepsy v3.5 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524; 34570759
Mitochondrial disorders v3.2 TARS2 Achchuthan Shanmugasundram Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21, OMIM:615918 to Combined oxidative phosphorylation deficiency 21, OMIM:615918, MONDO:0014398
Mitochondrial disorders v3.1 TARS2 Achchuthan Shanmugasundram reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21, MIM# 615918, MONDO:0014398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v2.3 PDGFRB Achchuthan Shanmugasundram edited their review of gene: PDGFRB: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
White matter disorders and cerebral calcification - childhood onset v2.3 PDGFRB Achchuthan Shanmugasundram Publications for gene: PDGFRB were set to 23255827 - original family report and sproadic case report; 24796542 - an additional case report of a idiopathic basal ganglia calcification patient with the p.R695C mutation, which resulted in partial loss of autophosphorylation; 25292412 - functional studies; 26599395 - mouse models and functional studies; 26129893
White matter disorders and cerebral calcification - childhood onset v2.2 PDGFRB Achchuthan Shanmugasundram reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 34494111; Phenotypes: Basal ganglia calcification, idiopathic, 4, MIM# 615007, MONDO:0014004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v3.2 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to microcephaly is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability. The occipitofrontal circumference (OFC) was at 3rd centile for individual 1 and at 10th centile for individual 2 and dropped to below 1st centile at eight months and five months respectively.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v3.16 TPR Achchuthan Shanmugasundram edited their review of gene: TPR: Changed rating: RED
Ataxia and cerebellar anomalies - childhood onset v3.16 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Cerebellar ataxia, MONDO:0000437
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to ataxia is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v4.11 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Intellectual disability, MONDO:0001071
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to intellectual disability is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Neurofibromatosis Type 1 v1.32 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, Renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Renal ciliopathies v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 15138899; 22982934; 15689444
Renal ciliopathies v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Retinal disorders v3.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Retinal disorders v3.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: ; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Unexplained young onset end-stage renal disease v2.3 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 266900; 34415307
Unexplained young onset end-stage renal disease v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 266900
Unexplained young onset end-stage renal disease v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Unexplained kidney failure in young people v1.116 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Cystic kidney disease v3.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Cystic kidney disease v3.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Tubulointerstitial kidney disease v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Tubulointerstitial kidney disease v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Congenital muscular dystrophy v3.7 GOSR2 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: GOSR2.
Congenital muscular dystrophy v3.7 GOSR2 Achchuthan Shanmugasundram Publications for gene: GOSR2 were set to 29855340
Congenital muscular dystrophy v3.6 GOSR2 Achchuthan Shanmugasundram Classified gene: GOSR2 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.6 GOSR2 Achchuthan Shanmugasundram Gene: gosr2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.5 GOSR2 Achchuthan Shanmugasundram reviewed gene: GOSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29855340, 33639315, 34167170; Phenotypes: Congenital muscular dystrophy, MONDO:0019950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.4 BET1 Achchuthan Shanmugasundram Phenotypes for gene: BET1 were changed from Epilepsy; congenical musculara dystrophy to Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v3.3 BET1 Achchuthan Shanmugasundram Publications for gene: BET1 were set to PMID: 34779586
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Red List (low evidence)
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v3.1 BET1 Achchuthan Shanmugasundram reviewed gene: BET1: Rating: RED; Mode of pathogenicity: None; Publications: 34779586; Phenotypes: Epilepsy, MONDO:0005027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v3.5 BET1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: BET1.
Congenital muscular dystrophy v3.5 BET1 Achchuthan Shanmugasundram Phenotypes for gene: BET1 were changed from Congenital muscular dystrophy with epilepsy to Congenital muscular dystrophy, MONDO:0019950
Congenital muscular dystrophy v3.4 BET1 Achchuthan Shanmugasundram Publications for gene: BET1 were set to
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.1 BET1 Achchuthan Shanmugasundram reviewed gene: BET1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34779586; Phenotypes: Congenital muscular dystrophy, MONDO:0019950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.10 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed phenotypes to: Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed phenotypes to: Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed rating: GREEN
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes gene: BAP1 was added
gene: BAP1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAP1 were set to 35051358
Added comment: Küry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Sources: Literature
Intellectual disability v4.10 BAP1 Mafalda Gomes reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35051358; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v3.4 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Limb disorders v3.4 SUFU Arina Puzriakova Added comment: Comment on list classification: Recessive phenotype fits the scope of this panel; however only two cases have been reported to date in a single paper. Monoallelic form does not appear to feature skeletal abnormalities but rather is dominated by neurological phenotypes. Therefore maintaining Amber rating and biallelic MOI on this panel but adding a watchlist tag.
Limb disorders v3.4 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Limb disorders v3.3 SUFU Arina Puzriakova Tag watchlist tag was added to gene: SUFU.
Limb disorders v3.3 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: AMBER; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on list classification: Recessive phenotype fits the scope of this panel; however only two cases have been reported to date in a single paper. Monoallelic form does not appear to feature skeletal abnormalities but rather is dominated by neurological phenotypes. Therefore maintaining Amber rating and biallelic MOI on this panel but adding a watchlist tag.
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v2.2 SUFU Arina Puzriakova Tag watchlist tag was added to gene: SUFU.
Skeletal ciliopathies v2.2 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: AMBER; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare multisystem ciliopathy disorders v1.168 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Classified gene: SUFU as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Added comment: Comment on list classification: Upgraded from Amber to Green under a monoallelic MOI - sufficient unrelated cases with heterozygous variants and a comparable phenotype within the Joubert spectrum.
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Gene: sufu has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.166 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Rare multisystem ciliopathy disorders v1.166 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova Tag watchlist was removed from gene: SUFU.
Tag watchlist_moi tag was added to gene: SUFU.
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.15 SUFU Arina Puzriakova Entity copied from Neurological ciliopathies v2.4
Ataxia and cerebellar anomalies - childhood onset v3.15 SUFU Arina Puzriakova gene: SUFU was added
gene: SUFU was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list,Expert Review Amber
watchlist_moi, Q4_22_MOI, Q4_22_promote_green tags were added to gene: SUFU.
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUFU were set to 21289193; 28965847; 33024317; 34675124
Phenotypes for gene: SUFU were set to Joubert syndrome 32, OMIM:617757
Ophthalmological ciliopathies v2.4 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v2.2 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Ophthalmological ciliopathies v2.2 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ophthalmological ciliopathies v2.1 SUFU Arina Puzriakova Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_MOI tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Ophthalmological ciliopathies v2.1 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Neurological ciliopathies v2.3 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurological ciliopathies v2.2 SUFU Arina Puzriakova Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_MOI tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Neurological ciliopathies v2.2 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v4.10 SUFU Arina Puzriakova edited their review of gene: SUFU: Changed publications to: 21289193, 28965847, 33024317, 34675124
Intellectual disability v4.10 SUFU Arina Puzriakova Penetrance for gene SUFU was set from to None
Intellectual disability v4.9 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Intellectual disability v4.9 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Intellectual disability v4.9 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v2.2 SUFU Arina Puzriakova Publications for gene: SUFU were set to
Intellectual disability v4.8 SUFU Arina Puzriakova Publications for gene: SUFU were set to 21289193; 28965847; 33024317, 34675124
Intellectual disability v4.7 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Intellectual disability v4.7 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v4.6 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847; 30914295
Intellectual disability v4.5 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Intellectual disability v4.4 SUFU Arina Puzriakova Tag Q4_22_MOI tag was added to gene: SUFU.
Intellectual disability v4.4 SUFU Arina Puzriakova Tag watchlist was removed from gene: SUFU.
Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Intellectual disability v4.4 SUFU Arina Puzriakova edited their review of gene: SUFU: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v4.4 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v2.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 34581780; 34935254; 35672413; 35915960; 35942668
Phenotypes for gene: MLIP were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Review for gene: MLIP was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in rhabdomyolysis, as identified from biallelic variants from four unrelated cases from multiple ethnicities.

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis (reported in five individuals from four families), and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years (PMID:34581780). However, patients carrying biallelic variants in MLIP gene were not reported with rhabdomyolysis in other studies (PMID:34935254; PMID:35672413; PMID:35915960).

The association of MLIP to rhabdomyolysis has now been documented in OMIM (#620138).
Sources: Literature
Cardiac arrhythmias - additional genes v2.3 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138, Arrhythmia, HP:0011675
Cardiac arrhythmias - additional genes v2.3 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Arrhythmia, HP:0011675 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Arrhythmia, HP:0011675
Congenital myopathy v3.8 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.4 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Acute rhabdomyolysis v1.4 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Acute rhabdomyolysis v1.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Acute rhabdomyolysis v1.2 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Acute rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 34581780; 34935254; 35672413; 35915960; 35942668
Phenotypes for gene: MLIP were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138
Review for gene: MLIP was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in rhabdomyolysis, as identified from biallelic variants from four unrelated cases from multiple ethnicities.

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis (reported in five individuals from four families), and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years (PMID:34581780). However, patients carrying biallelic variants in MLIP gene were not reported with rhabdomyolysis in other studies (PMID:34935254; PMID:35672413; PMID:35915960).

The association of MLIP to rhabdomyolysis has now been documented in OMIM (#620138).
Sources: Literature
Cardiac arrhythmias - additional genes v2.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Cardiac arrhythmias - additional genes. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254
Phenotypes for gene: MLIP were set to Arrhythmia, HP:0011675
Review for gene: MLIP was set to RED
Added comment: Comment on classification of this gene: The rating for this gene should be added as RED, as the implication of this gene in cardiac arrhythmias was identified from biallelic variants from only one family (despite a mild ventricular dysfunction in another unrelated individual). However, this is well supported by results from functional studies from human tissue samples and mouse models.

Five individuals from two different pedigrees carrying two different novel homozygous nonsense variants were reported with myopathy characterized by hyperCKemia and with absence of rhabdomyolysis. The age of onset of symptoms for the single patient from family 1 is 2.5 years. All four individuals (age ranges from 24 to 37) from family 2 (Amish ancestry) were reported either with Sinus arrhythmia or Sinus bradycardia and one of these individuals displayed left ventricular hypertrophy. It was also found that there is founder effect for this allele in the Amish population in the resident county of these individuals (PMID:34935254).

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years. However, mild left ventricular dysfunction was reported only in one patient, despite the presence of mild structural abnormalities in two other patients (PMID:34581780).

The expression of MLIP was identified to be reduced in patients with dilated cardiomyopathy, as studied from LV samples from patients with terminal-stage heart failure. In addition, deletion of MLIP gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models and overexpression prevented pathologic remodelling and preserved cardiac function (PMID:26436652). MLIP has also been identified as a regulator of myoblast differentiation (PMID:33802236) and myonuclear positioning (PMID:32719146).
Sources: Literature
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from MLIP-related myopathy with rhabdomyolysis to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 34581780
Congenital myopathy v3.4 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Congenital myopathy v3.4 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Congenital myopathy v3.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.2 MLIP Achchuthan Shanmugasundram reviewed gene: MLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 26436652, 32719146, 33802236, 34581780, 34935254, 35672413, 35915960, 35942668; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_MOI tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_expert_review tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_demote_amber tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Publications for gene: CCDC78 were set to 22818856
Congenital myopathy v3.1 CCDC78 Achchuthan Shanmugasundram reviewed gene: CCDC78: Rating: AMBER; Mode of pathogenicity: None; Publications: 22818856, 25635128; Phenotypes: centronuclear myopathy-4, MIM# 614807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v3.5 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, 614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Optic atrophy, MONDO:0003608
Optic neuropathy v3.4 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 23243084; 22864630
Optic neuropathy v3.3 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Optic atrophy, MONDO:0003608; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v3.3 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, OMIM:614707 to Brown-Vialetto-Van Laere syndrome 2, OMIM:614707, MONDO:0013867; Sensorineural hearing loss disorder, MONDO:0020678
Monogenic hearing loss v3.2 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 22740598; 22864630; 23243084; 24253200
Monogenic hearing loss v3.1 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.7 SLC52A2 Achchuthan Shanmugasundram Tag treatable tag was added to gene: SLC52A2.
Hereditary neuropathy or pain disorder v2.7 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364
Hereditary neuropathy or pain disorder v2.6 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to BVVL; Brown-Vialetto-Van Laere syndrome 2
Hereditary neuropathy or pain disorder v2.5 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Hereditary sensory and autonomic neuropathy, MONDO:0015364, Progressive bulbar palsy, MONDO:0008890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.14 SLC52A2 Achchuthan Shanmugasundram Tag treatable tag was added to gene: SLC52A2.
Tag Q4_22_promote_green tag was added to gene: SLC52A2.
Paediatric motor neuronopathies v2.3 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 23243084; 22864630
Paediatric motor neuronopathies v2.2 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, OMIM:614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364
Paediatric motor neuronopathies v2.1 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Hereditary sensory and autonomic neuropathy, MONDO:0015364, Progressive bulbar palsy, MONDO:0008890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.14 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, MIM# 614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - childhood onset v3.13 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 30377535
Ataxia and cerebellar anomalies - childhood onset v3.12 SLC52A2 Achchuthan Shanmugasundram Classified gene: SLC52A2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v3.12 SLC52A2 Achchuthan Shanmugasundram Gene: slc52a2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v3.11 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.5 SLC25A46 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SLC25A46.
Hereditary neuropathy or pain disorder v2.5 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, 616505; Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260
Hereditary neuropathy or pain disorder v2.4 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to 26168012
Hereditary neuropathy or pain disorder v2.3 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28376086, 28934388, 30178502; Phenotypes: Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v3.3 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB 616505 to Optic atrophy, MONDO:0003608; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260
Optic neuropathy v3.2 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to 26168012; 28369803
Optic neuropathy v3.1 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28369803, 28376086, 28558379, 28934388, 30178502, 33816684; Phenotypes: Optic atrophy, MONDO:0003608, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v3.5 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Hereditary motor and sensory neuropathy type VIB, 616505 to Cerebellar ataxia, MONDO:0000437; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Hereditary ataxia, adult onset v3.4 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to
Hereditary ataxia, adult onset v3.3 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 28376086, 28558379, 28934388; Phenotypes: Adult-onset ataxia, Cerebellar ataxia, MONDO:0000437, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.11 SLC25A46 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in ataxia, as identified from biallelic loss-of-function variants from at least 8 unrelated individuals/ families from multiple ethnicities and supported by results from animal models.

Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653).

A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012).

A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684).

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM.; to: Comment on classification of this gene:

The rating for this gene should be GREEN, as this gene has been identified to be implicated in cerebellar ataxia (MONDO:0000437) from biallelic loss-of-function variants from at least 8 unrelated individuals/ families and in pontocerebellar hypoplasia, type 1E (MIM# 619303) from biallelic loss-of-function variants from at least 6 unrelated individuals/ families. These cases were from multiple ethnicities and were supported by results from animal models.

In addition, this gene has also been identified to be implicated in cerebellar hypoplasia from monoallelic loss-of-function variants from a family of three siblings. As we currently do not have three unrelated cases for monoallelic inheritance, this gene is assigned only to biallelic MOI.

Cerebellar ataxia:

Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653).

A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012).

A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684).

Cerebellar hypoplasia:

Four infants from two different families with homozygous variants (family 1: c.1022T>C/ p.Leu341Pro; family 2: deletion of exon 1) were reported to have died soon after birth with a profound neurodevelopmental disorder associated with congenital pontocerebellar hypoplasia (PMID:27543974). The phenotypes are similar to a female infant from the United States with pontocerebellar atrophy who died at age 15 weeks. This infant reported by Abram et al (2015) exhibited compound heterozygous variants (c.882_885dupTTAC/ p.Asn296fs*297 & c.998C>T/ p.Pro333Leu) (PMID:26168012).

Four infants from two unrelated families of German and Italian descent were reported with PCH1E. All died in the first days or weeks of life. The German infants were identified with homozygous variant c.736A>T (p.Arg246Ter) and the Italian infants were identified with compound heterozygous variants c.42C>G (p.Tyr14Ter) & 462+ 1G>A (PMID:28653766).

Two siblings with bi-allelic compound heterozygous variants (a splicing variant - c.385-1G > A and a deletion) had a fulminant neonatal course. The mother of these siblings exhibited a heterozygous c.385-1G > A allele and the father had an 80-kb deletion spanning SLC25A46 and TMEM232 genes. Pontocerebellar hypoplasia was reported by postmortem brain CT imaging in one of the siblings (PMID:35012485).

Barth (1993) reported a Dutch family in which three siblings died within the first day of life due to lack of spontaneous respiration and profound muscle weakness (PMID:8147499). Although these infants displayed similarities to the clinical indications described by Wan et al, 2016 (PMID:27543974), they were identified to possess heterozygous variant leading to a premature stop codon (c.691C>T/ p.Arg231Ter) in exon 8 of the SLC25A46 gene (PMID:28637197).

Functional studies:

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM.
Ataxia and cerebellar anomalies - childhood onset v3.11 SLC25A46 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SLC25A46.
Ataxia and cerebellar anomalies - childhood onset v3.11 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505 to Cerebellar ataxia, MONDO:0000437; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Ataxia and cerebellar anomalies - childhood onset v3.10 SLC25A46 Achchuthan Shanmugasundram Classified gene: SLC25A46 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v3.10 SLC25A46 Achchuthan Shanmugasundram Gene: slc25a46 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v3.9 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28376086, 28558379, 28934388, 30178502, 33816684; Phenotypes: Cerebellar ataxia, MONDO:0000437, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.9 SCN2A Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SCN2A.
Ataxia and cerebellar anomalies - childhood onset v3.9 SCN2A Achchuthan Shanmugasundram Phenotypes for gene: SCN2A were changed from Epileptic encephalopathy, early infantile, 11, MIM# 613721 to Episodic ataxia, type 9, MIM# 618924, MONDO:0030064; Developmental and epileptic encephalopathy 11, MIM# 613721, MONDO:0013388
Ataxia and cerebellar anomalies - childhood onset v3.8 SCN2A Achchuthan Shanmugasundram Publications for gene: SCN2A were set to 31924505; 32893078; 31904126
Ataxia and cerebellar anomalies - childhood onset v3.7 SCN2A Achchuthan Shanmugasundram Mode of pathogenicity for gene: SCN2A was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Ataxia and cerebellar anomalies - childhood onset v3.6 SCN2A Achchuthan Shanmugasundram Classified gene: SCN2A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v3.6 SCN2A Achchuthan Shanmugasundram Gene: scn2a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v3.5 SCN2A Achchuthan Shanmugasundram reviewed gene: SCN2A: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20956790, 26291284, 26645390, 27159988, 27328862, 28065826, 30165711, 30741786, 30813219, 30928199, 32893078, 35219921; Phenotypes: Episodic ataxia, type 9, MIM# 618924, MONDO:0030064, Developmental and epileptic encephalopathy 11, MIM# 613721, MONDO:0013388; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia, adult onset v2.3 COQ4 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: COQ4.
Hereditary spastic paraplegia, adult onset v2.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v2.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, adult onset v2.2 COQ4 Achchuthan Shanmugasundram gene: COQ4 was added
gene: COQ4 was added to Hereditary spastic paraplegia - adult onset. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36047608
Phenotypes for gene: COQ4 were set to Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Review for gene: COQ4 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in adult onset hereditary spastic paraplegia, as identified from biallelic variants from three unrelated individuals.

Six patients from four families with bi-allelic variants were reported with adult-Onset ataxia-spasticity spectrum phenotype. Out of these, three patients (c.305G>A & c.473G>A, c.434G>A & c.437T>G, c.376G>A & c.473G>A) were identified with hereditary spastic paraparesis and their age of onset ranged from 15 to 24 (PMID:36047608).

COQ4 was not associated with hereditary spastic paraparesis in OMIM or Gene2Phenotype. However, functional studies performed in patient-derived fibroblasts, yeasts and zebrafish larvae confirms the role of COQ4 in brain development. The coq4 F0 CRISPR zebrafish line particularly showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum (PMID:33704555).
Sources: Literature
Hereditary ataxia, adult onset v3.3 COQ4 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: COQ4.
Hereditary ataxia, adult onset v3.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Hereditary ataxia, adult onset v3.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v3.2 COQ4 Achchuthan Shanmugasundram gene: COQ4 was added
gene: COQ4 was added to Hereditary ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36047608
Phenotypes for gene: COQ4 were set to Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Review for gene: COQ4 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in adult-onset ataxia, as identified from biallelic variants from three unrelated individuals/ families.

Six patients from four families with bi-allelic variants were reported with adult-Onset ataxia-spasticity spectrum phenotype. Out of these, five patients from three families with bi-allelic variants (c.305G>A & c.473G>A, c.434G>A & c.437T>G, c.202+4A>C & c.202+4A>C) were identified with gait and/or limb ataxia. The severity of the phenotype ranged from mild (c.305G>A & c.473G>A) to more severe (c.202+4A>C & c.202+4A>C ) and the age of onset ranged from 15 to 34 (PMID:36047608).

COQ4 was not associated with adult-onset ataxia-spasticity spectrum disease in OMIM or Gene2Phenotype. However, functional studies performed in patient-derived fibroblasts, yeasts and zebrafish larvae confirms the role of COQ4 in brain development. The coq4 F0 CRISPR zebrafish line particularly showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum (PMID:33704555).
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v3.5 COQ4 Achchuthan Shanmugasundram Tag treatable tag was added to gene: COQ4.
Tag Q4_22_promote_green tag was added to gene: COQ4.
Ataxia and cerebellar anomalies - childhood onset v3.5 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Childhood onset ataxia to Childhood-onset spinocerebellar ataxia; Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - childhood onset v3.4 COQ4 Achchuthan Shanmugasundram Publications for gene: COQ4 were set to PMID: 30225196; 33704555; 30847826
Ataxia and cerebellar anomalies - childhood onset v3.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v3.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v3.2 COQ4 Achchuthan Shanmugasundram reviewed gene: COQ4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30225196, 30847826, 33215859, 33704555, 36047608; Phenotypes: Childhood-onset spinocerebellar ataxia, Adult-onset ataxia-spasticity spectrum disease, Hereditary spastic paraparesis, MONDO:0019064, Cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SREBF1.
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Classified gene: SREBF1 as Amber List (moderate evidence)
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v2.2 SREBF1 Achchuthan Shanmugasundram gene: SREBF1 was added
gene: SREBF1 was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF1 were set to 31790666; 32497488; 32902915; 33253727; 33742461
Phenotypes for gene: SREBF1 were set to Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221; Mucoepithelial dysplasia, hereditary, MIM# 158310, MONDO:0008017
Review for gene: SREBF1 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in both hereditary hair and skin conditions, as identified from monoallelic variants from at least 18 unrelated individuals/ families from multiple ethnicities, and supported by results from in vitro functional studies.

As reviewed by Zornitza Stark, heterozygous variants in 11 unrelated, ethnically diverse individuals has resulted in IFAP syndrome (MIM# 619016), which is characterised generally by moderate or severe hypotrichosis or atrichia (hair), ichthyosis follicularis (skin), and photophobia, Meibomian gland dysfunction, keratitis and/or cataract (eye) (PMID:32497488). Similarly, autosomal-dominant IFAP syndrome was also observed in another report of a Japanese woman and her daughter displaying heterozygous variant c.1669C>T (p.Arg557Cys) in SREBF1 gene (PMID:33253727).

Seven patients from four families displaying heterozygous variants of SREBF1 gene (c.1669C>T (p.Arg557Cys) and c.1670G>A (p.Arg557His)) were reported with HMD (MIM# 158310), which is characterised by chronic keratitis, non-scarring alopecia, mucosal erythema, keratosis pilaris, perineal erythematous intertrigo, psoriatic-like perineal plaques, and involvement of the conjunctival mucosa (PMID:31790666). There are also two other reports of patients with c.1669C>T (p.Arg557Cys) variant displaying autosomal-dominant HMD (PMID:32902915, PMID:33742461). The clinical indications of IFAP and HMD suggests that these two diseases share a common clinical spectrum.

The association of both IFAP and HMD to SREBF1 has been documented in OMIM. In addition, results from in vitro investigation of SREBP1 variants confirms the essential role of SREBF1 in epidermal differentiation, skin barrier formation, hair growth, and eye function (PMID:32497488).
Sources: Literature
Ichthyosis and erythrokeratoderma v2.10 SREBF1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SREBF1.
Ichthyosis and erythrokeratoderma v2.10 SREBF1 Achchuthan Shanmugasundram Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221; Hereditary mucoepithelial dysplasia, MIM# 158310, MONDO:0008017
Ichthyosis and erythrokeratoderma v2.9 SREBF1 Achchuthan Shanmugasundram Publications for gene: SREBF1 were set to 32497488
Ichthyosis and erythrokeratoderma v2.8 SREBF1 Achchuthan Shanmugasundram Classified gene: SREBF1 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v2.8 SREBF1 Achchuthan Shanmugasundram Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v2.7 SREBF1 Achchuthan Shanmugasundram reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31790666, 32497488, 32902915, 33253727, 33742461; Phenotypes: Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221, Hereditary mucoepithelial dysplasia, MIM# 158310, MONDO:0008017; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratodermas v2.4 PERP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: PERP.
Palmoplantar keratodermas v2.4 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Dominant and Recessive Keratoderma to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; Ichthyosis, MONDO:0019269
Palmoplantar keratodermas v2.3 PERP Achchuthan Shanmugasundram Publications for gene: PERP were set to 30321533
Palmoplantar keratodermas v2.2 PERP Achchuthan Shanmugasundram Classified gene: PERP as Amber List (moderate evidence)
Palmoplantar keratodermas v2.2 PERP Achchuthan Shanmugasundram Gene: perp has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v2.1 PERP Achchuthan Shanmugasundram reviewed gene: PERP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898316, 30321533, 31361044, 34265120, 34863005, 32593191; Phenotypes: Olmsted syndrome-2, MIM# 619208, MONDO:003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941, Ichthyosis, MONDO:0019269, Alopecia universalis, Congenital hypotrichosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v2.7 PERP Achchuthan Shanmugasundram edited their review of gene: PERP: Changed phenotypes to: Olmsted syndrome-2, MIM# 619208, MONDO:003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941, Ichthyosis, MONDO:0019269, Alopecia universalis, congenital hypotrichosis
Ichthyosis and erythrokeratoderma v2.7 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; ichthyosis, MONDO:0019269 to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; Ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v2.6 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Olmsted syndrome-2, MIM# 619208, MONDO_003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941; ichthyosis, MONDO:0019269 to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; ichthyosis, MONDO:0019269
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Classified gene: CADM3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). To date only one paper reports three families with the same missense variant in CADM3. A separate report and/or another variant causing disease would help corroborate this association and so rating Amber for now with a 'watchlist' tag.
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Gene: cadm3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v2.2 CADM3 Arina Puzriakova Tag watchlist tag was added to gene: CADM3.
Ichthyosis and erythrokeratoderma v2.5 PERP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: PERP.
Ichthyosis and erythrokeratoderma v2.5 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Erythrokeratoderma, no OMIM # yet to Olmsted syndrome-2, MIM# 619208, MONDO_003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941; ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v2.4 PERP Achchuthan Shanmugasundram Publications for gene: PERP were set to 31898316
Ichthyosis and erythrokeratoderma v2.3 PERP Achchuthan Shanmugasundram Mode of inheritance for gene: PERP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v2.2 PERP Achchuthan Shanmugasundram Classified gene: PERP as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v2.2 PERP Achchuthan Shanmugasundram Gene: perp has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v2.1 PERP Achchuthan Shanmugasundram reviewed gene: PERP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898316, 30321533, 31361044, 34265120, 34863005, 32593191; Phenotypes: Olmsted syndrome-2, MIM# 619208, MONDO_003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941, ichthyosis, MONDO:0019269, Alopecia universalis, congenital hypotrichosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.2 CADM3 Arina Puzriakova Phenotypes for gene: CADM3 were changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, axonal, type 2FF, OMIM:619519
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.; to: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.
Paediatric disorders - additional genes v2.3 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v2.3 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v2.2 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Paediatric disorders - additional genes. Sources: Expert list
Q4_22_promote_green tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 25425325; 27342937; 30723199; 31299614; 32055997; 33215087; 34164833
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Gene was initially added to the Cardiomyopathy panel; however, after NHS GMS review it was determined that R27 (congenital malformation/syndromic) panel is more appropriate. Therefore adding here with the recommendation of upgrading to Green status at the next review.
-----
Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here. Patients present a severe multisystem phenotype with muscular dystrophy being the prominent feature observed in at least one case in each family, but additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

Note that one additional homozygous case has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325). Biallelic variants have also been linked to a congenital myasthenic syndrome in two unrelated families (PMID: 33215087; 34164833).
Sources: Expert list
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: At least two unrelated multiplex families reported with muscle fatigability, limb girdle weakness and impaired transmission at the neuromuscular synapse. Given the strong functional support including a concordant mouse model, this gene can be promoted to Green status on this panel at the next GMS panel update.
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v3.2 TOR1AIP1 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: TOR1AIP1.
Congenital myaesthenic syndrome v3.2 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141; 31299614
Congenital myaesthenic syndrome v3.1 TOR1AIP1 Arina Puzriakova edited their review of gene: TOR1AIP1: Changed publications to: 33215087, 34164833
Congenital myaesthenic syndrome v3.1 TOR1AIP1 Arina Puzriakova reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24856141, 27342937, 30723199, 31299614, 32055997; Phenotypes: Congenital myasthenic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis imperfecta v3.3 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v2.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from LANGER MESOMELIC DYSPLASIA; LERI-WEILL DYSCHONDROSTEOSIS to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
IUGR and IGF abnormalities v1.55 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
Osteogenesis imperfecta v3.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Short stature, idiopathic familial, 300582; Leri-Weill dyschondrosteosis, 127300; Langer mesomelic dysplasia, 249700; Proportionate Short Stature/Small for Gestational Age; Disproportionate Short Stature to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Skeletal dysplasia v3.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia 249700; Short stature, idiopathic familial 300582; Leri-Weill dyschondrosteosis 127300 to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Intellectual disability v4.4 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from SHOX deficiency (with Intellectual disability) to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
Radial dysplasia v1.23 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Leri-Weill dyschondrosteosis, 127300; bowing of the radius; radioulnar shortening; Langer mesomelic dysplasia, 249700; curved radius; dorsolateral bowed, short radii to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Limb disorders v3.3 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia, 249700; dorsolateral bowed, short radii; bowing of the radius; curved radius; radioulnar shortening; Leri-Weill dyschondrosteosis, 127300 to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Limb disorders v3.2 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v4.3 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.1 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: 14 cases with mostly recurrent missense variant in this gene is reported.
Sources: Literature
Intellectual disability v4.2 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Penetrance for gene: KLHL20 were set to unknown
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: More 14 individuals with mostly recurrent missense variant reported in KLHL20
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v3.1 TBX1 Ronnie Wright reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.1 POGLUT1 Katherine Schon reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31897643; Phenotypes: limb girdle weakness, thigh weakness, muscle MRI abnormality; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v2.1 GRM1 Zornitza Stark reviewed gene: GRM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 13 MIM#614831; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.2 PAX6 Tracy Lester reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v4.2 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524, Neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated Cardiomyopathy and conduction defects v1.81 PRDM16 Zornitza Stark reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411, 35862303, 32083975; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v4.2 BLM Zornitza Stark reviewed gene: BLM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bloom syndrome, MIM# 210900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.2 PRSS12 Sarah Leigh Publications for gene: PRSS12 were set to
Neurodegenerative disorders, adult onset v3.2 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Neurodegenerative disorders, adult onset v3.2 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.313 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Hereditary ataxia v1.313 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.2 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v3.1 COG5 Arina Puzriakova Tag watchlist_moi tag was added to gene: COG5.
Unexplained kidney failure in young people v1.116 FAN1 Yu Leng Phua reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35931300; Phenotypes: interstitial nephritis, chronic kidney disease, Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v2.1 FAN1 Yu Leng Phua reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35931300; Phenotypes: interstitial nephritis, chronic kidney disease, Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v2.1 LEF1 Yu Leng Phua reviewed gene: LEF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35583550; Phenotypes: Radial ray defects, polydactyly, split hand/foot, ectodermal dysplasia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hypotonic infant v18.2 Arina Puzriakova Panel version 18.1 has been signed off on 2022-11-30
Cardiac arrhythmias v11.2 Eleanor Williams Panel version 11.1 has been signed off on 2022-11-30
Leukodystrophy, childhood onset v10.3 Arina Puzriakova Panel version 10.2 has been signed off on 2022-11-30
Sudden unexplained death or survivors of a cardiac event v17.4 Eleanor Williams Panel version 17.3 has been signed off on 2022-11-30
Other rare neuromuscular disorders v12.2 Arina Puzriakova Panel version 12.1 has been signed off on 2022-11-30
Rare multisystem ciliopathy Super panel v8.3 Arina Puzriakova Panel version 8.2 has been signed off on 2022-11-30
Sudden unexplained death or survivors of a cardiac event v17.3 Eleanor Williams List of related panels changed from Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; 425 to Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; R425
Hypogonadotropic hypogonadism (GMS) v2.3 Achchuthan Shanmugasundram Panel version 2.2 has been signed off on 2022-11-30
Cerebral malformation v8.3 Eleanor Williams Panel version 8.2 has been signed off on 2022-11-30
Hypogonadotropic hypogonadism (GMS) v2.2 Achchuthan Shanmugasundram Panel signed off version 2.0 has been removed
Paediatric disorders v24.3 Arina Puzriakova Panel version 24.2 has been signed off on 2022-11-30
Cystic renal disease v5.2 Eleanor Williams Panel version 5.1 has been signed off on 2022-11-30
Pulmonary Fibrosis, Familial v1.4 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.3 has been signed off on 2022-11-30
Pulmonary Fibrosis, Familial v1.3 Achchuthan Shanmugasundram Panel signed off version 1.0 has been removed
Pulmonary Fibrosis, Familial v1.2 Achchuthan Shanmugasundram Panel signed off version 1.1 has been removed
Hereditary ataxia and cerebellar anomalies, childhood onset v9.2 Arina Puzriakova Panel version 9.1 has been signed off on 2022-11-30
Fetal anomalies v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Fetal anomalies v2.0 Eleanor Williams promoted panel to version 2.0
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.3 Eleanor Williams List of related panels changed from Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151; R152 to Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151
Panel version 3.2 has been signed off on 2022-11-30
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.2 Eleanor Williams Panel signed off version 3.0 has been removed
Auditory Neuropathy Spectrum Disorde v1.9 ATP11A Barbara Vona gene: ATP11A was added
gene: ATP11A was added to Auditory Neuropathy Spectrum Disorder. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to PMID: 36300302; 28601886
Phenotypes for gene: ATP11A were set to Auditory synaptopathy/neuropathy; AUNA2
Penetrance for gene: ATP11A were set to Complete
Mode of pathogenicity for gene: ATP11A was set to Other
Review for gene: ATP11A was set to RED
gene: ATP11A was marked as current diagnostic
Added comment: A large German family with auditory synaptopathy/neuropathy that originally mapped the AUNA2 locus to either chromosome 12q24 or 13q34 underwent genome sequencing. Affected individuals showed symmetrical, slowly progressive postlingual hearing loss starting late in the first decade that eventually advanced to to severe hearing impairment in the fifth decade. Auditory brainstem response thresholds were worse than otoacoustic emissions, suggesting a deficit in neural sound encoding. A 5.5 kb deletion encompassing the last coding exon of both RefSeq annotated ATP11A isoforms was found to segregate with the phenotype. RNA studies from an affected individual confirmed stable expression and both a deletion and activation of a cryptic splice acceptor that leads to inclusion of a pseudoexon and novel 38 amino acids at the C-terminus. ATP11A flippase activity was disrupted in mutant cells, compatible with a loss-of-function mechanism, although a gain of function of dominant negative effect could not be excluded. ATP11A is expressed in the mouse inner ear. Its function was explored in depth using a conditional knockout mouse that showed a progressive dysfunction or loss of spiral ganglion neurons. Additional families are needed to replicate an auditory synaptopathy/neuropathy phenotype.
Sources: Literature
Arrhythmogenic right ventricular cardiomyopathy v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Arrhythmogenic right ventricular cardiomyopathy v3.0 Arina Puzriakova promoted panel to version 3.0
Severe early-onset obesity v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Early onset or syndromic epilepsy v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Early onset or syndromic epilepsy v3.0 Catherine Snow promoted panel to version 3.0
Severe early-onset obesity v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Familial melanoma v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Familial melanoma v2.0 Catherine Snow promoted panel to version 2.0
Rare genetic inflammatory skin disorders v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Cytopenia - NOT Fanconi anaemia v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Rare genetic inflammatory skin disorders v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Cytopenia - NOT Fanconi anaemia v2.0 Catherine Snow promoted panel to version 2.0
Tubulointerstitial kidney disease v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Tubulointerstitial kidney disease v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.0 Catherine Snow promoted panel to version 2.0
Structural eye disease v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Structural eye disease v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Stickler syndrome v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Endocrine neoplasia v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Stickler syndrome v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Endocrine neoplasia v2.0 Catherine Snow promoted panel to version 2.0
Thrombophilia with a likely monogenic cause v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Thrombophilia with a likely monogenic cause v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Differences in sex development v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Thoracic aortic aneurysm or dissection (GMS) v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Differences in sex development v3.0 Catherine Snow promoted panel to version 3.0
Thoracic aortic aneurysm or dissection (GMS) v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Neonatal diabetes v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Laterality disorders and isomerism v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Neonatal diabetes v3.0 Catherine Snow promoted panel to version 3.0
Laterality disorders and isomerism v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Nephrocalcinosis or nephrolithiasis v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Ectodermal dysplasia v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Nephrocalcinosis or nephrolithiasis v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Ectodermal dysplasia v2.0 Catherine Snow promoted panel to version 2.0
Acute rhabdomyolysis v1.1 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.0 has been signed off on 2022-11-30
Acute rhabdomyolysis v1.0 Catherine Snow promoted panel to version 1.0
Paroxysmal central nervous system disorders v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Autoinflammatory disorders v1.1 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.0 has been signed off on 2022-11-30
Paroxysmal central nervous system disorders v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Autoinflammatory disorders v1.0 Catherine Snow promoted panel to version 1.0
Respiratory ciliopathies including non-CF bronchiectasis v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Neurodegenerative disorders, adult onset v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Respiratory ciliopathies including non-CF bronchiectasis v2.0 Arina Puzriakova promoted panel to version 2.0
Pulmonary arterial hypertension v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Neurodegenerative disorders, adult onset v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Pulmonary arterial hypertension v3.0 Eleanor Williams promoted panel to version 3.0
Unexplained young onset end-stage renal disease v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Pulmonary Fibrosis, Familial v1.1 Catherine Snow Panel version 1.0 has been signed off on 2022-11-30
Unexplained young onset end-stage renal disease v2.0 Arina Puzriakova promoted panel to version 2.0
Pulmonary Fibrosis, Familial v1.0 Catherine Snow promoted panel to version 1.0
Renal tubulopathies v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Osteogenesis imperfecta v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Corneal dystrophy v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Renal tubulopathies v3.0 Arina Puzriakova promoted panel to version 3.0
Proteinuric renal disease v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Osteogenesis imperfecta v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Corneal dystrophy v2.0 Catherine Snow promoted panel to version 2.0
Proteinuric renal disease v3.0 Eleanor Williams promoted panel to version 3.0
Retinal disorders v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Possible mitochondrial disorder, nuclear genes v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Retinal disorders v3.0 Arina Puzriakova promoted panel to version 3.0
Malignant hyperthermia v1.1 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.0 has been signed off on 2022-11-30
Leukodystrophy, adult onset v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Possible mitochondrial disorder, nuclear genes v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Leukodystrophy, adult onset v2.0 Eleanor Williams promoted panel to version 2.0
Skeletal muscle channelopathy v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Malignant hyperthermia v1.0 Catherine Snow promoted panel to version 1.0
Skeletal muscle channelopathy v2.0 Arina Puzriakova promoted panel to version 2.0
Rare anaemia v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Severe microcephaly v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Rare anaemia v2.0 Eleanor Williams promoted panel to version 2.0
Severe microcephaly v3.0 Arina Puzriakova promoted panel to version 3.0
Pancreatitis v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Bilateral congenital or childhood onset cataracts v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.0 Catherine Snow promoted panel to version 3.0
Primary lymphoedema v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Bilateral congenital or childhood onset cataracts v3.0 Arina Puzriakova promoted panel to version 3.0
Dystonia, chorea or related movement disorder, childhood onset v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Primary lymphoedema v3.0 Eleanor Williams promoted panel to version 3.0
Pancreatitis v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Dystonia, chorea or related movement disorder, childhood onset v2.0 Arina Puzriakova promoted panel to version 2.0
Cholestasis v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Pigmentary skin disorders v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Childhood solid tumours v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Cholestasis v2.0 Arina Puzriakova promoted panel to version 2.0
Pigmentary skin disorders v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Childhood solid tumours v3.0 Eleanor Williams promoted panel to version 3.0
Palmoplantar keratodermas v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Congenital adrenal hypoplasia v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Haematological malignancies cancer susceptibility v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Palmoplantar keratodermas v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Congenital adrenal hypoplasia v3.0 Catherine Snow promoted panel to version 3.0
Haematological malignancies cancer susceptibility v3.0 Eleanor Williams promoted panel to version 3.0
Multiple monogenic benign skin tumours v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Hereditary ataxia, adult onset v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Hereditary ataxia, adult onset v3.0 Eleanor Williams promoted panel to version 3.0
Multiple monogenic benign skin tumours v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Inherited pancreatic cancer v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Mitochondrial DNA maintenance disorder v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Inherited pancreatic cancer v2.0 Eleanor Williams promoted panel to version 2.0
Multi Locus Imprinting Disorder (MLID) v1.1 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.0 has been signed off on 2022-11-30
Mitochondrial DNA maintenance disorder v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Paediatric or syndromic cardiomyopathy v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Multi Locus Imprinting Disorder (MLID) v1.0 Catherine Snow promoted panel to version 1.0
Paediatric or syndromic cardiomyopathy v2.0 Arina Puzriakova promoted panel to version 2.0
Inherited predisposition to acute myeloid leukaemia (AML) v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Mitochondrial disorder with complex IV deficiency v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Dystonia, chorea or related movement disorder, adult onset v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Inherited predisposition to acute myeloid leukaemia (AML) v2.0 Eleanor Williams promoted panel to version 2.0
Cutaneous photosensitivity with a likely genetic cause v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Dystonia, chorea or related movement disorder, adult onset v2.0 Arina Puzriakova promoted panel to version 2.0
Mitochondrial disorder with complex IV deficiency v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Cutaneous photosensitivity with a likely genetic cause v2.0 Catherine Snow promoted panel to version 2.0
Bardet Biedl syndrome v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Hereditary haemorrhagic telangiectasia v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Bardet Biedl syndrome v2.0 Arina Puzriakova promoted panel to version 2.0
Mitochondrial disorder with complex I deficiency v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Hereditary haemorrhagic telangiectasia v3.0 Eleanor Williams promoted panel to version 3.0
Sporadic aniridia v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Sporadic aniridia v3.0 Arina Puzriakova promoted panel to version 3.0
Mitochondrial disorder with complex I deficiency v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Hereditary spastic paraplegia, childhood onset v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Hereditary spastic paraplegia, childhood onset v3.0 Eleanor Williams promoted panel to version 3.0
Albinism or congenital nystagmus v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Inherited breast cancer and ovarian cancer v1.1 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.0 has been signed off on 2022-11-30
Albinism or congenital nystagmus v2.0 Arina Puzriakova promoted panel to version 2.0
Arthrogryposis v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2022-11-30
Hereditary spastic paraplegia, adult onset v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Inherited breast cancer and ovarian cancer v1.0 Catherine Snow promoted panel to version 1.0
Hereditary spastic paraplegia, adult onset v2.0 Eleanor Williams promoted panel to version 2.0
Arthrogryposis v4.0 Arina Puzriakova promoted panel to version 4.0
Bleeding and platelet disorders v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Hypophosphataemia or rickets v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Bleeding and platelet disorders v2.0 Arina Puzriakova promoted panel to version 2.0
Short QT syndrome v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Hypophosphataemia or rickets v3.0 Eleanor Williams promoted panel to version 3.0
Short QT syndrome v3.0 Catherine Snow promoted panel to version 3.0
Hypogonadotropic hypogonadism (GMS) v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Hypogonadotropic hypogonadism (GMS) v2.0 Eleanor Williams promoted panel to version 2.0
Lysosomal storage disorder v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Catecholaminergic polymorphic VT v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Lysosomal storage disorder v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Catecholaminergic polymorphic VT v3.0 Arina Puzriakova promoted panel to version 3.0
Hyperthyroidism v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Hyperthyroidism v3.0 Eleanor Williams promoted panel to version 3.0
Brugada syndrome and cardiac sodium channel disease v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Familial Chylomicronaemia Syndrome v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Brugada syndrome and cardiac sodium channel disease v3.0 Arina Puzriakova promoted panel to version 3.0
Familial Chylomicronaemia Syndrome v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Ichthyosis and erythrokeratoderma v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Cardiac arrhythmias - additional genes v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Ichthyosis and erythrokeratoderma v2.0 Eleanor Williams promoted panel to version 2.0
Cardiac arrhythmias - additional genes v2.0 Arina Puzriakova promoted panel to version 2.0
Severe insulin resistance and lipodystrophy syndromes v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Inherited ovarian cancer (without breast cancer) v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Ataxia and cerebellar anomalies - childhood onset v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Inherited ovarian cancer (without breast cancer) v3.0 Eleanor Williams promoted panel to version 3.0
Ataxia and cerebellar anomalies - childhood onset v3.0 Arina Puzriakova promoted panel to version 3.0
Severe insulin resistance and lipodystrophy syndromes v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Progressive cardiac conduction disease v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Clefting v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Progressive cardiac conduction disease v2.0 Catherine Snow promoted panel to version 2.0
Mosaic skin disorders - Deep sequencing v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Clefting v3.0 Arina Puzriakova promoted panel to version 3.0
Congenital myaesthenic syndrome v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Holoprosencephaly v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Mosaic skin disorders - Deep sequencing v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Holoprosencephaly v3.0 Eleanor Williams promoted panel to version 3.0
Congenital myaesthenic syndrome v3.0 Catherine Snow promoted panel to version 3.0
Likely inborn error of metabolism v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Dilated and arrhythmogenic cardiomyopathy v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Likely inborn error of metabolism v3.0 Eleanor Williams promoted panel to version 3.0
Dilated and arrhythmogenic cardiomyopathy v2.0 Catherine Snow promoted panel to version 2.0
Paediatric motor neuronopathies v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Paediatric motor neuronopathies v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Neurological segmental overgrowth v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Renal ciliopathies v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Neurological segmental overgrowth v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Renal ciliopathies v2.0 Catherine Snow promoted panel to version 2.0
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.0 Arina Puzriakova promoted panel to version 3.0
White matter disorders and cerebral calcification - childhood onset v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Intellectual disability v4.1 Eleanor Williams Panel version 4.0 has been signed off on 2022-11-30
Ophthalmological ciliopathies v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
White matter disorders and cerebral calcification - childhood onset v2.0 Catherine Snow promoted panel to version 2.0
Intellectual disability v4.0 Eleanor Williams promoted panel to version 4.0
Ophthalmological ciliopathies v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Rhabdomyolysis and metabolic muscle disorders v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Hypertrophic cardiomyopathy v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Rhabdomyolysis and metabolic muscle disorders v2.0 Catherine Snow promoted panel to version 2.0
Hypertrophic cardiomyopathy v3.0 Eleanor Williams promoted panel to version 3.0
Neurological ciliopathies v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Skeletal dysplasia v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Skeletal dysplasia v3.0 Catherine Snow promoted panel to version 3.0
Neurological ciliopathies v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Hydrocephalus v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Hydrocephalus v3.0 Eleanor Williams promoted panel to version 3.0
Skeletal ciliopathies v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Skeletal ciliopathies v2.0 Catherine Snow promoted panel to version 2.0
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v2.23 Arina Puzriakova Panel name changed from Familial hyperparathyroidism to Familial hyperparathyroidism or hypocalciuric hypercalcaemia
List of related panels changed from R151 to Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151; R152
Paediatric disorders - additional genes v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2022-11-30
Segmental overgrowth disorders - Deep sequencing v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Segmental overgrowth disorders - Deep sequencing v3.0 Eleanor Williams promoted panel to version 3.0
Paediatric disorders - additional genes v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Segmental overgrowth disorders - Deep sequencing v2.17 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Distal myopathies v2.1 Catherine Snow Panel version 2.0 has been signed off on 2022-11-30
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Distal myopathies v2.0 Catherine Snow promoted panel to version 2.0
Hydrocephalus v2.133 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Cystic kidney disease v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Cystic kidney disease v3.0 Catherine Snow promoted panel to version 3.0
Optic neuropathy v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Optic neuropathy v3.0 Arina Puzriakova promoted panel to version 3.0
Optic neuropathy v2.79 Arina Puzriakova List of related panels changed from Inherited optic neuropathies; R41; R42.2 to Inherited optic neuropathies; R41
Hereditary neuropathy or pain disorder v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Malformations of cortical development v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Hereditary neuropathy or pain disorder v2.0 Eleanor Williams promoted panel to version 2.0
Malformations of cortical development v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Hereditary neuropathy or pain disorder v1.106 Eleanor Williams List of related panels changed from R78; Hereditary neuropathy or pain disorder – NOT PMP22 copy number to R78; Hereditary neuropathy or pain disorder - NOT PMP22 copy number
Congenital myopathy v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Inherited polyposis and early onset colorectal cancer - germline testing v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Inherited polyposis and early onset colorectal cancer - germline testing v2.0 Arina Puzriakova promoted panel to version 2.0
Inherited polyposis and early onset colorectal cancer - germline testing v1.33 Arina Puzriakova Panel name changed from Inherited polyposis to Inherited polyposis and early onset colorectal cancer - germline testing
List of related panels changed from R211; R209 to Inherited polyposis; R211
Congenital myopathy v3.0 Catherine Snow promoted panel to version 3.0
Limb disorders v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Limb disorders v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Congenital muscular dystrophy v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Congenital muscular dystrophy v3.0 Catherine Snow promoted panel to version 3.0
Mitochondrial disorders v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Congenital disorders of glycosylation v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Congenital disorders of glycosylation v3.0 Catherine Snow promoted panel to version 3.0
Monogenic hearing loss v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Monogenic hearing loss v3.0 Arina Puzriakova promoted panel to version 3.0
Fetal anomalies v1.993 Eleanor Williams List of related panels changed from R21; Fetal anomalies with a likely genetic cause to R21; Fetal anomalies with a likely genetic cause; Fetal anomalies with a likely genetic cause - non urgent; R412
Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Monogenic hearing loss v2.249 Arina Puzriakova Panel name changed from Hearing loss to Monogenic hearing loss
List of related panels changed from Congenital hearing impairment; Autosomal dominant deafness; Congenital hearing impairment (profound/severe); R67 to Hearing loss; Congenital hearing impairment; Autosomal dominant deafness; Congenital hearing impairment (profound/severe); Non-syndromic hearing loss; R67
Sudden unexplained death or survivors of a cardiac event v10.2 Eleanor Williams Panel name changed from Sudden cardiac death to Sudden unexplained death or survivors of a cardiac event
List of related panels changed from Molecular autopsy; R138; R408 to Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; 425
DDG2P v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Mitochondrial disorders v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
DDG2P v3.0 Catherine Snow promoted panel to version 3.0
Intestinal failure or congenital diarrhoea v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Long QT syndrome v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2022-11-30
Intestinal failure or congenital diarrhoea v2.0 Arina Puzriakova promoted panel to version 2.0
Primary immunodeficiency or monogenic inflammatory bowel disease v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Intestinal failure or congenital diarrhoea v1.51 Arina Puzriakova Panel name changed from Intestinal failure to Intestinal failure or congenital diarrhoea
List of related panels changed from R331 to R331; Intestinal failure
Long QT syndrome v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Primary immunodeficiency or monogenic inflammatory bowel disease v3.0 Eleanor Williams promoted panel to version 3.0
Primary immunodeficiency or monogenic inflammatory bowel disease v2.583 Eleanor Williams Panel name changed from Primary immunodeficiency to Primary immunodeficiency or monogenic inflammatory bowel disease
List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; R15 to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15
Intellectual disability v3.1771 RARB Dmitrijs Rots reviewed gene: RARB: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 27120018; Phenotypes: Intellectual Disability with Progressive Motor Impairment; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 IRF7 Dmitrijs Rots edited their review of gene: IRF7: Added comment: 7 families in total reported. Enough evidence for green classification.; Changed rating: GREEN; Changed publications to: 35986347, 35670811
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 KCNA5 Inga Nartisa gene: KCNA5 was added
gene: KCNA5 was added to Primary immunodeficiency. Sources: Literature,Expert Review
Mode of inheritance for gene: KCNA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNA5 were set to PMID: 35748970; PMID: 34536415
Phenotypes for gene: KCNA5 were set to autoimmunity; autoinflammation
Review for gene: KCNA5 was set to GREEN
Added comment: Sources: Literature, Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 DIAPH1 Inga Nartisa gene: DIAPH1 was added
gene: DIAPH1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: DIAPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DIAPH1 were set to PMID: 35748970; PMID: 33662367
Phenotypes for gene: DIAPH1 were set to microcephaly; epilepsy; cortical blindness; poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells.
Review for gene: DIAPH1 was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 CHUK Inga Nartisa gene: CHUK was added
gene: CHUK was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: CHUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHUK were set to PMID: 35748970; PMID: 34533979
Phenotypes for gene: CHUK were set to recurrent infections; skeletal abnormalities; absent secondary lymphoid structures; reduced B cell numbers; hypogammaglobulinemia; lymphocytic infiltration of intestine and liver
Review for gene: CHUK was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 COPG1 Inga Nartisa gene: COPG1 was added
gene: COPG1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: COPG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPG1 were set to PMID: 35748970; PMID: 33529166
Phenotypes for gene: COPG1 were set to persistent bacterial infection; persistent viral infections; defective humoral and cellular immunity
Review for gene: COPG1 was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 MAN2B2 Inga Nartisa gene: MAN2B2 was added
gene: MAN2B2 was added to Primary immunodeficiency. Sources: Other
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to PMID: 31775018
Review for gene: MAN2B2 was set to GREEN
Added comment: Sources: Other
Ataxia and cerebellar anomalies - childhood onset v2.318 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.317 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Ataxia and cerebellar anomalies - childhood onset v2.317 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1771 FBXW7 Arina Puzriakova Phenotypes for gene: FBXW7 were changed from Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate to Developmental delay, hypotonia, and impaired language, OMIM:620012
Intellectual disability v3.1770 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from Congenital heart defects, nonsyndromic, 2, 614980 to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Paediatric or syndromic cardiomyopathy v1.83 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Fetal anomalies v1.992 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from CONGENITAL HEART DISEASE, NONSYNDROMIC, 2 to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Hereditary neuropathy or pain disorder v1.105 ARHGEF10 Dmitrijs Rots reviewed gene: ARHGEF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy v1.457 ARHGEF10 Dmitrijs Rots reviewed gene: ARHGEF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.301 AIPL1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: AIPL1.
Retinal disorders v2.301 AIPL1 Arina Puzriakova edited their review of gene: AIPL1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Retinal disorders v2.301 AIPL1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): Achromatopsia, Cone, and Cone-rod Dystrophy; Cone-rod dystrophy (AD); Leber congenital amaurosis 4 (AR); Retinitis pigmentosa, juvenile (AD); Leber Congenital Amaurosis; Leber congenital amaurosis; Leber congenital amaurosis 4, 604393; Retinitis pigmentosa, juvenile, 604393; Cone-rod dystrophy, 604393; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa
Retinal disorders v2.301 AIPL1 Arina Puzriakova Phenotypes for gene: AIPL1 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Cone-rod dystrophy (AD); Leber congenital amaurosis 4 (AR); Retinitis pigmentosa, juvenile (AD); Leber Congenital Amaurosis; Leber congenital amaurosis; Leber congenital amaurosis 4, 604393; Retinitis pigmentosa, juvenile, 604393; Cone-rod dystrophy, 604393; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa to Cone-rod dystrophy, OMIM:604393; Retinitis pigmentosa, juvenile, OMIM:604393; Leber congenital amaurosis 4, OMIM:604393
Retinal disorders v2.300 AIPL1 Arina Puzriakova Publications for gene: AIPL1 were set to
Retinal disorders v2.299 AIPL1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'biallelic' to 'both mono- and biallelic (but biallelic mutations cause a more SEVERE disease form) at the next GMS panel update.

This gene is typically associated with recessive inheritance of a Leber congenital amaurosis (LCA) phenotype. However, some patients with heterozygous variants have also been identified, usually presenting less severe phenotypes within the retinal dystrophy spectrum such as retinitis pigmentosa and rod-cone dystrophy/dysfunction - although heterozygous variants act with reduced penetrance (PMID: 10873396; 15249368; 21900377; 33067476)

Both MOIs are also listed in OMIM.
Retinal disorders v2.299 AIPL1 Arina Puzriakova Mode of inheritance for gene: AIPL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams changed review comment from: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; to: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Added comment: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.316 PITRM1 Eleanor Williams Tag gene-checked tag was added to gene: PITRM1.
Nephrocalcinosis or nephrolithiasis v2.40 WDR72 Detlef Bockenhauer gene: WDR72 was added
gene: WDR72 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to PMID: 30028003; 30779877; 31959358; 33033857
Phenotypes for gene: WDR72 were set to distal renal tubular acidosis; amelogenesis imperfecta
Penetrance for gene: WDR72 were set to Complete
Review for gene: WDR72 was set to GREEN
Added comment: Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 SASH3 Eleanor Williams commented on gene: SASH3
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 SASH3 Eleanor Williams Tag gene-checked was removed from gene: SASH3.
Severe microcephaly v2.322 PRIM1 Eleanor Williams commented on gene: PRIM1
Severe microcephaly v2.322 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Severe microcephaly v2.321 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 PRIM1 Eleanor Williams commented on gene: PRIM1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Primary immunodeficiency or monogenic inflammatory bowel disease v2.581 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Fetal anomalies v1.991 PRIM1 Eleanor Williams commented on gene: PRIM1
Fetal anomalies v1.991 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Fetal anomalies v1.990 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Intellectual disability v3.1769 JARID2 Eleanor Williams commented on gene: JARID2
Intellectual disability v3.1769 JARID2 Eleanor Williams Phenotypes for gene: JARID2 were changed from Intellectual disability; Neurodevelopmental syndrome to Intellectual disability; Neurodevelopmental syndrome; Developmental delay with variable intellectual disability and dysmorphic facies, OMIM:620098
Intellectual disability v3.1768 JARID2 Eleanor Williams Tag gene-checked was removed from gene: JARID2.
Intellectual disability v3.1768 HNRNPR Eleanor Williams commented on gene: HNRNPR
Intellectual disability v3.1768 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
Intellectual disability v3.1767 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
Early onset or syndromic epilepsy v2.606 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
DDG2P v2.84 HNRNPR Eleanor Williams commented on gene: HNRNPR
DDG2P v2.84 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from INTELLECTUAL DISABILITY 616579 to Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
DDG2P v2.83 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Dystonia, chorea or related movement disorder, childhood onset v1.265 HNRNPH1 Eleanor Williams commented on gene: HNRNPH1
Dystonia, chorea or related movement disorder, childhood onset v1.265 HNRNPH1 Eleanor Williams Phenotypes for gene: HNRNPH1 were changed from HNRNPH1-related neurodevelopmental disorder to HNRNPH1-related neurodevelopmental disorder; Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, OMIM:620083
Dystonia, chorea or related movement disorder, childhood onset v1.264 HNRNPH1 Eleanor Williams Tag gene-checked was removed from gene: HNRNPH1.
Intellectual disability v3.1767 HNRNPH1 Eleanor Williams commented on gene: HNRNPH1
Intellectual disability v3.1767 HNRNPH1 Eleanor Williams Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability to HNRNPH1‐related syndromic intellectual disability; Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, OMIM:620083
Intellectual disability v3.1766 HNRNPH1 Eleanor Williams Tag gene-checked was removed from gene: HNRNPH1.
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams commented on gene: HID1
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Early onset or syndromic epilepsy v2.605 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Pituitary hormone deficiency v2.103 HID1 Eleanor Williams commented on gene: HID1
Pituitary hormone deficiency v2.103 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Pituitary hormone deficiency v2.102 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Intellectual disability v3.1766 HID1 Eleanor Williams commented on gene: HID1
Intellectual disability v3.1766 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Intellectual disability v3.1765 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Childhood solid tumours cancer susceptibility v1.23 GPR161 Eleanor Williams commented on gene: GPR161
Childhood solid tumours cancer susceptibility v1.23 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from Predisposition to paediatric medulloblastoma to {Medulloblastoma predisposition syndrome}, OMIM:155255
Childhood solid tumours cancer susceptibility v1.22 GPR161 Eleanor Williams Tag gene-checked was removed from gene: GPR161.
Childhood solid tumours v2.38 GPR161 Eleanor Williams commented on gene: GPR161
Childhood solid tumours v2.38 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from Medulloblastoma predisposition to {Medulloblastoma predisposition syndrome}, OMIM:155255
Childhood solid tumours v2.37 GPR161 Eleanor Williams Tag gene-checked was removed from gene: GPR161.
Intellectual disability v3.1765 CACNA1I Eleanor Williams commented on gene: CACNA1I
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams commented on gene: CACNA1I
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with speech impairment and with or without seizures, OMIM:620114
Early onset or syndromic epilepsy v2.604 CACNA1I Eleanor Williams Tag gene-checked was removed from gene: CACNA1I.
Intellectual disability v3.1765 CACNA1I Eleanor Williams Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with speech impairment and with or without seizures, OMIM:620114
Intellectual disability v3.1764 CACNA1I Eleanor Williams Tag gene-checked was removed from gene: CACNA1I.
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Structural eye disease v1.152 DDX58 Eleanor Williams commented on gene: DDX58
Structural eye disease v1.152 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Intellectual disability v3.1763 DDX58 Eleanor Williams commented on gene: DDX58
Intellectual disability v3.1763 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
DDG2P v2.83 DDX58 Eleanor Williams commented on gene: DDX58
DDG2P v2.83 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
COVID-19 research v1.134 DDX58 Eleanor Williams commented on gene: DDX58
COVID-19 research v1.134 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Glaucoma (developmental) v1.42 DDX58 Eleanor Williams commented on gene: DDX58
Glaucoma (developmental) v1.42 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Hereditary neuropathy or pain disorder v1.105 FAM126A Eleanor Williams commented on gene: FAM126A
Hereditary neuropathy or pain disorder v1.105 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Structural eye disease v1.152 FAM126A Eleanor Williams commented on gene: FAM126A
Structural eye disease v1.152 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Hereditary neuropathy v1.457 FAM126A Eleanor Williams commented on gene: FAM126A
Hereditary neuropathy v1.457 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
DDG2P v2.83 FAM126A Eleanor Williams commented on gene: FAM126A
DDG2P v2.83 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Inherited white matter disorders v1.163 FAM126A Eleanor Williams commented on gene: FAM126A
Inherited white matter disorders v1.163 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Bilateral congenital or childhood onset cataracts v2.111 FAM126A Eleanor Williams commented on gene: FAM126A
Bilateral congenital or childhood onset cataracts v2.111 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Fetal anomalies v1.990 FAM126A Eleanor Williams commented on gene: FAM126A
Fetal anomalies v1.990 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Intellectual disability v3.1763 FAM126A Eleanor Williams commented on gene: FAM126A
Intellectual disability v3.1763 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
White matter disorders and cerebral calcification - childhood onset v1.246 FAM126A Eleanor Williams commented on gene: FAM126A
White matter disorders and cerebral calcification - childhood onset v1.246 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Familial melanoma v1.14 TERT Arina Puzriakova Publications for gene: TERT were set to 23348503
Familial melanoma v1.13 TERT Arina Puzriakova Tag watchlist tag was added to gene: TERT.
Familial melanoma v1.13 TERT Arina Puzriakova reviewed gene: TERT: Rating: ; Mode of pathogenicity: None; Publications: 23348503, 23348506, 35912549; Phenotypes: {Melanoma, cutaneous malignant, 9}, OMIM:615134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia, adult onset v2.169 TERT Arina Puzriakova Publications for gene: TERT were set to
Hereditary ataxia, adult onset v2.168 TERT Arina Puzriakova Classified gene: TERT as Green List (high evidence)
Hereditary ataxia, adult onset v2.168 TERT Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update as there is no link with adult-onset ataxia associated with this gene.

Cerebellar hypoplasia (but without ataxia) has been identified in 2/5 unrelated AR cases to date, who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115). Furthermore, literature search only revealed a single adult patient (31 years old) who did not present any signs of ataxia (PMID: 18042801).
Hereditary ataxia, adult onset v2.168 TERT Arina Puzriakova Gene: tert has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.316 TERT Arina Puzriakova changed review comment from: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.; to: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases to date, who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.
Hereditary ataxia, adult onset v2.167 TERT Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: TERT.
Cerebellar hypoplasia v1.70 TERT Arina Puzriakova Publications for gene: TERT were set to 17785587; 16247010
Cerebellar hypoplasia v1.69 TERT Arina Puzriakova reviewed gene: TERT: Rating: AMBER; Mode of pathogenicity: None; Publications: 17785587, 34890115; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.316 TERT Arina Puzriakova changed review comment from: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases displaying a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.; to: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.
Ataxia and cerebellar anomalies - childhood onset v2.316 TERT Arina Puzriakova Tag watchlist tag was added to gene: TERT.
Ataxia and cerebellar anomalies - childhood onset v2.316 TERT Arina Puzriakova Classified gene: TERT as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.316 TERT Arina Puzriakova Gene: tert has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.315 TERT Arina Puzriakova reviewed gene: TERT: Rating: AMBER; Mode of pathogenicity: None; Publications: 17785587, 34890115; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.167 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, 613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Ataxia and cerebellar anomalies - childhood onset v2.315 TERT Arina Puzriakova Deleted their review
Ataxia and cerebellar anomalies - childhood onset v2.315 TERT Arina Puzriakova Deleted their comment
Ataxia and cerebellar anomalies - childhood onset v2.315 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Ataxia and cerebellar anomalies - childhood onset v2.314 TERT Arina Puzriakova Mode of inheritance for gene: TERT was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.69 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Intellectual disability v3.1763 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal recessive 4 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Adult solid tumours cancer susceptibility v2.24 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Cerebellar hypoplasia v1.68 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from dyskeratosis congenita-2 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Skeletal dysplasia v2.228 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2 and autosomal recessive 4 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Childhood solid tumours cancer susceptibility v1.22 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dynkeratosis Congenita to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Primary immunodeficiency or monogenic inflammatory bowel disease v2.581 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Pigmentary skin disorders v1.54 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 2; DKCA2, DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 4, INCLUDED; Melanoma; Dyskeratosis congenita; DKCB4, INCLUDED to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Familial melanoma v1.13 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from to {Melanoma, cutaneous malignant, 9}, OMIM:615134
COVID-19 research v1.134 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Childhood solid tumours v2.37 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Ataxia and cerebellar anomalies - childhood onset v2.313 TERT Arina Puzriakova Classified gene: TERT as Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.313 TERT Arina Puzriakova Added comment: Comment on list classification: Couldn't find any evidence linking TERT with ataxia and therefore demoting from Amber to Red.
Ataxia and cerebellar anomalies - childhood onset v2.313 TERT Arina Puzriakova Gene: tert has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.312 TERT Arina Puzriakova Mode of inheritance for gene: TERT was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.311 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from dyskeratosis congenita-2 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Familial pulmonary fibrosis v1.30 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}, 614742; Familial Pulmonary Fibrosis; Pulmonary Fibrosis and Hermansky-Pudlak Syndrome; Pulmonary Disease to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Cytopenia - NOT Fanconi anaemia v1.73 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Pulmonary fibrosis, telomere-related, 1}, 614742; {Dyskeratosis congenita, autosomal dominant 2}, 613989; Coronary artery disease; {Melanoma, cutaneous malignant, 9}, 615134; 614742 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1; Aplastic Anemia; 614742 {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}; {Leukemia, acute myeloid}, 601626; 613989 Dyskeratosis congenita; {Dyskeratosis congenita, autosomal recessive 4}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Inherited predisposition to acute myeloid leukaemia (AML) v1.25 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Haematological malignancies for rare disease v1.16 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Haematological malignancies cancer susceptibility v2.39 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Bone marrow failure, macrocytosis; Skin, head and neck, and anogenital squamous cell cancers, Oral and GI squamous cell carcinoma to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Cytopenias and congenital anaemias v1.111 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Aplastic Anemia; Coronary artery disease; {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989; {Pulmonary fibrosis, telomere-related, 1}, 614742; {Leukemia, acute myeloid}, 601626; {Melanoma, cutaneous malignant, 9}, 615134 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742 (AD)
Haematological malignancies for rare disease v1.15 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Bone marrow failure, macrocytosis; Skin, head and neck, and anogenital squamous cell cancers, Oral and GI squamous cell carcinoma to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Haematological malignancies cancer susceptibility v2.38 MBD4 Arina Puzriakova changed review comment from: Re-tagging on this panel following a separate Green expert review on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.; to: Re-tagging on this panel following a new Green expert review by Dr Claire Palles on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.
Haematological malignancies cancer susceptibility v2.38 RAD21 Arina Puzriakova Tag missense tag was added to gene: RAD21.
Haematological malignancies cancer susceptibility v2.38 RAD21 Arina Puzriakova Mode of pathogenicity for gene: RAD21 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: RAD21.
Tag Q4_22_expert_review tag was added to gene: RAD21.
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Added comment: Comment on list classification: RAD21 will be flagged for expert review at the next GMS panel update to determine whether there is enough evidence to classify this gene as Green.

Somatic variants have been found in multiple AML cohorts (PMID: 34157074); however, only one recurrent germline variant (c.892C>T/G, p.P298S/A) was found in three unrelated children with lymphoblastic leukemia or lymphoma (PMID:35563565). The same variant was also found in an adult patient with a solid tumour (malignant peripheral nerve sheath tumour).
Functional studies showed the variant disrupted RAD21 gene expression and DNA damage response but did not perturb formation of the cohesin complex. Notably 2/3 patients harboured known pathogenic somatic KRAS hot-spot variants.

Heterozygous variants in the RAD21 gene are also associated with Cornelia-de-Lange syndrome (MIM# 614701) which is not known to confer cancer predisposition.
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Catecholaminergic polymorphic VT v2.21 CALM2 Sarah Leigh Phenotypes for gene: CALM2 were changed from catecholaminergic polymorphic ventricular tachycardia, MONDO:0017990 to Long QT syndrome 15, OMIM:616249; long QT syndrome 15, MONDO:0014550
Long QT syndrome v2.34 CALM2 Sarah Leigh Phenotypes for gene: CALM2 were changed from Long QT syndrome 15 to Long QT syndrome 15, OMIM:616249; long QT syndrome 15, MONDO:0014550
Catecholaminergic polymorphic VT v2.20 CALM2 Sarah Leigh Publications for gene: CALM2 were set to 27114410; 27100291; 24917665
Long QT syndrome v2.33 CALM2 Sarah Leigh Publications for gene: CALM2 were set to
Clefting v2.73 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Clefting v2.73 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Clefting v2.72 RAD21 Arina Puzriakova gene: RAD21 was added
gene: RAD21 was added to Clefting. Sources: Literature
Q4_22_promote_green tags were added to gene: RAD21.
Mode of inheritance for gene: RAD21 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD21 were set to 22633399; 27882533; 31334757; 32193685
Phenotypes for gene: RAD21 were set to Cornelia de Lange syndrome 4, OMIM:614701
Review for gene: RAD21 was set to GREEN
Added comment: At least 33 unrelated families published with RAD21 alterations. Of these, 6 cases presented with cleft palate or submucous cleft palate. Although only displayed by a subset of patients, clefting is a congenital anomaly that may aid earlier diagnosis if other features such as ID have not yet become apparent. Therefore there would be value in including RAD21 on this panel with a Green rating.
Sources: Literature
Intellectual disability v3.1762 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to
Skeletal dysplasia v2.227 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 30716475; 24378232; 27882533; 27620904
Intellectual disability v3.1761 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4, 614701; COHESINOPATHY to Cornelia de Lange syndrome 4, OMIM:614701
Radial dysplasia v1.22 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Radial dysplasia v1.22 RAD21 Arina Puzriakova Added comment: Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now.

Krab et al. 2020 (PMID: 32193685) collated details on 33 unrelated families (previously and newly published) with RAD21 alterations. In the 22 families with sufficient clinical data available, authors noted that major limb malformations are generally not present. However, minor skeletal anomalies such as clinodactyly of fifth finger (13), camptodactyly (3), scoliosis (2), hip dislocation/dysplasia (2) are reported.
Radial dysplasia v1.22 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Radial dysplasia v1.21 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 31334757; 32193685
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Added comment: Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now.
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.225 RAD21 Arina Puzriakova reviewed gene: RAD21: Rating: ; Mode of pathogenicity: None; Publications: 32193685; Phenotypes: Cornelia de Lange syndrome 4, OMIM:614701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Radial dysplasia v1.20 RAD21 Arina Puzriakova Tag watchlist was removed from gene: RAD21.
Radial dysplasia v1.20 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 31334757
Skeletal dysplasia v2.225 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4 614701 to Cornelia de Lange syndrome 4, OMIM:614701
Radial dysplasia v1.19 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4, 614701 to Cornelia de Lange syndrome 4, OMIM:614701
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Classified gene: FOXI3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
A recent study (highlighted by GEL Clinical Team) provides corroborating evidence linking FOXI3 with microtia with or without atresia. Sufficient unrelated cases and supported by concordant animal models.
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Gene: foxi3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.107 FOXI3 Arina Puzriakova gene: FOXI3 was added
gene: FOXI3 was added to Paediatric disorders - additional genes. Sources: Expert Review
Q4_22_promote_green tags were added to gene: FOXI3.
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 36260083; 25655429; 18787161; 24650709
Phenotypes for gene: FOXI3 were set to Bilateral Microtia; Congenital aural atresia
Review for gene: FOXI3 was set to GREEN
Added comment: Quiat et al. 2022 (PMID: 36260083) reported 4 unrelated families affected by microtia with or without atresia and different predicted deleterious heterozygous variants in the FOXI3 gene. Variants segregated with disease, including in multiplex families, albeit with reduced penetrance. In vitro studies showed that patient variants conferred abnormal FOXI3 nuclear and cytoplasmic localization.

Tassano et al. 2015 (PMID: 25655429) also identified a patient with microtia, aural atresia, and ipsilateral agenesis of the carotid artery who harboured a 2.5 Mb deletion overlapping the FOXI3 gene.

Congenital ear malformations with variable penetrance have been described in a Foxi3 knockout mouse model and haploinsufficient canine breeds supporting a role of FOXI3 in the human phenotype (PMID: 18787161; 24650709)
Sources: Expert Review
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Classified gene: FOXI3 as Green List (high evidence)
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Added comment: Comment on list classification: Promoting from Red to Green as a recent study (highlighted by GEL Clinical Team) provides corroborating evidence linking FOXI3 with microtia with or without atresia. Sufficient unrelated cases and supported by concordant animal models.
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Gene: foxi3 has been classified as Green List (High Evidence).
Deafness and congenital structural abnormalities v1.21 FOXI3 Arina Puzriakova Publications for gene: FOXI3 were set to
Deafness and congenital structural abnormalities v1.20 FOXI3 Arina Puzriakova Mode of inheritance for gene: FOXI3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Deafness and congenital structural abnormalities v1.19 FOXI3 Arina Puzriakova reviewed gene: FOXI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36260083, 25655429, 18787161, 24650709; Phenotypes: Microtia with or without atresia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.990 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED to Mental retardation, X-linked, syndromic, Claes-Jensen type, OMIM:300534
Fetal anomalies v1.989 KDM5C Arina Puzriakova Publications for gene: KDM5C were set to
Fetal anomalies v1.988 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304) showing that females can be symptomatic.

Therefore, the MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update. This also reflects the current MOI on all other relevant panels.
Fetal anomalies v1.988 KDM5C Arina Puzriakova Mode of inheritance for gene: KDM5C was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.987 KDM5C Arina Puzriakova Tag Q4_22_MOI tag was added to gene: KDM5C.
Neurodegenerative disorders, adult onset v2.296 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Hereditary spastic paraplegia, adult onset v1.104 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Hereditary spastic paraplegia, childhood onset v2.153 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Hereditary spastic paraplegia v1.297 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Classified gene: CNGB3 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (sufficient number of cases, already green on other panels, phenotypic relevance confirmed by clinician).
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Gene: cngb3 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.26 CNGB3 Arina Puzriakova gene: CNGB3 was added
gene: CNGB3 was added to Albinism or congenital nystagmus. Sources: Expert Review
Q4_22_promote_green tags were added to gene: CNGB3.
Mode of inheritance for gene: CNGB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNGB3 were set to 10888875; 10958649; 35332618
Phenotypes for gene: CNGB3 were set to Achromatopsia 3, OMIM:262300
Review for gene: CNGB3 was set to GREEN
Added comment: Added to this panel following suggestion from Dr Helen Brittain (Genomics England Clinical Team) who highlighted a patient who would have benefitted from inclusion of CNGB3 on R39 Albinism or congenital nystagmus. Biallelic variants cause achromatopsia, featuring total colour blindness, photophobia, reduced visual acuity and nystagmus.
Sources: Expert Review
Retinal disorders v2.298 CNGB3 Arina Puzriakova Phenotypes for gene: CNGB3 were changed from Achromatopsia; Macular degeneration, juvenile; Achromatopsia-3, 262300; Macular degeneration, juvenile, 248200 -3; Stargardt Disease, Recessive; Macular Dystrophy/Degeneration/Stargardt Disease; Achromatopsia-3; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy to Achromatopsia 3, OMIM:262300; Macular degeneration, juvenile
Early onset or syndromic epilepsy v2.603 CUX2 Tracy Lester edited their review of gene: CUX2: Added comment: Almost all cases reported to date have a de novo E590K variant, there is currently no evidence supporting this gene being imprinted or for LOF variants being pathogenic. I suggest the inheritance model should be updated to be monoallelic, NOT imprinted.; Changed mode of pathogenicity: Other; Changed publications to: 29795476, 29630738
Intellectual disability v3.1760 FMR1 Arina Puzriakova Publications for gene: FMR1 were set to
Intellectual disability v3.1759 FMR1 Arina Puzriakova reviewed gene: FMR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21267007, 25171808, 28176767, 29178241; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ataxia and cerebellar anomalies - childhood onset v2.310 FMR1 Arina Puzriakova Classified gene: FMR1 as Green List (high evidence)
Ataxia and cerebellar anomalies - childhood onset v2.310 FMR1 Arina Puzriakova Added comment: Comment on list classification: FMR1 should be demoted from Green to Red at the next GMS panel update as the disease mechanism for FXTAS (includes ataxia) is repeat expansions and SNVs are not relevant. Furthermore, the FMR1_CGG STR entity will not be added as FXTAS is a late-onset condition and this panel feeds into the childhood-onset ataxia super panel (R55). The STR is already Green on the R45 Hereditary ataxia - adult onset (v2.13) panel.
Ataxia and cerebellar anomalies - childhood onset v2.310 FMR1 Arina Puzriakova Gene: fmr1 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.309 FMR1 Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: FMR1.
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Classified gene: FMR1 as Red List (low evidence)
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Green to Red as the disease mechanism is repeat expansion and SNVs are not relevant to FXTAS.
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Gene: fmr1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.603 SNIP1 Helen Lord reviewed gene: SNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34570759, 2279524, 31589614; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 CLPB Helen Lord reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 25597510, 25597511, 26916670; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary ciliary disorders v1.40 OFD1 Amelia Shoemark reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31373179 31366608; Phenotypes: ciliopathies, primary ciliary dyskinesia, joubert; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.603 ASH1L Helen Lord reviewed gene: ASH1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 34373061, 25961944, 34782621, 32469098; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital muscular dystrophy v2.31 POGLUT1 Anna Sarkozy changed review comment from: in addition to adult-onset LGMD R21 (OMIM# 617232), biallelic variants in POGLUT1 gene have been reported in one patient with congenital muscular dystrophy and in two further patients with onset before 3 years of age. The presenting symptom were hypotonia with lower limb proximal weakness after gait acquisition, and further progression with mild weakness, wasting and contractures of the upper limbs, mild facial weakness, ptosis, and nasal voice. weakness was more severe and had faster progression compared to later onset patients. Muscle biopsies shows evidence of α-dystroglycan hypoglycosylation. POGLUT1 activity is critical for the Notch signaling pathway, as JAG2. Inview of these evidences, this gene should be considered green for CMD panel as well, in addition to LGMD panel.; to: in addition to adult-onset LGMD R21 (OMIM# 617232), biallelic variants in POGLUT1 gene have been reported in one patient with congenital muscular dystrophy and in two further patients with onset before 3 years of age. The presenting symptom were hypotonia with lower limb proximal weakness after gait acquisition, and further progression with mild weakness, wasting and contractures of the upper limbs, mild facial weakness, ptosis, and nasal voice. weakness was more severe and had faster progression compared to later onset patients. Muscle biopsies show evidence of α-dystroglycan hypoglycosylation. POGLUT1 activity is critical for the Notch signalling pathway, as JAG2. In view of these evidences, this gene should be considered green for CMD panel as well, in addition to LGMD panel.
Congenital muscular dystrophy v2.31 POGLUT1 Anna Sarkozy reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33861953; Phenotypes: muscular dystrophy, secondary alpha-dystroglycanopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.31 JAG2 Anna Sarkozy reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33861953; Phenotypes: muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.93 KY Anna Sarkozy edited their review of gene: KY: Added comment: Two brothers reported with homozygous c405 C > A (pY135*) nonsense mutation in the KY (Kyphoscoliosis peptidase) gene encoding the KY protein. the phenotype is myopathic, with prenatal onset, progressive muscle weakness and atrophy in limbs, face and tongue, contractures and rigid spine. CK is elevated. Muscle biopsy showed Cores and absence of the mutant protein.; Changed mode of pathogenicity: Other
Congenital myopathy v2.93 TNNC2 Anna Sarkozy reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arrhythmogenic right ventricular cardiomyopathy v2.18 RYR2 Matthew Edwards Deleted their review
Congenital muscular dystrophy v2.31 HNRNPA2B1 Anna Sarkozy edited their review of gene: HNRNPA2B1: Added comment: ten independent families reported with a severe, progressive muscular dystrophy with early onset, and de novo frameshift variants in this gene. phenotype is caractherised by symptoms onset before 2 years of age with severe respiratory insufficiency, delayed motor milestones, ptosis and ophthalmoplegia, axial weakness, progressive proximal and distal weakness. Creatine kinase levels were elevated. Disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and alter the nucleocytoplasmic transport dynamics. in view of this evidence this gene should be upgraded to green; Changed publications to: 35484142; Changed phenotypes to: early-onset oculopharyngeal muscular dystrophy, muscular dystrophy, congenital myopathy
Congenital muscular dystrophy v2.31 GGPS1 Anna Sarkozy reviewed gene: GGPS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35869884, 32403198; Phenotypes: GGPS1-associated muscular dystrophy with and without hearing loss.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.31 DPM3 Anna Sarkozy reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19576565, 35932216, 33200426, 31266720; Phenotypes: Congenital muscular dystrophy, secondary alpha-dystroglycanopathy, limb girdle muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.93 UNC45B Anna Sarkozy reviewed gene: UNC45B: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33217308, 31852522, 35292251; Phenotypes: congenital myopathy, progressive myopathy with eccentric cores, core myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Classified gene: RPS6KB1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (5 unrelated cases plus functional data)
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.43 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
Q4_22_promote_green tags were added to gene: RPS6KB1.
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Classified gene: ARSK as Amber List (moderate evidence)
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Added comment: Comment on list classification: Rating Amber awaiting further cases.
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Gene: arsk has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Classified gene: ARSK as Amber List (moderate evidence)
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Added comment: Comment on list classification: Rating Amber awaiting further cases.
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Gene: arsk has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.223 ARSK Arina Puzriakova gene: ARSK was added
gene: ARSK was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSK were set to 34916232
Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex
Review for gene: ARSK was set to AMBER
Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities.
Sources: Literature
Likely inborn error of metabolism v2.328 ARSK Arina Puzriakova gene: ARSK was added
gene: ARSK was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSK were set to 34916232
Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex
Review for gene: ARSK was set to AMBER
Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities.
Sources: Literature
Skeletal ciliopathies v1.19 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Dystonia, chorea or related movement disorder, childhood onset v1.264 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Neurological ciliopathies v1.33 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Ophthalmological ciliopathies v1.32 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Limb disorders v2.84 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757; Joubert Syndrome with Cranio-facial and Skeletal Defects to Joubert syndrome 32, OMIM:617757
Holoprosencephaly v2.31 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Basal cell nevus syndrome, 109400 to Basal cell nevus syndrome, OMIM:109400
Genodermatoses with malignancies v1.9 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours for rare disease v1.36 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial Tumours Syndromes of the central & peripheral Nervous system v1.14 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours cancer susceptibility v2.23 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Childhood solid tumours cancer susceptibility v1.21 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Childhood solid tumours v2.36 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Medulloblastoma, desmoplastic, 155255; Basal cell nevus syndrome, 109400; SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours for rare disease v1.35 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial Tumours Syndromes of the central & peripheral Nervous system v1.13 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Brain, CNS, and PNS Cancer to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Genodermatoses with malignancies v1.8 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Medulloblastoma; Medulloblastoma, desmoplastic; {Meningioma, familial, susceptibility to}; (originally on Gorlin syndrome gene panel) to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Intellectual disability v3.1759 FOXP4 Ian Berry reviewed gene: FOXP4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33110267; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1759 AGO1 Arina Puzriakova Publications for gene: AGO1 were set to 26350204; 30213762; 22495306; 23020937; 25363768; 25356899; 27620904; 29346770; 28135719
Pulmonary arterial hypertension v2.24 ATP13A3 Arina Puzriakova Publications for gene: ATP13A3 were set to 29650961; 30545973
Intellectual disability v3.1758 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to
Severe microcephaly v2.321 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to 25326669; 26968164
Hereditary spastic paraplegia, childhood onset v2.152 CTNNB1 Arina Puzriakova Classified gene: CTNNB1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.152 CTNNB1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Hereditary spastic paraplegia, childhood onset v2.152 CTNNB1 Arina Puzriakova Gene: ctnnb1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.151 CTNNB1 Arina Puzriakova gene: CTNNB1 was added
gene: CTNNB1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q4_22_promote_green tags were added to gene: CTNNB1.
Mode of inheritance for gene: CTNNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNNB1 were set to 23033978; 24614104; 25326669; 26968164; 27915094; 34321325
Phenotypes for gene: CTNNB1 were set to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Review for gene: CTNNB1 was set to GREEN
Added comment: Childhood-onset spasticity is a key feature of the neurodevelopmental phenotype caused by pathogenic monoallelic variants in the CTNNB1 gene. Over 15 unrelated cases reported in literature, almost all of which developed spasticity which significantly affected ability to walk.
Sources: Literature
Intellectual disability v3.1757 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Mental retardation, autosomal dominant 19, 615075Colorectal cancer, somatic, 114500Pilomatricoma, somatic, 132600Ovarian cancer, somatic, 167000Hepatocellular carcinoma, somatic, 114550; MENTAL RETARDATION, AUTOSOMAL DOMINANT 19 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Severe microcephaly v2.320 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from primary microcephaly; Mental retardation, autosomal dominant 19, 615075 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Retinal disorders v2.297 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Exudative vitreoretinopathy 7 617572 to Exudative vitreoretinopathy 7, OMIM:617572
Familial diabetes v1.67 HNF1A Arina Puzriakova Phenotypes for gene: HNF1A were changed from MODY, type III, 600496{Diabetes mellitus, noninsulin-dependent, 2}, 125853{Diabetes mellitus, insulin-dependent}, 222100Hepatic adenoma, somatic, 142330Renal cell carcinoma, 144700Diabetes mellitus, insulin-dependent, 20, 612520; Maturity Onset Diabetes of the Young to Diabetes mellitus, insulin-dependent, 20, OMIM:612520; {Diabetes mellitus, noninsulin-dependent, 2}, OMIM:125853; MODY, type III, OMIM:600496
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.67 HNF1A Arina Puzriakova Phenotypes for gene: HNF1A were changed from MODY, type III, 600496; {Diabetes mellitus, noninsulin-dependent, 2}, 125853; {Diabetes mellitus, insulin-dependent}, 222100; Hepatic adenoma, somatic, 142330; Renal cell carcinoma, 144700; Diabetes mellitus, insulin-dependent, 20, 612520; Maturity Onset Diabetes of the Young; Maturity-onset diabetes of the young (MODY); Maturity-Onset Diabetes Of The Young; MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3 to Diabetes mellitus, insulin-dependent, 20, OMIM:612520; {Diabetes mellitus, noninsulin-dependent, 2}, OMIM:125853; MODY, type III, OMIM:600496
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Tag watchlist_moi tag was added to gene: HNF1A.
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous loss-of-function germline variants are thought to be embryonically lethal, however one family including three insulin-treated family members diagnosed with diabetes before 20 years of age was identified by Misra et al. 2020 (PMID: 32001615) with a homozygous hypomorphic variant in the HNF1A gene. This is not yet sufficient to update the MOI but should be noted if further recessive cases are reported in the future.
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Mode of inheritance for gene: HNF1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v2.78 HK1 Arina Puzriakova Classified gene: HK1 as Amber List (moderate evidence)
Optic neuropathy v2.78 HK1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Optic atrophy identified in 5/7 patients reported to date with HK1-related neurodevelopmental disorder (AD inheritance).
Optic neuropathy v2.78 HK1 Arina Puzriakova Gene: hk1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.77 HK1 Arina Puzriakova Added comment: Comment on mode of inheritance: Setting to 'monoallelic' as this is the appropriate MOI for this panel (MIM# 618547). Incorrect biallelic MOI was copied from ID panel which will be rectified following GMS approval (Q3_22).
Optic neuropathy v2.77 HK1 Arina Puzriakova Mode of inheritance for gene: HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v2.76 HK1 Arina Puzriakova Tag missense was removed from gene: HK1.
Tag Q3_22_MOI was removed from gene: HK1.
Tag Q3_22_NHS_review was removed from gene: HK1.
Tag Q4_22_promote_green tag was added to gene: HK1.
Optic neuropathy v2.76 HK1 Arina Puzriakova Entity copied from Intellectual disability v3.1756
Optic neuropathy v2.76 HK1 Arina Puzriakova gene: HK1 was added
gene: HK1 was added to Optic neuropathy. Sources: Expert Review Green,BRIDGE study SPEED NEURO Tier1 Gene
missense, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: HK1.
Mode of inheritance for gene: HK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HK1 were set to 30778173; 28135719
Phenotypes for gene: HK1 were set to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Penetrance for gene: HK1 were set to Complete
Mode of pathogenicity for gene: HK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Retinal disorders v2.296 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79, OMIM:617460; retinitis pigmentosa 79,MONDO:0044320 to Retinitis pigmentosa 79, OMIM:617460; Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Intellectual disability v3.1756 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807 to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Hereditary neuropathy or pain disorder v1.105 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neuropathy, hereditary motor and sensory, Russe type, 605285; Hemolytic anemia due to hexokinase deficiency, 235700 to Neuropathy, hereditary motor and sensory, Russe type, OMIM:605285
Hereditary neuropathy v1.457 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neuropathy, hereditary motor and sensory, Russe type, 605285; Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285 to Neuropathy, hereditary motor and sensory, Russe type, OMIM:605285
Rare anaemia v1.46 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from 235700 Hemolytic anemia due to hexokinase deficiency; Hemolytic anemia due to hexokinase deficiency, 235700; 235700 Enzyme Disorder; Hemolytic anemia due to hexokinase deficiency; Enzyme Disorder to Hemolytic anemia due to hexokinase deficiency, OMIM:235700; Enzyme disorder
Cytopenias and congenital anaemias v1.110 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Enzyme Disorder; Hemolytic anemia due to hexokinase deficiency, 235700 to Hemolytic anemia due to hexokinase deficiency, OMIM:235700
Paediatric or syndromic cardiomyopathy v1.82 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from DCM; Iron overload, liver disease, diabetes, hypogonadism; Hypertrophic-hypocontractile cardiomyopathy; Hereditary haemochromatosis Type 1 (Disorder of iron metabolism); Haemochromatosis; Hemochromatosis, 235200; Hemochromatosis; HCM to Hemochromatosis, OMIM:235200; Iron overload, liver disease, diabetes, hypogonadism; Hypertrophic-hypocontractile cardiomyopathy
Undiagnosed metabolic disorders v1.569 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hereditary haemochromatosis Type 1 (Disorder of iron metabolism); Hemochromatosis, 235200 to Hemochromatosis, OMIM:235200; Disorder of iron metabolism
Hypogonadotropic hypogonadism v1.36 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hemochromatosis, 235200 to Hemochromatosis, OMIM:235200
Likely inborn error of metabolism v2.327 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hemochromatosis, 235200; Hereditary haemochromatosis Type 1 (Disorder of iron metabolism) to Hemochromatosis, OMIM:235200
Iron metabolism disorders - NOT common HFE mutations v1.36 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from 235200 HEMOCHROMATOSIS, TYPE 1; HFE1; 235200 Hemochromatosis; 235200HEMOCHROMATOSIS, TYPE 1 to Hemochromatosis, OMIM:235200
Fetal anomalies v1.987 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Fetal hydrops; Thalassemia, alpha-, 604131 to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Fetal hydrops v1.57 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from HYDROPS FETALIS, NONIMMUNE, 236750; NIHF; HYDROPS FETALIS, ALPHA-THALASSEMIA-RELATED, INCLUDED; Hemoglobin H disease, nondeletional, 613978; HEMOGLOBIN H HYDROPS FETALIS SYNDROME; Thalassemia, alpha-, 604131; Alpha thalassaemia; Hb H disease to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Rare anaemia v1.45 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Hypochromic microcytic anemia; Heinz body anemia,140700; Globin Disorder; Erythrocytosis; Thalassemia, alpha-, 604131; 604131 Alpha thalassaemia; 60413 Thalassemia, alpha; Hemoglobin H disease, nondeletional, 613978 to Erythrocytosis 7, OMIM:617981; Heinz body anemia, OMIM:140700; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Thalassemia, alpha-, OMIM:604131
Cytopenias and congenital anaemias v1.109 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Globin Disorder; Erythrocytosis; Heinz body anemia,140700; Hemoglobin H disease, nondeletional, 613978; Hypochromic microcytic anemia; Thalassemia, alpha-, 60413 to Erythrocytosis 7, OMIM:617981; Heinz body anemia, OMIM:140700; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Thalassemia, alpha-, OMIM:604131
Rare anaemia v1.44 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from 604131 Thalassemias, alpha; Erythremias, alpha-; Globin Disorder; Methemoglobinemias, alpha-; Heinz body anemias, alpha-, 140700; 604131 Alpha thalassaemia; Hemoglobin H disease, nondeletional, 613978; Thalassemias, alpha-, 604131 to Erythrocytosis 7, OMIM:617981; Heinz body anemias, alpha-, OMIM:140700; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Thalassemias, alpha-, OMIM:604131
Cytopenias and congenital anaemias v1.108 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from Globin Disorder; Erythremias, alpha-; Heinz body anemias, alpha-, 140700; Hemoglobin H disease, nondeletional, 613978; Methemoglobinemias, alpha-; Thalassemias, alpha-, 604131 to Erythrocytosis 7, OMIM:617981; Heinz body anemias, alpha-, OMIM:140700; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Thalassemias, alpha-, OMIM:604131
Fetal anomalies v1.986 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from Fetal hydrops; Thalassemia, alpha-, 604131 to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Fetal hydrops v1.56 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from HYDROPS FETALIS, NONIMMUNE, 236750; NIHF; HYDROPS FETALIS, ALPHA-THALASSEMIA-RELATED, INCLUDED; Hemoglobin H disease, nondeletional, 613978; Hb H disease; HEMOGLOBIN H HYDROPS FETALIS SYNDROME; Thalassemia, alpha-, 604131; Alpha thalassaemia; alpha thalassaemia major; Hb Bart's to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Hereditary ataxia, adult onset v2.166 GRN Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Multiple cases reported with variable ages of onset but mostly in adulthood. Cerebellar ataxia with cerebellar atrophy on brain MRI is a prominent feature detected in almost all cases with homozygous pathogenic variants in this gene.
Ataxia and cerebellar anomalies - childhood onset v2.309 GRN Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Multiple cases reported with variable ages of onset. Cerebellar ataxia with cerebellar atrophy on brain MRI is a prominent feature detected in almost all cases with homozygous pathogenic variants in this gene.
Hereditary ataxia, adult onset v2.166 GRN Arina Puzriakova Entity copied from Neuronal ceroid lipofuscinosis v1.25
Hereditary ataxia, adult onset v2.166 GRN Arina Puzriakova gene: GRN was added
gene: GRN was added to Hereditary ataxia - adult onset. Sources: London North GLH,NHS GMS,Expert Review Amber
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Ataxia and cerebellar anomalies - childhood onset v2.309 GRN Arina Puzriakova Entity copied from Neuronal ceroid lipofuscinosis v1.25
Ataxia and cerebellar anomalies - childhood onset v2.309 GRN Arina Puzriakova gene: GRN was added
gene: GRN was added to Ataxia and cerebellar anomalies - narrow panel. Sources: London North GLH,NHS GMS,Expert Review Amber
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Retinal disorders v2.295 GRN Arina Puzriakova Added comment: Comment on mode of inheritance: Only found evidence of infraclinical lesions of retinal lipofuscinosis detected in heterozygous carriers (PMID: 28404863) and therefore the MOI of 'biallelic' on this panel is correct.
Retinal disorders v2.295 GRN Arina Puzriakova Mode of inheritance for gene: GRN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.295 GRN Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.
Neurodegenerative disorders, adult onset v2.295 GRN Arina Puzriakova Mode of inheritance for gene: GRN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v2.294 GRN Arina Puzriakova Phenotypes for gene: GRN were changed from Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485 to Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485; Ceroid lipofuscinosis, neuronal, 11, OMIM:614706
Neurodegenerative disorders, adult onset v2.293 GRN Arina Puzriakova Publications for gene: GRN were set to 20301545; 17923627
Neurodegenerative disorders, adult onset v2.292 GRN Arina Puzriakova Tag Q4_22_MOI tag was added to gene: GRN.
Neurodegenerative disorders, adult onset v2.292 GRN Arina Puzriakova reviewed gene: GRN: Rating: ; Mode of pathogenicity: None; Publications: 27021778, 28000352, 31855245; Phenotypes: Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485, Aphasia, primary progressive, OMIM:607485, Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Classified gene: GRN as Amber List (moderate evidence)
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Gene: grn has been classified as Amber List (Moderate Evidence).
Neuronal ceroid lipofuscinosis v1.24 GRN Arina Puzriakova Publications for gene: GRN were set to
Neuronal ceroid lipofuscinosis v1.23 GRN Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: GRN.
Neuronal ceroid lipofuscinosis v1.23 GRN Arina Puzriakova reviewed gene: GRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608501, 27021778, 28000352, 28404863, 30922528, 31855245; Phenotypes: Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.152 GRN Arina Puzriakova Phenotypes for gene: GRN were changed from CEROID LIPOFUSCINOSIS, NEURONAL, 11, 614706; Eye Disorders to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706
Fetal anomalies v1.985 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Neurodegenerative disorders, adult onset v2.292 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders, adult onset v2.291 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691
Ataxia and cerebellar anomalies - childhood onset v2.308 GRM1 Arina Puzriakova commented on gene: GRM1
Intellectual disability v3.1755 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13, 614831; CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Ataxia and cerebellar anomalies - childhood onset v2.308 GRM1 Arina Puzriakova Tag watchlist_moi tag was added to gene: GRM1.
Hereditary ataxia v1.311 GRM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic'. At least two unrelated cases in literature characterised by AD adult-onset ataxia and supported by functional data, plus additional patients mentioned in Tracy Lester patient cohort.
Hereditary ataxia v1.311 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.310 GRM1 Arina Puzriakova reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223, 36140834, 28886343; Phenotypes: Spinocerebellar ataxia 44, OMIM:617691, Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.165 GRM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel review. At least two unrelated cases in literature characterised by AD adult-onset ataxia and supported by functional data, plus additional patients mentioned in Tracy Lester patient cohort.
Hereditary ataxia, adult onset v2.165 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1754 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia v1.310 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Ataxia and cerebellar anomalies - childhood onset v2.308 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Ataxia and cerebellar anomalies - childhood onset v2.307 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia, adult onset v2.164 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia, adult onset v2.163 GRM1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: GRM1.
Hereditary ataxia, adult onset v2.163 GRM1 Arina Puzriakova reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223, 36140834, 28886343; Phenotypes: Spinocerebellar ataxia 44, OMIM:617691, Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v2.11 CYP11B2 Abhijit Dixit gene: CYP11B2 was added
gene: CYP11B2 was added to Congenital adrenal hypoplasia. Sources: Literature
Mode of inheritance for gene: CYP11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP11B2 were set to 1594605; 8439335; 9360501; 12788848
Phenotypes for gene: CYP11B2 were set to Hypoaldosteronism; Hyponatremia; Hyperkalemia; Increased serum renin; Dehydration; Failure to thrive
Penetrance for gene: CYP11B2 were set to Complete
Review for gene: CYP11B2 was set to GREEN
Added comment: There are numerous reports of aldosterone deficiency as a consequence of biallelic CYP11B2 variants in literature from 1990s onwards. Miao et al. reviewed 45 published cases in 2019 - see PubMed 31302112.
Sources: Literature
Hereditary ataxia v1.309 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Hereditary ataxia, adult onset v2.163 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13; Spinocerebellar ataxia 44, 617691, autosomal recessive spinocerebellar ataxia type 13, 614831 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh commented on gene: STX16: When the copy number coordinates have been established by ClinGen for STX16, this information will be added to the Familial hypoparathyroidism panel
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: STX16.
Tag cnv tag was added to gene: STX16.
Intellectual disability v3.1753 GPHN Arina Puzriakova Publications for gene: GPHN were set to
Likely inborn error of metabolism v2.326 GPHN Arina Puzriakova Publications for gene: GPHN were set to 27604308
Undiagnosed metabolic disorders v1.568 GPHN Arina Puzriakova Publications for gene: GPHN were set to 27604308
Intellectual disability v3.1752 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C to Molybdenum cofactor deficiency C, OMIM:615501
Intellectual disability v3.1751 GPHN Arina Puzriakova Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, 615501 to Molybdenum cofactor deficiency C, OMIM:615501
Likely inborn error of metabolism v2.325 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C 615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism); epileptic encephalopathy to Molybdenum cofactor deficiency C, OMIM:615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism)
Undiagnosed metabolic disorders v1.567 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism); epileptic encephalopathy; Molybdenum cofactor deficiency C 615501 to Molybdenum cofactor deficiency C, OMIM:615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism)
Paediatric disorders - additional genes v1.106 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Right atrial isomerism (Ivemark), 208530; Congenital heart defects, multiple types, 6, 613854 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Fetal anomalies v1.984 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Congenital heart defects, multiple types; Right atrial isomerism (Ivemark) to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Laterality disorders and isomerism v1.54 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Right atrial isomerism, 208530 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Familial non syndromic congenital heart disease v1.79 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Tetralogy of Fallot; Double-outlet right ventricle, 217095; Right atrial isomerism, 208530; Visceral Heterotaxy, Transposition Of The Great Arteries, Dextro-Looped 3 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530; Tetralogy of Fallot; Double-outlet right ventricle; Right atrial isomerism; Visceral Heterotaxy, Transposition Of The Great Arteries
Familial non syndromic congenital heart disease v1.78 GDF1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'monoallelic' only to 'both mono- and biallelic' to maintain consistency with other panels (including GMS) where is was determined that the evidence is sufficient, albeit limited, to justify this MOI.
Familial non syndromic congenital heart disease v1.78 GDF1 Arina Puzriakova Mode of inheritance for gene: GDF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.566 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Arginine:glycine amidinotransferase deficiency (Mitochondrial respiratory chain disorders (caused by nuclear variants only), disorders of creatinine metabolism); Cerebral creatine deficiency syndrome 3, 612718; arginine:glycine amidinotransferase deficiency to Cerebral creatine deficiency syndrome 3, OMIM:612718; Arginine:glycine amidinotransferase deficiency; Mitochondrial respiratory chain disorders (caused by nuclear variants only); Disorders of creatinine metabolism
Fetal anomalies v1.983 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY to Cerebral creatine deficiency syndrome 3, OMIM:612718
Early onset or syndromic epilepsy v2.602 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718 to Cerebral creatine deficiency syndrome 3, OMIM:612718
Intellectual disability v3.1750 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718; ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY (AGAT DEFICIENCY) to Cerebral creatine deficiency syndrome 3, OMIM:612718
Mitochondrial disorders v2.178 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718; arginine:glycine amidinotransferase deficiency to Cerebral creatine deficiency syndrome 3, OMIM:612718
Possible mitochondrial disorder, nuclear genes v1.161 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718 to Cerebral creatine deficiency syndrome 3, OMIM:612718
Renal tubulopathies v2.63 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure (no MIM number); Cerebral creatine deficiency syndrome 3, 612718 (AR) to Fanconi renotubular syndrome 1, OMIM:134600
Unexplained young onset end-stage renal disease v1.42 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure to Fanconi renotubular syndrome 1, OMIM:134600
Tubulointerstitial kidney disease v1.23 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure to Fanconi renotubular syndrome 1, OMIM:134600
Retinal disorders v2.294 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from Macular Degeneration to Macular degeneration, age-related, 3, OMIM:608895; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review according to the recommendations from Helen Brittain (Genomics England, Clinical Fellow).
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Helen Brittain (Genomics England, Clinical Fellow) agreed that DAW1 should be green on this panel.
Sources: Literature
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, according to the recommendations from Helen Brittain (Genomics England, Clinical Fellow).
Hereditary neuropathy or pain disorder v1.104 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to Charcot-Marie-Tooth disease, demyelinating, type 1H, OMIM:619764; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Hereditary neuropathy v1.456 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to Charcot-Marie-Tooth disease, demyelinating, type 1H, OMIM:619764; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Fetal anomalies v1.982 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from Cutis laxa 614434; Cutis laxa 219100 to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Rare genetic inflammatory skin disorders v1.55 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Classified gene: FBLN5 as Green List (high evidence)
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Added comment: Comment on list classification: Updating rating from Red to Green to match the rating on the GMS Thoracic aortic aneurysm and dissection (v1.2) panel.
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Gene: fbln5 has been classified as Green List (High Evidence).
Thoracic aortic aneurysm or dissection v1.125 FBLN5 Arina Puzriakova Publications for gene: FBLN5 were set to
Thoracic aortic aneurysm or dissection (GMS) v1.29 FBLN5 Arina Puzriakova Publications for gene: FBLN5 were set to 12189163; 27089918
Thoracic aortic aneurysm or dissection v1.124 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Thoracic aortic aneurysm or dissection (GMS) v1.28 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.60 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.60 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.59 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Supportive functional studies and a mouse model were also reported in PMID: 36074124.
Sources: Literature
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh Classified gene: DAW1 as Green List (high evidence)
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh Gene: daw1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.28 DAW1 Sarah Leigh Tag Q4_22_MOI was removed from gene: DAW1.
Tag Q4_22_promote_green was removed from gene: DAW1.
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.52 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Supportive functional studies and a mouse model were also reported in PMID: 36074124.
Sources: Literature
Non-CF bronchiectasis v1.28 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Non-CF bronchiectasis. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.59 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Laterality disorders and isomerism v1.52 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Laterality disorders and isomerism. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Leukodystrophy, adult onset v1.49 ADAR Arina Puzriakova Classified gene: ADAR as Green List (high evidence)
Leukodystrophy, adult onset v1.49 ADAR Arina Puzriakova Added comment: Comment on list classification: Could not find any evidence of adult-onset disease in literature. Even in atypically late-onset cases of AGS, symptoms typically begin with the first 5 years of life.
Leukodystrophy, adult onset v1.49 ADAR Arina Puzriakova Gene: adar has been classified as Green List (High Evidence).
Leukodystrophy, adult onset v1.48 ADAR Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: ADAR.
Intellectual disability v3.1749 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Dyschromatosis symmetrica hereditaria, 127400Aicardi-Goutieres syndrome 6, 615010; DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Dystonia, chorea or related movement disorder, childhood onset v1.263 ADAR Arina Puzriakova Tag Q4_22_MOI tag was added to gene: ADAR.
Early onset dystonia v1.130 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Early onset dystonia v1.129 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic only to both mono- and biallelic.

Dystonia is an established feature of AGS6 (MIM# 615010) associated with AR variants in this gene. Overall the AD condition (dyschromatosis symmetrica hereditaria, MIM# 127400) often presents with changes in skin pigmentation as the only sign of disease. However, there have also been reports of neurologic deficits including ID, developmental regression, brain calcification, seizures and dystonia in some affected individuals, particularly with the Gly1007Arg variant (PMID: 16225627; 16817193; 19017046). Although the penetrance of extracutaneous features is reduced, there is value in testing heterozygous ADAR variants on these panels to ensure syndromic cases are not missed if not tested in the context of the skin phenotype.
Early onset dystonia v1.129 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.263 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from biallelic only to both mono- and biallelic at the next GMS panel update.

Dystonia is an established feature of AGS6 (MIM# 615010) associated with AR variants in this gene. Overall the AD condition (dyschromatosis symmetrica hereditaria, MIM# 127400) often presents with changes in skin pigmentation as the only sign of disease. However, there have also been reports of neurologic deficits including ID, developmental regression, brain calcification, seizures and dystonia in some affected individuals, particularly with the Gly1007Arg variant (PMID: 16225627; 16817193; 19017046). Although the penetrance of extracutaneous features is reduced, there is value in testing heterozygous ADAR variants on these panels to ensure syndromic cases are not missed if not tested in the context of the skin phenotype.
Dystonia, chorea or related movement disorder, childhood onset v1.263 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1748 ADAR Arina Puzriakova reviewed gene: ADAR: Rating: ; Mode of pathogenicity: None; Publications: 16225627, 16817193, 19017046; Phenotypes: Aicardi-Goutieres syndrome 6, OMIM:615010, Dyschromatosis symmetrica hereditaria, OMIM:127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.262 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Early onset or syndromic epilepsy v2.601 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Inherited white matter disorders v1.163 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from both mono- and biallelic to biallelic only. Monoallelic variants have been linked to brain calcification in AD disease (MIM# 127400) with neurological symptoms, however, white matter abnormalities were not reported.
Inherited white matter disorders v1.163 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.162 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Aicardi-Goutieres syndrome 6, OMIM:615010; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Intracerebral calcification disorders v1.35 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6; Aicardi-Goutieres syndrome; Aicardi-Goutières, isolated spasticity, bilateral striatal necrosis to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Leukodystrophy, adult onset v1.48 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
White matter disorders and cerebral calcification - childhood onset v1.246 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Aicardi-Goutieres syndrome; Aicardi-Gouti res, isolated spasticity, bilateral striatal necrosis; Aicardi-Goutieres syndrome 6 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Retinal disorders v2.293 COQ5 Sarah Leigh Classified gene: COQ5 as Amber List (moderate evidence)
Retinal disorders v2.293 COQ5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated amber.
Retinal disorders v2.293 COQ5 Sarah Leigh Gene: coq5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.292 COQ5 Sarah Leigh gene: COQ5 was added
gene: COQ5 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: COQ5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ5 were set to 36266294
Phenotypes for gene: COQ5 were set to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; coenzyme q10 deficiency, primary, 9, MONDO:0033615
Review for gene: COQ5 was set to AMBER
Added comment: Associated with Coenzyme Q10 deficiency, primary, 9, OMIM:619028 and as limited Gen2Phen gene for this condition. PMID: 36266294 reports three variants in two unrelated cases with retinitis pigmentosa.
Sources: Literature
Retinal disorders v2.291 COQ4 Sarah Leigh gene: COQ4 was added
gene: COQ4 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36266294
Phenotypes for gene: COQ4 were set to Coenzyme Q10 deficiency, primary, 7, OMIM:616276; neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome, MONDO:0014562
Review for gene: COQ4 was set to RED
Added comment: Associated with Coenzyme Q10 deficiency, primary, 7, OMIM:616276 and as strong Gen2Phen gene for this condition. PMID: 36266294 reports two variants in a case with retinitis pigmentosa.
Sources: Literature
Retinal disorders v2.290 COQ2 Sarah Leigh Classified gene: COQ2 as Amber List (moderate evidence)
Retinal disorders v2.290 COQ2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.290 COQ2 Sarah Leigh Gene: coq2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.289 COQ2 Sarah Leigh gene: COQ2 was added
gene: COQ2 was added to Retinal disorders. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: COQ2.
Mode of inheritance for gene: COQ2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ2 were set to 36266294
Phenotypes for gene: COQ2 were set to Coenzyme Q10 deficiency, primary, 1, OMIM:607426; coenzyme Q10 deficiency, primary, 1, MONDO:0011829
Review for gene: COQ2 was set to GREEN
Added comment: Associated with Coenzyme Q10 deficiency, primary, 1, OMIM:607426 and as definitive Gen2Phen gene for this condition. PMID: 36266294 reports four variants in three unrelated cases with retinitis pigmentosa.
Sources: Literature
Structural basal ganglia disorders v1.33 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Likely inborn error of metabolism v2.324 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Fetal anomalies v1.981 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1; AICARDI-GOUTIERES SYNDROME ASSOCIATED WITH A TYPE I INTERFERON SIGNATURE to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Undiagnosed metabolic disorders v1.565 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010; Dyschromatosis symmetrica hereditaria 127400 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Neurodegenerative disorders, adult onset v2.290 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010
Hereditary spastic paraplegia, adult onset v1.103 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 autosomal recessive; Dyschromatosis symmetrica hereditaria, autosomal dominant, 127400 to Aicardi-Goutieres syndrome 6, OMIM:615010
Hereditary spastic paraplegia, childhood onset v2.150 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Hereditary spastic paraplegia v1.296 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Primary immunodeficiency or monogenic inflammatory bowel disease v2.580 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; AGS6; Type 1 interferonopathies; Classical AGS, BSN, SP; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders
COVID-19 research v1.133 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders
Pigmentary skin disorders v1.53 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from AGS6; DYSCHROMATOSIS SYMMETRICA HEREDITARIA; DSH, AICARDI-GOUTIERES SYNDROME 6; Dyschromatosis symmetrica hereditaria (AKA reticulate acropigmentation of Dohi) to Dyschromatosis symmetrica hereditaria, OMIM:127400; Aicardi-Goutieres syndrome 6, OMIM:615010
Pigmentary skin disorders v1.52 ADAR Arina Puzriakova Publications for gene: ADAR were set to 12916015; 23001123
Retinal disorders v2.288 PDSS1 Sarah Leigh Classified gene: PDSS1 as Amber List (moderate evidence)
Retinal disorders v2.288 PDSS1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.288 PDSS1 Sarah Leigh Gene: pdss1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.287 PDSS1 Sarah Leigh gene: PDSS1 was added
gene: PDSS1 was added to Retinal disorders. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: PDSS1.
Mode of inheritance for gene: PDSS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDSS1 were set to 36266294
Phenotypes for gene: PDSS1 were set to Coenzyme Q10 deficiency, primary, 2, OMIM:614651; deafness-encephaloneuropathy-obesity-valvulopathy syndromeMONDO:0013837
Review for gene: PDSS1 was set to GREEN
Added comment: Associated with Coenzyme Q10 deficiency, primary, 2, OMIM:614651 and as strong Gen2Phen gene for this condition. PMID: 36266294 reports nine variants in six unrelated cases with retinitis pigmentosa.
Sources: Literature
Intellectual disability v3.1748 FBXW7 Julia Baptista reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: 35395208; Phenotypes: developmental delay, ID, language disorder, hypotonia, brain anomalies, gastrointestinal issues; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1748 ACOX1 Arina Puzriakova Added comment: Comment on mode of inheritance: Adding 'watchlist_moi' tag to monitor for evidence supporting association of monoallelic variants in this gene with ID. To date, three unrelated cases have been reported (PMID: 32169171) with dominant variants. Two patients had impaired cognition while one remained cognitively intact. These cases should be picked up via other routes (neuropathy, hearing loss) but monitoring evidence pertaining to monoallelic variants may be of value.
Intellectual disability v3.1748 ACOX1 Arina Puzriakova Mode of inheritance for gene: ACOX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1747 ACOX1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ACOX1.
Likely inborn error of metabolism v2.323 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Tag Q4_22_MOI was removed from gene: ACOX1.
Intellectual disability v3.1747 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, 264470; ADRENOLEUKODYSTROPHY PSEUDONEONATAL (PSEUDO-NALD) to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v2.600 ACOX1 Arina Puzriakova Publications for gene: ACOX1 were set to 18536048
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Early onset or syndromic epilepsy v2.599 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Inherited white matter disorders v1.161 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960; General Leukodystrophy & Mitochondrial Leukoencephalopathy
White matter disorders and cerebral calcification - childhood onset v1.245 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Intellectual disability v3.1746 ADAR Tracy Lester reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1746 BAP1 Rachel Challis gene: BAP1 was added
gene: BAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to 35051358
Phenotypes for gene: BAP1 were set to Intellectual disability; short stature; autism spectrum disorder
Review for gene: BAP1 was set to GREEN
gene: BAP1 was marked as current diagnostic
Added comment: 11 de novo BAP1 missense variants identified predominantly in UCH domain. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. Analysis of blood from affected patients demonstrated impaired H2A deubiquitination compared to controls.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.579 RANBP2 Dmitrijs Rots reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35748970, 25522933, 29687329, 30796099, 35381605; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1746 YARS Dmitrijs Rots changed review comment from: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.; to: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.
Intellectual disability v3.1746 YARS Dmitrijs Rots reviewed gene: YARS: Rating: ; Mode of pathogenicity: None; Publications: PMID: 34536092; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.51 NODAL Arina Puzriakova commented on gene: NODAL
Fetal anomalies v1.980 EDA Eleanor Williams Tag Q3_22_expert_review was removed from gene: EDA.
Neonatal cholestasis v1.26 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neonatal cholestasis v1.25 GNAS Sarah Leigh Deleted their comment
Neonatal cholestasis v1.25 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: this gene is imprinted, but maternal and paternal alleles are imprinted in different conditions
Neonatal cholestasis v1.25 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.222 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Skeletal dysplasia v2.222 GNAS Sarah Leigh edited their review of gene: GNAS: Added comment: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Skeletal dysplasia panel is representing various phenotypes, the MOI has been set to monoallelic, imprinted status unknown.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.222 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia 103580; Pseudopseudohypoparathyroidism 612463; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ib 603233; Pseudohypoparathyroidism Ic 612462; ACTH-independent macronodular adrenal hyperplasia 219080 IC; McCune-Albright syndrome, somatic, mosaic 174800 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Congenital hypothyroidism v2.13 GNAS Sarah Leigh changed review comment from: Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal allele. Therefore, the mode of inheritance for GNAS in this panel should be monoallelic maternally imprinted.; to: Pseudohypothyroidism Ia & Ic are caused by GNAS variants arising in the maternal alleles, therefore the paternal alleles are imprinted. In Pseudohypothyroidism Ib the imprinting of the maternal allele is disrupted by deletions in STX16. Therefore, the mode of inheritance for GNAS in this panel should be monoallelic, imprinted status unknown as either allele could be imprinted.
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: FASTKD2.
Fetal anomalies v1.980 EDA Eleanor Williams Tag Q3_22_expert_review tag was added to gene: EDA.
Congenital hypothyroidism v2.13 GNAS Sarah Leigh edited their review of gene: GNAS: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Classified gene: KIF24 as Amber List (moderate evidence)
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update, on the basis of three unrelated cases harbouring distinct biallelic variants in this gene, all presenting with variable skeletal manifestations.
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Gene: kif24 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.220 KIF24 Arina Puzriakova gene: KIF24 was added
gene: KIF24 was added to Skeletal dysplasia. Sources: Literature
Q4_22_promote_green tags were added to gene: KIF24.
Mode of inheritance for gene: KIF24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF24 were set to 35748595
Phenotypes for gene: KIF24 were set to Skeletal dysplasia
Review for gene: KIF24 was set to GREEN
Added comment: Reilly et al., 2022 (PMID: 35748595) identified six individuals from three unrelated families affected by a spectrum of skeletal abnormalities ranging from a lethal fetal skeletal ciliopathy to acromesomelic skeletal dysplasia and a less severe spondylometaphyseal dysplasia. All subjects harboured different biallelic missense variants in KIF24 which segregated with the phenotype. In vitro studies showed that ciliogenesis and cytokinesis were severely affected in amnioblasts of one affected fetus.
Sources: Literature
Severe early-onset obesity v2.52 GNAS Sarah Leigh reviewed gene: GNAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v2.52 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Congenital Obesity; Pseudohypoparathyroidism Ia, OMIM:103580; Pseudohypoparathyroidism Ib, OMIM:603233; Pseudohypoparathyroidism Ic, OMIM:612462 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Severe early-onset obesity v2.51 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Neurofibromatosis Type 1 v1.32 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168 to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Neurofibromatosis Type 1 v1.31 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome, 174800; Pseudohypoparathyroidism Ia to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Neurofibromatosis Type 1 v1.30 GNAS Sarah Leigh Publications for gene: GNAS were set to 1944469,1594625
Fetal anomalies v1.980 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; progressive osseous heteroplasia, MONDO:0008153; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Mosaic skin disorders - Deep sequencing v1.24 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Limb disorders v2.83 GNAS Sarah Leigh Tag mosaicism tag was added to gene: GNAS.
Tag Q4_22_MOI tag was added to gene: GNAS.
Limb disorders v2.83 GNAS Sarah Leigh edited their review of gene: GNAS: Added comment: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Limb disorders panel is encompassing various phenotypes, the MOI should been set to monoallelic, imprinted status unknown.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.83 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from ACTH-independent macronodular adrenal hyperplasia 219080 IC; McCune-Albright syndrome, somatic, mosaic 174800; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ia 103580; Pseudohypoparathyroidism Ib 603233; Pseudohypoparathyroidism Ic 612462; Pseudopseudohypoparathyroidism 612463 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Intellectual disability v3.1746 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580McCune-Albright syndrome, 174800Pseudohypoparathyroidism Ic, 612462Osseous heteroplasia, progressive, 166350Pseudohypoparathyroidism Ib, 603233Prolonged bleeding time, brachydactyly and mental retardationAcromegaly, 102200Pseudopseudohypoparathyroidism, 612463Prolonged bleeding time, brachydactyly, and mental retardationACTH-independent macronodular adrenal hyperplasia, 219080; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA (AIMAH) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Fetal anomalies v1.979 DMPK Eleanor Williams Tag Q3_21_expert_review tag was added to gene: DMPK.
Intellectual disability v3.1745 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 is associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in this condition should be monoallelic paternally imprinted. Because intellectual disability is seen in these phenotypes, the MOI has been set to monoallelic, imprinted status unknown.
Intellectual disability v3.1745 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.979 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Fetal anomalies panel is representing various phenotypes, the MOI has been set to monoallelic, imprinted status unknown.
Fetal anomalies v1.979 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.978 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from GNAS HYPERFUNCTION; ALBRIGHT HEREDITARY OSTEODYSTROPHY; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; PSEUDOHYPOPARATHYROIDISM TYPE 1B to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Congenital hypothyroidism v2.13 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:00 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911
Congenital hypothyroidism v2.12 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Congenital hypothyroidism v2.12 GNAS Sarah Leigh reviewed gene: GNAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Tag Q4_22_MOI tag was added to gene: STX16.
Tag Q4_22_promote_green tag was added to gene: STX16.
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Classified gene: STX16 as Amber List (moderate evidence)
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Gene: stx16 has been classified as Amber List (Moderate Evidence).
Familial hypoparathyroidism v2.6 STX16 Sarah Leigh Entity copied from Genomic imprinting v0.147
Familial hypoparathyroidism v2.6 STX16 Sarah Leigh gene: STX16 was added
gene: STX16 was added to Familial hypoparathyroidism. Sources: Literature
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STX16 were set to 14561710; 15579741; 15800843; 33320452; 32337648; 35119251
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301
Proteinuric renal disease v2.77 EMP2 Eleanor Williams Tag Q2_22_expert_review tag was added to gene: EMP2.
Dystonia, chorea or related movement disorder, childhood onset v1.261 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Intellectual disability v3.1744 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Hydrocephalus v2.132 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Fetal anomalies v1.977 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Ichthyosis and erythrokeratoderma v1.73 TRPV3 Eleanor Williams commented on gene: TRPV3
Ichthyosis and erythrokeratoderma v1.73 TRPV3 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: TRPV3.
Neurodegenerative disorders, adult onset v2.289 STUB1 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: STUB1.
Neurodegenerative disorders, adult onset v2.289 STUB1 Eleanor Williams commented on gene: STUB1
Neurodegenerative disorders, adult onset v2.289 STUB1 Eleanor Williams Mode of inheritance for gene: STUB1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.288 STUB1 Eleanor Williams Tag Q3_22_rating tag was added to gene: STUB1.
Tag Q3_22_MOI tag was added to gene: STUB1.
Neurodegenerative disorders, adult onset v2.288 STUB1 Eleanor Williams Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.287 STUB1 Eleanor Williams Tag Q3_22_rating was removed from gene: STUB1.
Tag Q3_22_MOI was removed from gene: STUB1.
Neurodegenerative disorders, adult onset v2.287 STUB1 Eleanor Williams Tag Q3_22_rating tag was added to gene: STUB1.
Intellectual disability v3.1744 ROR2 Arina Puzriakova Classified gene: ROR2 as Green List (high evidence)
Intellectual disability v3.1744 ROR2 Arina Puzriakova Added comment: Comment on list classification: Following a Red review by Tracy Lester (Genetics laboratory, Oxford UK) this gene was re-curated showing the neurocognitive function in patients with monoallelic and biallelic variants is typically normal. Cases are more likely to be picked up via skeletal abnormalities route. Therefore, ROR2 should be downgraded to Red on this panel at the next GMS panel update.
Intellectual disability v3.1744 ROR2 Arina Puzriakova Gene: ror2 has been classified as Green List (High Evidence).
Intellectual disability v3.1743 ROR2 Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: ROR2.
Tag Q4_22_NHS_review tag was added to gene: ROR2.
DDG2P v2.83 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROBINOW SYNDROME, AUTOSOMAL DOMINANT 180700; BRACHYDACTYLY, TYPE B1 113000; ROR2-RELATED DISORDERS AR 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Fetal anomalies v1.977 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROR2-RELATED DISORDERS AR; BRACHYDACTYLY, TYPE B1; ROBINOW SYNDROME, AUTOSOMAL DOMINANT to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Skeletal dysplasia v2.219 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Brachydactyly, type B1 113000; Robinow syndrome, autosomal recessive 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Intellectual disability v3.1743 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from BRACHYDACTYLY, TYPE B1 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Limb disorders v2.82 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Brachydactyly, type B1 113000; Robinow syndrome, autosomal recessive 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
IUGR and IGF abnormalities v1.54 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Robinow to Robinow syndrome, autosomal recessive, OMIM:268310
Clefting v2.71 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROBINOW SYNDROME, AUTOSOMAL RECESSIVE; RRS to Robinow syndrome, autosomal recessive, OMIM:268310
Fetal anomalies v1.976 COL1A2 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: COL1A2.
Congenital hypothyroidism v2.12 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580 (Hypothyroidism) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:00
Early onset or syndromic epilepsy v2.598 CLPB Eleanor Williams Tag Q3_21_MOI was removed from gene: CLPB.
Tag Q3_22_MOI tag was added to gene: CLPB.
Pigmentary skin disorders v1.51 GNAS Sarah Leigh Tag mosaicism tag was added to gene: GNAS.
Pigmentary skin disorders v1.51 GNAS Sarah Leigh Tag somatic tag was added to gene: GNAS.
Cerebral vascular malformations v2.63 SETD5 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: SETD5.
Cerebral vascular malformations v2.63 CNOT3 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: CNOT3.
Cerebral vascular malformations v2.63 CHD4 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: CHD4.
Rare anaemia v1.43 RHAG Arina Puzriakova Phenotypes for gene: RHAG were changed from Anemia, hemolytic, Rh-null, regulator type (BIALLELIC, autosomal or pseudoautosomal), 268150; 268150 Anemia, hemolytic, Rh-null, regulator type; Overhydrated hereditary stomatocytosis (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 185000; 185000 Overhydrated hereditary stomatocytosis; Stomatocytosis to Anemia, hemolytic, Rh-null, regulator type, OMIM:268150 (AR); Overhydrated hereditary stomatocytosis, OMIM:185000 (AD)
Cytopenias and congenital anaemias v1.107 RHAG Arina Puzriakova Phenotypes for gene: RHAG were changed from Stomatocytosis; Overhydrated hereditary stomatocytosis (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 185000; Anemia, hemolytic, Rh-null, regulator type (BIALLELIC, autosomal or pseudoautosomal), 268150 to Anemia, hemolytic, Rh-null, regulator type, OMIM:268150 (AR); Overhydrated hereditary stomatocytosis, OMIM:185000 (AD)
Intellectual disability v3.1742 PDZD8 Eleanor Williams commented on gene: PDZD8
Intellectual disability v3.1742 PDZD8 Eleanor Williams Tag Q3_22_MOI was removed from gene: PDZD8.
Intellectual disability v3.1742 NRCAM Eleanor Williams commented on gene: NRCAM
Intellectual disability v3.1742 NRCAM Eleanor Williams Tag Q3_22_MOI was removed from gene: NRCAM.
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh edited their review of gene: CNOT3: Changed rating: AMBER
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh changed review comment from: Green rating recommended based on four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) with CNOT3 variants reported in PMID: 31474762, all of these cases had features of moyamoya disease.; to: After consultation with Helen Brittain (Clinical Fellow, Genomics England), SETD5 has been given an amber rating as the evidence of association was from a single publication. PMID: 31474762 reported CNOT3 variants in four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672), all of these cases had features of moyamoya disease.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh changed review comment from: Comment on list classification: Moyamoya disease MONDO:0016820 is relevant to this panel - Cerebral vascular malformations.
PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).; to: Comment on list classification: After consultation with Helen Brittain (Clinical Fellow, Genomics England), CHD4 has been given an amber rating, as the clinical features of the cases reported may not be relevant to this panel. PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh edited their review of gene: CHD4: Changed rating: AMBER
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Deleted their comment
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh changed review comment from: Amber rating based on SETD5 variants reported in PMID: 24680889, 2302093, 25138099 & 31474762. There was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.; to: After consultation with Helen Brittain (Clinical Fellow, Genomics England), SETD5 has been given an amber rating. SETD5 variants were reported in PMID: 24680889, 2302093, 25138099 & 31474762, but there was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.
Intellectual disability v3.1742 DOCK8 Eleanor Williams Tag Q3_22_MOI tag was added to gene: DOCK8.
Intellectual disability v3.1742 DOCK8 Eleanor Williams Tag Q3_22_MOI was removed from gene: DOCK8.
Intellectual disability v3.1742 CHKA Eleanor Williams commented on gene: CHKA
Intellectual disability v3.1742 CHKA Eleanor Williams Tag Q3_22_MOI was removed from gene: CHKA.
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams changed review comment from: Removed the Q3_22_MOI tag as the MOI has been proposed to be Monoallelic by all.; to: Removed the Q3_22_MOI tag as the MOI has been proposed to be Monoallelic by all reviewers
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams commented on gene: ATP6V0A1
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh edited their review of gene: CNOT3: Added comment: Green rating recommended based on four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) with CNOT3 variants reported in PMID: 31474762, all of these cases had features of moyamoya disease.; Changed rating: GREEN
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh edited their review of gene: CHD4: Added comment: Green recommendation based on seven unrelated cases of Sifrim-Hitz-Weiss syndrome (OMIM:617159) with CHD4 variants reported in PMID: 31474762, who all had ischemic stroke due to bilateral moyamoya angiopathy.; Changed rating: GREEN
Inherited bleeding disorders v1.174 SERPINC1 Arina Puzriakova Phenotypes for gene: SERPINC1 were changed from Antithrombin deficiency; Thrombophilia due to antithrombin III deficiency 613118; Antithrombin III Deficiency; Antithrombin-III Deficiency to Thrombophilia due to antithrombin III deficiency, OMIM:613118
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh edited their review of gene: SETD5: Changed rating: AMBER
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh edited their review of gene: SETD5: Added comment: Amber rating based on SETD5 variants reported in PMID: 24680889, 2302093, 25138099 & 31474762. There was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.; Changed rating: GREEN
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Classified gene: HK1 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Added comment: Comment on list classification: Recommended for GREEN rating following GMS review. Sufficient cases. The paper has not yet been published but has been accepted for publication. Note that the variants are in a non-coding region and therefore may not be prioritised by tiering in the current Genomics England pipeline.
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Gene: hk1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Classified gene: ZNF808 as Amber List (moderate evidence)
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for GREEN rating following GMs review. Paper not yet published but from GLH source.
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Gene: znf808 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.63 SETD5 Eleanor Williams Tag Q3_22_expert_review was removed from gene: SETD5.
Cerebral vascular malformations v2.63 CNOT3 Eleanor Williams Tag Q3_22_expert_review was removed from gene: CNOT3.
Cerebral vascular malformations v2.63 CHD4 Eleanor Williams Tag Q3_22_expert_review was removed from gene: CHD4.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to CHD4 variants.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946 to Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.62 CNOT3 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to CNOT3 variants.
Cerebral vascular malformations v2.62 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864 to Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Cerebral vascular malformations v2.61 SETD5 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to SETD5 variants.
Cerebral vascular malformations v2.61 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336 to Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Primary immunodeficiency or monogenic inflammatory bowel disease v2.579 TCF3 Arina Puzriakova Phenotypes for gene: TCF3 were changed from Agammaglobulinemia; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency; Recurrent bacterial infections; Predominantly Antibody Deficiencies to Agammaglobulinemia 8A, autosomal dominant, OMIM:616941; Agammaglobulinemia 8B, autosomal recessive, OMIM:619824; Recurrent bacterial infections; Predominantly Antibody Deficiencies
COVID-19 research v1.132 TCF3 Arina Puzriakova Phenotypes for gene: TCF3 were changed from Agammaglobulinemia; Recurrent bacterial infections; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency; Predominantly Antibody Deficiencies to Agammaglobulinemia 8A, autosomal dominant, OMIM:616941; Agammaglobulinemia 8B, autosomal recessive, OMIM:619824; Recurrent bacterial infections; Predominantly Antibody Deficiencies
Inherited bleeding disorders v1.173 TBXA2R Arina Puzriakova Phenotypes for gene: TBXA2R were changed from Thromboxane A2 receptor defect to {Bleeding disorder, platelet-type, 13, susceptibility to}, OMIM:614009
Bleeding and platelet disorders v1.45 TBXA2R Arina Puzriakova Phenotypes for gene: TBXA2R were changed from 614009.BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO; BDPLT13; 614009 BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO to {Bleeding disorder, platelet-type, 13, susceptibility to}, OMIM:614009
Monogenic hearing loss v2.248 FOXI1 Eleanor Williams Tag Q1_22_expert_review tag was added to gene: FOXI1.
Intellectual disability v3.1742 TGFB1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.; to: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. Cognition is typically normal in Camurati-Engelmann disease (caused by monoallelic TGFB1 variants).
Intellectual disability v3.1742 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease, 131300; {Cystic fibrosis lung; disease, modifier of}, 219700 to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
Intellectual disability v3.1741 TGFB1 Arina Puzriakova Publications for gene: TGFB1 were set to
Intellectual disability v3.1740 TGFB1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.
Intellectual disability v3.1740 TGFB1 Arina Puzriakova Mode of inheritance for gene: TGFB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1739 TGFB1 Arina Puzriakova Tag watchlist_moi tag was added to gene: TGFB1.
Osteopetrosis v1.28 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease OMIM:131300 to Camurati-Engelmann disease, OMIM:131300
DDG2P v2.82 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from CAMURATI-ENGELMANN DISEASE 131300 to Camurati-Engelmann disease, OMIM:131300
Fetal anomalies v1.976 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from CAMURATI-ENGELMANN DISEASE to Camurati-Engelmann disease, OMIM:131300
Skeletal dysplasia v2.218 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease 131300; Camurati-Engelmann disease 131300 to Camurati-Engelmann disease, OMIM:131300
Primary immunodeficiency or monogenic inflammatory bowel disease v2.578 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; 618213; Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM; TGFB1 deficiency; Diseases of Immune Dysregulation; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
COVID-19 research v1.131 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
Structural eye disease v1.151 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from [Skin/hair/eye pigmentation 3, blue/green eyes]; Albinism, oculocutaneous, type IB, 606952; Eye Disorders; Waardenburg syndrome/albinism, digenic, 103470; [Skin/hair/eye pigmentation 3, light/dark/freckling skin], 601800; Albinism, oculocutaneous, type IA, 203100; {Melanoma, cutaneous malignant, susceptibility to, 8} to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Structural eye disease v1.150 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1739 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Albinism, oculocutaneous, type IA, 203100; Waardenburg; syndrome/albinism, digenic, 103470; Albinism, oculocutaneous, type IB, 606952; [Skin/hair/eye pigmentation 3, light/dark/freckling skin], 601800; {Melanoma, cutaneous malignant, susceptibility to, 8}, 601800; [Skin/hair/eye pigmentation 3, blue/green eyes], 601800 to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Pigmentary skin disorders v1.51 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from ALBINISM, OCULOCUTANEOUS, TYPE IA; Oculocutaneous albinism; OCA1B; OCA1A, ALBINISM, OCULOCUTANEOUS, TYPE IB to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Ocular and oculo-cutaneous albinism v1.23 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' only.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Ocular and oculo-cutaneous albinism v1.23 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Infantile nystagmus v1.6 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' only.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Infantile nystagmus v1.6 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.25 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Albinism or congenital nystagmus v1.25 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infantile nystagmus v1.5 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Oculocutaneous Albinism; Albinism, oculocutaneous, type IA; Albinism, oculocutaneous, type IB; Waardenburg syndrome/albinism, digenic to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Ocular and oculo-cutaneous albinism v1.22 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Oculocutaneous Albinism; Albinism, oculocutaneous, type IA; Albinism, oculocutaneous, type IB; Waardenburg syndrome/albinism, digenic to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Albinism or congenital nystagmus v1.24 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Albinism, oculocutaneous, type IA; Waardenburg syndrome/albinism, digenic; Albinism, oculocutaneous, type IB; Oculocutaneous Albinism to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Albinism or congenital nystagmus v1.23 TYR Arina Puzriakova Tag Q4_22_MOI tag was added to gene: TYR.
Intellectual disability v3.1738 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325{Schizophrenia, susceptibility to, 17}, 614332; AUTISM to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Early onset or syndromic epilepsy v2.598 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325 to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.47 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Gene has been re-curated and the MOI should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.

Association with monoallelic variants is well-established. There are now at least four families in literature with recessive variants and myopathy (PMIDs: 14659406; 25666907; 17372140; 31130376). Most commonly described is scapuloperoneal and proximal distribution of muscle weakness, which are within the scope of this panel.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.47 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.46 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal recessive, OMIM:255160; Scapuloperoneal syndrome, myopathic type, OMIM:181430
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.45 MYH7 Arina Puzriakova Publications for gene: MYH7 were set to 15322983
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 MYH7 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: MYH7.
Congenital myopathy v2.93 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal recessive, OMIM:255160
Congenital myopathy v2.92 MYH7 Arina Puzriakova Publications for gene: MYH7 were set to 15322983
Congenital myopathy v2.91 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: There are now at least four families in literature with recessive variants and myopathy (PMIDs: 14659406; 25666907; 17372140; 31130376). Congenital manifestation in some cases. Therefore, the MOI can now be updated from 'monoallelic' to 'both mono- and biallelic' at the next GMS panel update.
Congenital myopathy v2.91 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v2.90 MYH7 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: MYH7.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.; to: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to DCM.
Dilated and arrhythmogenic cardiomyopathy v1.34 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to DCM.
Dilated and arrhythmogenic cardiomyopathy v1.34 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated and arrhythmogenic cardiomyopathy v1.33 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.80 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Hypertrophic cardiomyopathy v2.42 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.
Hypertrophic cardiomyopathy v2.42 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy v2.41 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Paediatric or syndromic cardiomyopathy v1.81 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Arrhythmogenic right ventricular dysplasia 12 to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Dilated and arrhythmogenic cardiomyopathy v1.33 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease (601214); Arrhythmogenic right ventricular dysplasia 12; Arrhythmogenic right ventricular dysplasia 12 (611528) to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Arrhythmogenic right ventricular cardiomyopathy v2.18 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12 , OMIM:611528 to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Dilated Cardiomyopathy and conduction defects v1.80 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Arrhythmogenic right ventricular cardiomyopathy v2.17 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Arrhythmogenic right ventricular dysplasia 12 ; Arrhythmogenic right ventricular dysplasia 12 (611528); Naxos disease (601214) to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12 , OMIM:611528
Palmoplantar keratodermas v1.21 JUP Arina Puzriakova Added comment: Comment on mode of inheritance: Pathogenic heterozygous germline variants in JUP are associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) without abnormalities of hair or skin. On the other hand, recessive variants are associated with Naxos disease which manifests a range of ectodermal features including palmoplantar keratoderma.

Therefore, the MOI should be changed from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update.
Palmoplantar keratodermas v1.21 JUP Arina Puzriakova Mode of inheritance for gene: JUP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.20 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease; Desmosomal disorders to Naxos disease, OMIM:601214; Palmoplantar keratoderma, keratoderma with woolly hair
Palmoplantar keratodermas v1.19 JUP Arina Puzriakova Tag Q4_22_MOI tag was added to gene: JUP.
Epidermolysis bullosa and congenital skin fragility v1.55 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Severe generalised Epidermolysis bullosa simplex to Naxos disease, OMIM:601214; Generalised skin fragility, epidermolysis bullosa
Epidermolysis bullosa v1.11 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, 601214; Severe generalised Epidermolysis bullosa simplex to Naxos disease, OMIM:601214; Generalised skin fragility, epidermolysis bullosa
Palmoplantar keratoderma and erythrokeratodermas v1.26 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, 601214; palmoplantar keratoderma (PPK), keratoderma with woolly hair; KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY; WOOLLY HAIR, PALMOPLANTAR KERATODERMA, AND CARDIAC ABNORMALITIES; PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR to Naxos disease, OMIM:601214; Palmoplantar keratoderma, keratoderma with woolly hair, generalised skin fragility, epidermolysis bullosa
Fetal anomalies v1.975 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Arrhythmogenic right ventricular dysplasia 8 607450; Keratosis palmoplantaris striata II, 612908; Cardiomyopathy, dilated, with woolly hair and keratoderma 605676; Skin fragility-woolly hair syndrome 607655; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 615821; Epidermolysis bullosa, lethal acantholytic 609638 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638 (AR); Skin fragility-woolly hair syndrome, OMIM:607655 (AR); Keratosis palmoplantaris striata II, OMIM:612908 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Dilated and arrhythmogenic cardiomyopathy v1.32 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic (609638); Skin fragility-woolly hair syndrome (607655); Arrhythmogenic right ventricular dysplasia 8; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (615821); Arrhythmogenic right ventricular dysplasia 8 (607450); Keratosis palmoplantaris striata II (612908); Cardiomyopathy, dilated, with woolly hair and keratoderma (605676) to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Dilated Cardiomyopathy and conduction defects v1.79 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Dilated cardiomyopathy with woolly hair and keratoderma to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Paediatric or syndromic cardiomyopathy v1.80 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 to Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD)
Arrhythmogenic right ventricular cardiomyopathy v2.16 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Keratosis palmoplantaris striata II (612908); Skin fragility-woolly hair syndrome (607655); Arrhythmogenic right ventricular dysplasia 8 (607450); Epidermolysis bullosa, lethal acantholytic (609638); Arrhythmogenic right ventricular dysplasia 8 ; Cardiomyopathy, dilated, with woolly hair and keratoderma (605676); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (615821) to Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD)
Palmoplantar keratodermas v1.19 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Desmosomal disorders to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Keratosis palmoplantaris striata II, OMIM:612908 (AD)
Epidermolysis bullosa and congenital skin fragility v1.54 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic, OMIM:609638 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638; Skin fragility-woolly hair syndrome, OMIM:607655
Epidermolysis bullosa v1.10 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic, 609638; Severe generalised Epidermolysis bullosa simplex; Lethal acantholytic epidermolysis bullosa; Skin fragility-woolly hair syndrome,607655 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638; Skin fragility-woolly hair syndrome, OMIM:607655
Palmoplantar keratoderma and erythrokeratodermas v1.25 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Striate keratoderma with woolly hair and cardiomyopathy; Keratosis palmoplantaris striata II, 612908; CARVAJAL SYNDROME; Dilated cardiomyopathy with woolly hair and keratoderma, 605676; Arrhythmogenic right ventricular dysplasia 8, 607450; Skin fragility-woolly hair syndrome, 607655; Epidermolysis bullosa, lethal acantholytic; Keratosis palmoplantaris striata II; Skin fragility-woolly hair syndrome; striate keratoderma; diffuse keratoderma; lethal acantholytic epidermolysis bullosa, 609638; alopecia, follicular hyperkeratoses and keratoderma; oligodontia or hypodontia to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Keratosis palmoplantaris striata II, OMIM:612908 (AD)
Structural eye disease v1.149 ARR3 Dmitrijs Rots gene: ARR3 was added
gene: ARR3 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: ARR3 was set to Other
Publications for gene: ARR3 were set to 35001458
Penetrance for gene: ARR3 were set to unknown
Review for gene: ARR3 was set to AMBER
Added comment: 3 multigenerational families with X-linked dominant, female limited high myopia reported in 35001458. Each family has different trucating variant in ARR3
Sources: Literature
Intellectual disability v3.1737 PRRT2 Dmitrijs Rots reviewed gene: PRRT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36180924; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.597 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 31997314, 31997314; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1737 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 33381903; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.90 CCDC78 Tracy Lester reviewed gene: CCDC78: Rating: RED; Mode of pathogenicity: None; Publications: 25635128; Phenotypes: congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1737 MTSS1L Eleanor Williams Tag Q4_22_rating was removed from gene: MTSS1L.
Tag Q4_22_promote_green tag was added to gene: MTSS1L.
Intellectual disability v3.1737 DPH5 Eleanor Williams Tag Q4_22_rating was removed from gene: DPH5.
Tag Q4_22_promote_green tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Eleanor Williams Tag Q4_22_rating was removed from gene: DPH5.
Tag Q4_22_promote_green tag was added to gene: DPH5.
Intellectual disability v3.1737 DOHH Eleanor Williams Tag Q4_22_rating was removed from gene: DOHH.
Tag Q4_22_promote_green tag was added to gene: DOHH.
Severe microcephaly v2.319 DOHH Eleanor Williams Tag Q4_22_rating was removed from gene: DOHH.
Tag Q4_22_promote_green tag was added to gene: DOHH.
Congenital hyperinsulinism v2.29 AKT2 Eleanor Williams Tag Q4_22_rating was removed from gene: AKT2.
Tag Q4_21_rating tag was added to gene: AKT2.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams commented on gene: SLC12A6: Removed the for-review tag as this is a 100,000 genomes project panel that does not need GMS approval for changes.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams Added comment: Comment on mode of inheritance: Changing the mode of inheritance as this is a 100K only panel.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams Mode of inheritance for gene: SLC12A6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.454 SLC12A6 Eleanor Williams Tag for-review was removed from gene: SLC12A6.
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Classified gene: CAPN15 as Green List (high evidence)
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Added comment: Comment on list classification: Removed for-review tag and promoting this gene to green as this is a 100K only panel.
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Gene: capn15 has been classified as Green List (High Evidence).
Anophthalmia or microphthalmia v1.50 CAPN15 Eleanor Williams Tag for-review was removed from gene: CAPN15.
Endocrine neoplasia v1.25 PTEN Eleanor Williams Tag Q2_21_expert_review tag was added to gene: PTEN.
Endocrine neoplasia v1.25 PMS2 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: PMS2.
Endocrine neoplasia v1.25 MSH6 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MSH6.
Endocrine neoplasia v1.25 MSH2 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MSH2.
Endocrine neoplasia v1.25 MLH1 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MLH1.
Possible mitochondrial disorder, nuclear genes v1.160 PDK3 Eleanor Williams Tag Q1_22_expert_review tag was added to gene: PDK3.
Dystonia, chorea or related movement disorder, childhood onset v1.261 AFG3L2 Eleanor Williams commented on gene: AFG3L2
Dystonia, chorea or related movement disorder, childhood onset v1.261 AFG3L2 Eleanor Williams Tag Q2_21_rating tag was added to gene: AFG3L2.
Skeletal muscle channelopathy v1.39 SLC2A1 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC2A1.
Tag Q2_21_expert_review tag was added to gene: SLC2A1.
Skeletal muscle channelopathy v1.39 SLC1A3 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC1A3.
Tag Q2_21_expert_review tag was added to gene: SLC1A3.
Skeletal muscle channelopathy v1.39 PYGM Eleanor Williams Tag Q2_21_rating tag was added to gene: PYGM.
Tag Q2_21_expert_review tag was added to gene: PYGM.
Skeletal muscle channelopathy v1.39 CACNA1A Eleanor Williams Tag Q2_21_rating tag was added to gene: CACNA1A.
Tag Q2_21_expert_review tag was added to gene: CACNA1A.
Skeletal muscle channelopathy v1.39 ATP1A2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ATP1A2.
Tag Q2_21_expert_review tag was added to gene: ATP1A2.
Fetal anomalies v1.974 FOXP4 Eleanor Williams Tag Q2_21_rating tag was added to gene: FOXP4.
Tag Q2_21_expert_review tag was added to gene: FOXP4.
Congenital myopathy v2.90 MYH8 Eleanor Williams Tag Q2_21_rating tag was added to gene: MYH8.
Tag Q2_21_expert_review tag was added to gene: MYH8.
Monogenic hearing loss v2.248 COL9A3 Eleanor Williams Tag Q2_21_rating tag was added to gene: COL9A3.
Tag Q2_21_expert_review tag was added to gene: COL9A3.
Mitochondrial disorders v2.177 XPNPEP3 Eleanor Williams Tag Q1_22_rating was removed from gene: XPNPEP3.
Tag Q2_21_rating tag was added to gene: XPNPEP3.
Structural eye disease v1.149 TSC2 Eleanor Williams commented on gene: TSC2
Structural eye disease v1.149 TSC2 Eleanor Williams Tag Q1_22_NHS_review was removed from gene: TSC2.
Pancreatitis v2.16 TRPV6 Eleanor Williams commented on gene: TRPV6
Pancreatitis v2.16 TRPV6 Eleanor Williams Tag Q1_22_NHS_review was removed from gene: TRPV6.
Intellectual disability v3.1737 FBXW7 Eleanor Williams commented on gene: FBXW7
Intellectual disability v3.1737 FBXW7 Eleanor Williams Tag Q3_22_phenotype was removed from gene: FBXW7.
Pituitary hormone deficiency v2.102 ROBO1 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: ROBO1.
Tag Q3_22_NHS_review tag was added to gene: ROBO1.
Intellectual disability v3.1737 ANK3 Eleanor Williams commented on gene: ANK3
Intellectual disability v3.1737 ANK3 Eleanor Williams Tag Q2_22_MOI was removed from gene: ANK3.
Tag Q3_22_MOI tag was added to gene: ANK3.
Bleeding and platelet disorders v1.44 F12 Eleanor Williams commented on gene: F12
Bleeding and platelet disorders v1.44 F12 Eleanor Williams Tag Q2_22_rating tag was added to gene: F12.
Congenital muscular dystrophy v2.31 MYMK Eleanor Williams commented on gene: MYMK
Congenital muscular dystrophy v2.31 MYMK Eleanor Williams Tag Q3_21_rating tag was added to gene: MYMK.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 DCLRE1B Eleanor Williams commented on gene: DCLRE1B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 DCLRE1B Eleanor Williams Tag Q3_21_rating tag was added to gene: DCLRE1B.
Severe microcephaly v2.319 DPP6 Eleanor Williams commented on gene: DPP6
Severe microcephaly v2.319 DPP6 Eleanor Williams Tag Q4_21_rating tag was added to gene: DPP6.
Leukodystrophy, adult onset v1.47 RNASET2 Eleanor Williams commented on gene: RNASET2
Leukodystrophy, adult onset v1.47 RNASET2 Eleanor Williams Tag Q4_21_rating tag was added to gene: RNASET2.
Leukodystrophy, adult onset v1.47 POLR1C Eleanor Williams commented on gene: POLR1C
Leukodystrophy, adult onset v1.47 POLR1C Eleanor Williams Tag Q4_21_rating tag was added to gene: POLR1C.
Hydrocephalus v2.132 HYLS1 Eleanor Williams commented on gene: HYLS1
Hydrocephalus v2.132 HYLS1 Eleanor Williams Tag Q4_21_rating tag was added to gene: HYLS1.
Leukodystrophy, adult onset v1.47 COL4A2 Eleanor Williams commented on gene: COL4A2
Leukodystrophy, adult onset v1.47 COL4A2 Eleanor Williams Tag Q4_21_rating tag was added to gene: COL4A2.
Hydrocephalus v2.132 MYMK Eleanor Williams commented on gene: MYMK
Hydrocephalus v2.132 MYMK Eleanor Williams Tag Q4_21_rating tag was added to gene: MYMK.
Congenital hyperinsulinism v2.29 GPC3 Eleanor Williams Tag Q4_21_rating tag was added to gene: GPC3.
Congenital hyperinsulinism v2.29 AKT2 Eleanor Williams Tag Q4_22_rating tag was added to gene: AKT2.
Leukodystrophy, adult onset v1.47 AARS Eleanor Williams commented on gene: AARS
Leukodystrophy, adult onset v1.47 AARS Eleanor Williams Tag Q4_21_rating tag was added to gene: AARS.
Dystonia, chorea or related movement disorder, adult onset v1.174 GBA Eleanor Williams commented on gene: GBA
Dystonia, chorea or related movement disorder, adult onset v1.174 GBA Eleanor Williams Tag Q4_21_rating tag was added to gene: GBA.
Leukodystrophy, adult onset v1.47 MARS Eleanor Williams commented on gene: MARS
Leukodystrophy, adult onset v1.47 MARS Eleanor Williams Tag Q4_21_rating tag was added to gene: MARS.
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Deleted their comment
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Tag Q4_21_expert_review was removed from gene: SNIP1.
Tag Q3_22_rating tag was added to gene: SNIP1.
Tag Q3_22_expert_review tag was added to gene: SNIP1.
Holoprosencephaly v2.30 DISP1 Eleanor Williams commented on gene: DISP1
Holoprosencephaly v2.30 DISP1 Eleanor Williams Tag Q2_21_rating tag was added to gene: DISP1.
Hydrocephalus v2.132 ERF Eleanor Williams commented on gene: ERF
Hydrocephalus v2.132 ERF Eleanor Williams Tag Q2_21_rating tag was added to gene: ERF.
Cerebral vascular malformations v2.60 SETD5 Eleanor Williams commented on gene: SETD5
Cerebral vascular malformations v2.60 SETD5 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SETD5.
Tag Q3_22_rating tag was added to gene: SETD5.
Tag Q3_22_expert_review tag was added to gene: SETD5.
Cerebral vascular malformations v2.60 CHD4 Eleanor Williams commented on gene: CHD4
Cerebral vascular malformations v2.60 CHD4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CHD4.
Tag Q3_22_rating tag was added to gene: CHD4.
Tag Q3_22_expert_review tag was added to gene: CHD4.
Hypogonadotropic hypogonadism (GMS) v1.54 FGF17 Eleanor Williams commented on gene: FGF17
Hypogonadotropic hypogonadism (GMS) v1.54 FGF17 Eleanor Williams Tag Q2_21_expert_review was removed from gene: FGF17.
Tag Q3_22_rating tag was added to gene: FGF17.
Tag Q3_22_expert_review tag was added to gene: FGF17.
Hypogonadotropic hypogonadism (GMS) v1.54 DUSP6 Eleanor Williams commented on gene: DUSP6
Hypogonadotropic hypogonadism (GMS) v1.54 DUSP6 Eleanor Williams Tag Q2_21_expert_review was removed from gene: DUSP6.
Tag Q3_22_rating tag was added to gene: DUSP6.
Tag Q3_22_expert_review tag was added to gene: DUSP6.
Hypogonadotropic hypogonadism (GMS) v1.54 CCDC141 Eleanor Williams commented on gene: CCDC141
Hypogonadotropic hypogonadism (GMS) v1.54 CCDC141 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CCDC141.
Laterality disorders and isomerism v1.51 NODAL Eleanor Williams commented on gene: NODAL
Laterality disorders and isomerism v1.51 NODAL Eleanor Williams Tag Q2_21_expert_review was removed from gene: NODAL.
Tag Q3_22_rating tag was added to gene: NODAL.
Tag Q3_22_expert_review tag was added to gene: NODAL.
Lysosomal storage disorder v1.78 VPS33A Eleanor Williams commented on gene: VPS33A
Lysosomal storage disorder v1.78 VPS33A Eleanor Williams Tag Q2_21_expert_review was removed from gene: VPS33A.
Tag Q3_22_rating tag was added to gene: VPS33A.
Tag Q3_22_expert_review tag was added to gene: VPS33A.
Rare anaemia v1.42 RPL27 Eleanor Williams commented on gene: RPL27
Rare anaemia v1.42 RPL27 Eleanor Williams Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Haematological malignancies cancer susceptibility v2.36 RPL27 Eleanor Williams Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Haematological malignancies cancer susceptibility v2.36 RPL27 Eleanor Williams commented on gene: RPL27
Cytopenia - NOT Fanconi anaemia v1.72 RPL27 Eleanor Williams commented on gene: RPL27
Cytopenia - NOT Fanconi anaemia v1.72 RPL27 Eleanor Williams Tag Q2_21_expert_review was removed from gene: RPL27.
Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Ataxia and cerebellar anomalies - childhood onset v2.306 SPG7 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SPG7.
Tag Q3_22_rating tag was added to gene: SPG7.
Tag Q3_22_expert_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - childhood onset v2.306 SPG7 Eleanor Williams commented on gene: SPG7
Ataxia and cerebellar anomalies - childhood onset v2.306 CYP2U1 Eleanor Williams commented on gene: CYP2U1
Ataxia and cerebellar anomalies - childhood onset v2.306 CYP2U1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CYP2U1.
Tag Q3_22_rating tag was added to gene: CYP2U1.
Tag Q3_22_expert_review tag was added to gene: CYP2U1.
White matter disorders and cerebral calcification - childhood onset v1.244 CYP7B1 Eleanor Williams commented on gene: CYP7B1
White matter disorders and cerebral calcification - childhood onset v1.244 CYP7B1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CYP7B1.
Tag Q3_22_rating tag was added to gene: CYP7B1.
Tag Q3_22_expert_review tag was added to gene: CYP7B1.
Childhood solid tumours v2.35 MAX Eleanor Williams commented on gene: MAX
Childhood solid tumours v2.35 MAX Eleanor Williams Tag Q2_21_expert_review was removed from gene: MAX.
Tag Q3_22_rating tag was added to gene: MAX.
Tag Q3_22_expert_review tag was added to gene: MAX.
Cerebral vascular malformations v2.60 CNOT3 Eleanor Williams commented on gene: CNOT3
Cerebral vascular malformations v2.60 CNOT3 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CNOT3.
Tag Q3_22_rating tag was added to gene: CNOT3.
Tag Q3_22_expert_review tag was added to gene: CNOT3.
Segmental overgrowth disorders - Deep sequencing v2.16 NLRP2 Eleanor Williams commented on gene: NLRP2
Segmental overgrowth disorders - Deep sequencing v2.16 NLRP2 Eleanor Williams Tag Q2_21_expert_review was removed from gene: NLRP2.
Tag Q3_22_rating tag was added to gene: NLRP2.
Tag Q3_22_expert_review tag was added to gene: NLRP2.
Hypertrophic cardiomyopathy v2.41 JPH2 Eleanor Williams commented on gene: JPH2
Hypertrophic cardiomyopathy v2.41 JPH2 Eleanor Williams Tag Q2_21_expert_review was removed from gene: JPH2.
Tag Q3_22_rating tag was added to gene: JPH2.
Tag Q3_22_expert_review tag was added to gene: JPH2.
Differences in sex development v2.66 FGFR2 Eleanor Williams commented on gene: FGFR2
Hypogonadotropic hypogonadism (GMS) v1.54 SPRY4 Eleanor Williams commented on gene: SPRY4
Hypogonadotropic hypogonadism (GMS) v1.54 SPRY4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SPRY4.
Tag Q3_22_rating tag was added to gene: SPRY4.
Tag Q3_22_expert_review tag was added to gene: SPRY4.
Cardiac arrhythmias - additional genes v1.15 ANK2 Eleanor Williams Tag Q3_21_expert_review was removed from gene: ANK2.
Tag Q3_22_rating tag was added to gene: ANK2.
Tag Q3_22_expert_review tag was added to gene: ANK2.
Cutaneous photosensitivity with a likely genetic cause v1.10 HMBS Eleanor Williams commented on gene: HMBS
Cutaneous photosensitivity with a likely genetic cause v1.10 HMBS Eleanor Williams Tag Q3_21_expert_review was removed from gene: HMBS.
Tag Q3_22_rating tag was added to gene: HMBS.
Tag Q3_22_expert_review tag was added to gene: HMBS.
Rare anaemia v1.42 RPS27 Eleanor Williams commented on gene: RPS27
Rare anaemia v1.42 RPS27 Eleanor Williams Tag Q3_21_expert_review was removed from gene: RPS27.
Tag Q3_22_rating tag was added to gene: RPS27.
Tag Q3_22_expert_review tag was added to gene: RPS27.
Retinal disorders v2.286 PRPF6 Eleanor Williams commented on gene: PRPF6
Retinal disorders v2.286 PRPF6 Eleanor Williams Tag Q3_21_expert_review was removed from gene: PRPF6.
Tag Q3_22_rating tag was added to gene: PRPF6.
Tag Q3_22_expert_review tag was added to gene: PRPF6.
Osteogenesis imperfecta v2.48 DSPP Eleanor Williams commented on gene: DSPP: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Osteogenesis imperfecta v2.48 DSPP Eleanor Williams Tag Q3_21_expert_review was removed from gene: DSPP.
Tag Q3_22_rating tag was added to gene: DSPP.
Tag Q3_22_expert_review tag was added to gene: DSPP.
Sarcoma susceptibility v1.72 FANCC Eleanor Williams commented on gene: FANCC
Fetal anomalies v1.974 SCUBE3 Eleanor Williams commented on gene: SCUBE3: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Fetal anomalies v1.974 SCUBE3 Eleanor Williams Tag Q4_21_expert_review was removed from gene: SCUBE3.
Tag Q3_22_rating tag was added to gene: SCUBE3.
Tag Q3_22_expert_review tag was added to gene: SCUBE3.
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams commented on gene: CLPB
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams Tag Q4_21_expert_review was removed from gene: CLPB.
Tag Q3_21_MOI tag was added to gene: CLPB.
Tag Q3_22_rating tag was added to gene: CLPB.
Tag Q3_22_expert_review tag was added to gene: CLPB.
Malformations of cortical development v2.149 DAG1 Eleanor Williams commented on gene: DAG1
Malformations of cortical development v2.149 DAG1 Eleanor Williams Tag Q4_21_expert_review was removed from gene: DAG1.
Tag Q3_22_rating tag was added to gene: DAG1.
Tag Q3_22_expert_review tag was added to gene: DAG1.
Rhabdomyolysis and metabolic muscle disorders v1.78 FKTN Eleanor Williams commented on gene: FKTN
Rhabdomyolysis and metabolic muscle disorders v1.78 FKTN Eleanor Williams Tag Q4_21_expert_review was removed from gene: FKTN.
Tag Q3_22_rating tag was added to gene: FKTN.
Tag Q3_22_expert_review tag was added to gene: FKTN.
Sarcoma susceptibility v1.72 FANCC Eleanor Williams Tag Q3_22_rating tag was added to gene: FANCC.
Epidermolysis bullosa and congenital skin fragility v1.53 SPINK5 Eleanor Williams Tag Q3_22_rating tag was added to gene: SPINK5.
Haematological malignancies cancer susceptibility v2.36 MBD4 Eleanor Williams Tag Q3_22_rating tag was added to gene: MBD4.
Renal ciliopathies v1.64 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Renal ciliopathies v1.64 ZNF423 Eleanor Williams commented on gene: ZNF423
Neurological ciliopathies v1.32 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Neurological ciliopathies v1.32 ZNF423 Eleanor Williams commented on gene: ZNF423
Cystic kidney disease v2.53 ZNF423 Eleanor Williams commented on gene: ZNF423
Cystic kidney disease v2.53 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Intellectual disability v3.1737 DPH5 Sarah Leigh Tag Q4_22_rating tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Tag Q4_22_rating tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Classified gene: DPH5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Gene: dph5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1737 DPH5 Sarah Leigh Classified gene: DPH5 as Amber List (moderate evidence)
Intellectual disability v3.1737 DPH5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1737 DPH5 Sarah Leigh Gene: dph5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1736 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Intellectual disability v3.1736 DPH5 Sarah Leigh Added comment: Comment on phenotypes: As described by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4902).
Intellectual disability v3.1736 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Added comment: Comment on phenotypes: As described by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4902)
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Intellectual disability v3.1735 ROR2 Tracy Lester reviewed gene: ROR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1735 PRDM13 Sarah Leigh Publications for gene: PRDM13 were set to 34730112
Clefting v2.70 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Only two cases with clefting have been reported to date. Following consultation with Clinical team, decided to maintain Green rating as CNVs with variable penetrance are reported in clinical practice and can be relevant diagnostically; however, adding watchlist tag to monitor for clear evidence of particularly reduced penetrance at which stage the rating may be reviewed.; Changed phenotypes to: 26097203
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Only two cases with epilepsy have been reported to date. Following consultation with Clinical team, decided to maintain Green rating as CNVs with variable penetrance are reported in clinical practice and can be relevant diagnostically; however, adding watchlist tag to monitor for clear evidence of particularly reduced penetrance at which stage the rating may be reviewed.; Changed publications to: 26097203
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova Tag watchlist tag was added to Region: ISCA-37423-Gain.
Clefting v2.70 ISCA-37423-Gain Arina Puzriakova Tag watchlist tag was added to Region: ISCA-37423-Gain.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 LYN Boaz Palterer gene: LYN was added
gene: LYN was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LYN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LYN were set to 36122175
Phenotypes for gene: LYN were set to Autoinflammatory; Neutrophilic vasculitis; Liver fibrosis; Chronic urticaria; Atopic dermatitis; Fever
Penetrance for gene: LYN were set to unknown
Review for gene: LYN was set to GREEN
Added comment: Louvrier et al. described 1 patient ( PMID 36122175 ) and De Jesus et al ( https://www.medrxiv.org/content/10.1101/2022.09.27.22280319v1.full.pdf ) 3 additional patients, for a total of 4 kindreds with de novo LYN mutations.
Strong functional evidence: p.Tyr508His, p.Tyr508Phe and p.Tyr508* cause inhibition loss, leading to Tyr397 autophosphorylation and functional GOF.
Sources: Literature
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Classified gene: MTSS1L as Amber List (moderate evidence)
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases with shared phenotype and supported by functional studies to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Gene: mtss1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1733 MTSS1L Arina Puzriakova gene: MTSS1L was added
gene: MTSS1L was added to Intellectual disability. Sources: Literature
new-gene-name, Q4_22_rating tags were added to gene: MTSS1L.
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MTSS1L were set to 36067766
Phenotypes for gene: MTSS1L were set to Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms
Review for gene: MTSS1L was set to GREEN
Added comment: Huang et al. 2022 (PMID: 36067766) reported five unrelated individuals with the same heterozygous de novo variant (c.2011C>T; p.Arg671Trp) in MTSS2 (formally known as MTSS1L). Linkage analysis was not performed but given the variants arose de novo and the mixed ethnicity of the affected individuals (4 European, 1 Chinese) a founder effect can be ruled out.

Subjects displayed a shared phenotype of GDD and/or ID, ophthalmological anomalies (most commonly nystagmus), microcephaly (primary in 2, relative in 3) and shared mild facial dysmorphisms. The single adult patient also presented with seizures and optic atrophy.

Functional studies showed the variant leads to a decrease in mRNA level but does not impact protein levels of MTSS2. However, a Drosophila model demonstrated that loss of the fly ortholog results in defects in locomotor and visual functions which were rescued by human MTSS2 and only partially rescued by the MTSS2 c.2011C>T variant. Overexpression of the c.2011C>T variant caused similar phenotypes as the LoF mutant indicating a possible dominant-negative effect.
Sources: Literature
Skeletal muscle channelopathy v1.39 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG: Added the tag of Q4_21_rating as this STR only had an expert review tag and would not be picked up for a GMS report with just that.
Skeletal muscle channelopathy v1.39 CNBP_CCTG Eleanor Williams Tag Q4_21_rating tag was added to STR: CNBP_CCTG.
Possible mitochondrial disorder, nuclear genes v1.160 PDK3 Eleanor Williams Tag Q1_22_rating tag was added to gene: PDK3.
Intellectual disability v3.1732 RELN Dmitrijs Rots changed review comment from: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense.; to: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense. The inheritance should be changed to both.
Intellectual disability v3.1732 RELN Dmitrijs Rots reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lisencephaly, seizures, autism; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Leukodystrophy, adult onset v1.47 TPP2 Eleanor Williams Phenotypes for gene: TPP2 were changed from White matter abnormalities; autoimmunity; immunodefficiency; developmental delay to White matter abnormalities; Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
Leukodystrophy, adult onset v1.46 TPP2 Eleanor Williams changed review comment from: Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.

2 cases reported of homozygous missense variants in TPP2 and a MS-type phenotype. However, 1 of the variants is also found in some MS patients in the heterozygous state.

PMID: 33586135 - Atallah et al 2021- (not PMID: 25414442) summarises 14 patients with TPP2 pathogenic variants reported in their study and other publications. They report that 'the adult form, described in four patients, manifests as a chronic non-infectious brain inflammation with demyelinating brain disease and calcifications somewhat similar to multiple sclerosis.'. These 4 patients are reported in PMID: 30533531 (Reinthaler et al 2018) who describe a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. A Jordian patient with MS was also identified to have a homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2. This variant also occurs in heterozygous form in other MS cases and in 6 ExAC control individuals so the authors acknowledge that it may not be pathogenic.; to: Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.

2 cases reported of homozygous missense variants in TPP2 and a MS-type phenotype. However, 1 of the variants is also found in some MS patients in the heterozygous state.

PMID: 33586135 - Atallah et al 2021- (not PMID: 25414442) summarises 14 patients with TPP2 pathogenic variants reported in their study and other publications. They report that 'the adult form, described in four patients, manifests as a chronic non-infectious brain inflammation with demyelinating brain disease and calcifications somewhat similar to multiple sclerosis.'. These 4 patients are reported in PMID: 30533531 (Reinthaler et al 2018) who describe a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. A Jordian patient with MS was also identified to have a homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2. This variant also occurs in heterozygous form in other MS cases and in 6 ExAC control individuals so the authors acknowledge that it may not be pathogenic. Age of diagnosis for these patients was 35 year plus.

Other cases with variants in this gene are reported in PMIDS: 25414442; 25525876; 30533531, however these present in childhood with a recurrent respiratory infections, autoimmune cytopenias, developmental delay and progressive combined immunodeficiency.
Leukodystrophy, adult onset v1.46 TPP2 Eleanor Williams Publications for gene: TPP2 were set to 33586135
Leukodystrophy, adult onset v1.45 TPP2 Eleanor Williams Publications for gene: TPP2 were set to PMID:25414442
Leukodystrophy, adult onset v1.44 TPP2 Eleanor Williams Classified gene: TPP2 as Amber List (moderate evidence)
Leukodystrophy, adult onset v1.44 TPP2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases (4 individuals) with homozygous variants in this gene reported with an MS-like phenotype, but some doubt over the pathogenicity of the variant in 1 case.
Leukodystrophy, adult onset v1.44 TPP2 Eleanor Williams Gene: tpp2 has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v1.43 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: None; Publications: 33586135, 25414442, 25525876, 30533531; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1732 DOHH Sarah Leigh Classified gene: DOHH as Amber List (moderate evidence)
Intellectual disability v3.1732 DOHH Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1732 DOHH Sarah Leigh Gene: dohh has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.319 DOHH Sarah Leigh Classified gene: DOHH as Amber List (moderate evidence)
Severe microcephaly v2.319 DOHH Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.319 DOHH Sarah Leigh Gene: dohh has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.318 DOHH Sarah Leigh Entity copied from Intellectual disability v3.1731
Severe microcephaly v2.318 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Severe microcephaly. Sources: Literature
Q4_22_rating, Q4_22_MOI tags were added to gene: DOHH.
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Intellectual disability v3.1731 DOHH Sarah Leigh Tag Q4_22_rating tag was added to gene: DOHH.
Tag Q4_22_MOI tag was added to gene: DOHH.
Intellectual disability v3.1731 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Review for gene: DOHH was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35858628 reports six DOHH variants in three unrelated cases of a neurodevelopmental disorder. All of these cases had intellectual disability, microcephaly and hypotonia.
Sources: Literature
Intellectual disability v3.1730 TPP2 Arina Puzriakova Tag Q3_22_MOI was removed from gene: TPP2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 SYNE2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: SYNE2.
Tag Q3_22_NHS_review tag was added to gene: SYNE2.
Early onset dystonia v1.128 XK Sarah Leigh Classified gene: XK as Red List (low evidence)
Early onset dystonia v1.128 XK Sarah Leigh Gene: xk has been classified as Red List (Low Evidence).
Early onset dystonia v1.127 XK Sarah Leigh edited their review of gene: XK: Changed rating: RED
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Ataxia and cerebellar anomalies - childhood onset v2.306 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Ataxia and cerebellar anomalies - childhood onset v2.305 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Ataxia and cerebellar anomalies - childhood onset v2.305 CACNA1A Sarah Leigh reviewed gene: CACNA1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amyotrophic lateral sclerosis/motor neuron disease v1.62 KIF5A Sarah Leigh Phenotypes for gene: KIF5A were changed from Amyotrophic lateral sclerosis to {Amyotrophic lateral sclerosis, susceptibility to, 25}, OMIM:617921; amyotrophic lateral sclerosis, susceptibility to, 25, MONDO:0060670
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh reviewed gene: KIF5A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh Classified gene: KIF5A as Green List (high evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh Gene: kif5a has been classified as Green List (High Evidence).
Familial cerebral small vessel disease v1.14 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance has been changed to Both mono and biallelic
Familial cerebral small vessel disease v1.14 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral vascular malformations v2.60 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Cerebral vascular malformations v2.60 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v2.59 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: COL3A1.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v1.44 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Bleeding and platelet disorders v1.44 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v1.43 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams changed review comment from: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changes to Both mono and biallelic following GMS review.; to: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changed to Both mono and biallelic following GMS review.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changes to Both mono and biallelic following GMS review.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v2.65 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Thoracic aortic aneurysm or dissection (GMS) v1.27 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: As this is a red gene the mode of inheritance has been left as it is, Both mono and biallelic. However, if promoted to green the evidence for biallelic cases should be reviewed.
Thoracic aortic aneurysm or dissection (GMS) v1.27 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.974 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as both mono and biallelic for now, but only Ehlers-Danlos syndrome, cardiac valvular type is associated with biallelic variants and this does not seem relevant to the fetal panel. Recommendation to change to Monoallelic only, if the GMS groups agree.
Fetal anomalies v1.974 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.973 COL1A2 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL1A2.
Rare multisystem ciliopathy disorders v1.164 TTC21B Eleanor Williams commented on gene: TTC21B
Rare multisystem ciliopathy disorders v1.164 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Renal ciliopathies v1.64 TTC21B Eleanor Williams commented on gene: TTC21B
Renal ciliopathies v1.64 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Unexplained kidney failure in young people v1.116 TTC21B Eleanor Williams commented on gene: TTC21B
Unexplained kidney failure in young people v1.116 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Cystic kidney disease v2.53 TTC21B Eleanor Williams commented on gene: TTC21B
Cystic kidney disease v2.53 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.22 TTC21B Eleanor Williams Tag Q2_22_expert_review tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.22 TTC21B Eleanor Williams Publications for gene: TTC21B were set to
Tubulointerstitial kidney disease v1.21 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now. It does appear that monoallelic variants are potential genetic modifiers and are found in combination with variants in other renal disease associated genes (see PMID: 26940125, PMID: 21258341) so seeking GMS review as to the best mode of inheritance.
Tubulointerstitial kidney disease v1.21 TTC21B Eleanor Williams Mode of inheritance for gene: TTC21B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Tag Q3_22_expert_review tag was added to gene: TTC21B.
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now. It does appear that monoallelic variants are potential genetic modifiers and are found in combination with variants in other renal disease associated genes (see PMID: 26940125, PMID: 21258341) so seeking GMS review as to the best mode of inheritance.
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Mode of inheritance for gene: TTC21B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.40 TTC21B Eleanor Williams Tag Q3_22_MOI tag was added to gene: TTC21B.
Intellectual disability v3.1730 TPP2 Eleanor Williams Classified gene: TPP2 as Amber List (moderate evidence)
Intellectual disability v3.1730 TPP2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber with a recommendation for GREEN rating following GMS review. Clinical advice was to be inclusive since the intellectual disability phenotype is relatively consistent.
Intellectual disability v3.1730 TPP2 Eleanor Williams Gene: tpp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1729 TPP2 Eleanor Williams Tag Q3_22_rating tag was added to gene: TPP2.
Tag Q3_22_MOI tag was added to gene: TPP2.
Nephrocalcinosis or nephrolithiasis v2.40 RRAGD Eleanor Williams Mode of inheritance for gene: RRAGD was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Classified gene: RRAGD as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation of green rating following GMS review.
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Gene: rragd has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.38 RRAGD Eleanor Williams Tag Q3_22_rating tag was added to gene: RRAGD.
Tag Q3_22_MOI tag was added to gene: RRAGD.
Tag Q3_22_NHS_review tag was added to gene: RRAGD.
Nephrocalcinosis or nephrolithiasis v2.38 RRAGD Eleanor Williams Phenotypes for gene: RRAGD were changed from hypomagnesaemia, nephrocalcinosis, salt wasting, cardiomyopathy to hypomagnesaemia; nephrocalcinosis; salt wasting; cardiomyopathy; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130
Nephrocalcinosis or nephrolithiasis v2.37 RRAGD Eleanor Williams Mode of inheritance for gene: RRAGD was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nephrocalcinosis or nephrolithiasis v2.36 RRAGD Eleanor Williams commented on gene: RRAGD
Retinal disorders v2.286 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79, OMIM:617460, MONDO:0044320 to Retinitis pigmentosa 79, OMIM:617460; retinitis pigmentosa 79,MONDO:0044320
Intellectual disability v3.1729 HK1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: HK1.
Tag Q3_22_NHS_review tag was added to gene: HK1.
Intellectual disability v3.1729 HK1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as biallelic for now but with the recommendation of changing to monallelic following GMS review.
Intellectual disability v3.1729 HK1 Eleanor Williams Mode of inheritance for gene: HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1728 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807
Intellectual disability v3.1727 HK1 Eleanor Williams commented on gene: HK1: As noted by Tracy Lester, the cases reported by Okur et al. 2019 - PMID: 30778173 are have heterozygous de novo variants in HK1 and a phenotype of developmental delay, intellectual disability, structural brain abnormality, and visual impairments, therefore the mode of inheritance should be changed from biallelic to monoallelic.
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH Eleanor Williams Classified gene: ASPH as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for a green rating following GMS review. There are sufficient cases with a cardiac phenotype relevant to this panel.
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH Eleanor Williams Gene: asph has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.25 ASPH Eleanor Williams Tag Q3_22_rating tag was added to gene: ASPH.
Tag Q3_22_MOI tag was added to gene: ASPH.
Tag Q3_22_NHS_review tag was added to gene: ASPH.
Thoracic aortic aneurysm or dissection (GMS) v1.25 ASPH Eleanor Williams Phenotypes for gene: ASPH were changed from ocular features; anterior segment abnormalities; distinctive facial appearance; aortic root dilatation to Traboulsi syndrome, OMIM:601552; facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, MONDO:0011106
Thoracic aortic aneurysm or dissection (GMS) v1.24 ASPH Eleanor Williams Publications for gene: ASPH were set to PMID: 35918038
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Eleanor Williams commented on gene: ASPH
Neonatal diabetes v2.59 ZNF808 Eleanor Williams Phenotypes for gene: ZNF808 were changed from to neonatal diabetes mellitus, MONDO:0016391; pancreatic agenesis, MONDO:0009832
Neonatal diabetes v2.58 ZNF808 Eleanor Williams Mode of inheritance for gene: ZNF808 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.57 ZNF808 Eleanor Williams Tag Q3_22_rating tag was added to gene: ZNF808.
Tag Q3_22_NHS_review tag was added to gene: ZNF808.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams changed review comment from: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; to: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without an identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams changed review comment from: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) there are 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; to: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams edited their review of gene: ZNF808: Added comment: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) there are 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; Changed phenotypes to: neonatal diabetes mellitus, MONDO:0016391, pancreatic agenesis, MONDO:0009832
Neonatal diabetes v2.57 FICD Eleanor Williams changed review comment from: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.; to: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). Age of diabetes onset was a mean of 29 weeks (range 12-43). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.
Neonatal diabetes v2.57 EIF2B1 Eleanor Williams changed review comment from: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.; to: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). Onset of diabetes was at 21 weeks or less in 4 patients, and at 56 weeks in the 5th. The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: ONECUT1.
Tag Q3_21_expert_review was removed from gene: ONECUT1.
Tag Q3_22_NHS_review tag was added to gene: ONECUT1.
Tag Q3_22_expert_review tag was added to gene: ONECUT1.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: ONECUT1.
Tag Q3_21_expert_review tag was added to gene: ONECUT1.
Tag Q3_22_rating tag was added to gene: ONECUT1.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Classified gene: ONECUT1 as Amber List (moderate evidence)
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, but with a recommendation for green rating following GMS expert review as to whether the age of onset of the cases indicates this gene-disease association is suitable for this panel. In 1 case the age of onset was 1 day old, in the other 14 months. The age of onset in the 3rd case is not known.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Gene: onecut1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.56 ONECUT1 Eleanor Williams Phenotypes for gene: ONECUT1 were changed from to ONECUT1-associated neonatal diabetes; neonatal diabetes mellitus, MONDO:0016391
Neonatal diabetes v2.55 ONECUT1 Eleanor Williams Publications for gene: ONECUT1 were set to
Neonatal diabetes v2.54 ONECUT1 Eleanor Williams Mode of inheritance for gene: ONECUT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.53 ONECUT1 Eleanor Williams commented on gene: ONECUT1: Not associated with a phenotype in OMIM but is associated with ONECUT1-associated neonatal diabetes (strong) in Gene2Phenotype.

As reported by the reviewer Philippi et al 2021 report two unrelated (French and Turkish) patients from consanguineous families with homozgyous variants in OMECUT1 (1 nonsense, 1 missense) and a phenotype characterised by characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia. Diabetes onset was at 1 day and 14 months in the two children respectively. Studies of the heterozygous carriers suggests that they are part of a distinctive subgroup of diabetic patients with early-onset, non-autoimmune diabetes, who respond well to diabetes treatment.

Note the eligibility criteria for this panel indicates that patients should be diagnosed with diabetes at less than 9 months of age.
Intellectual disability v3.1727 FICD Eleanor Williams Entity copied from Diabetes - neonatal onset v2.53
Intellectual disability v3.1727 FICD Eleanor Williams gene: FICD was added
gene: FICD was added to Intellectual disability. Sources: Expert review,Expert Review Amber
watchlist tags were added to gene: FICD.
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FICD were set to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities.
Neonatal diabetes v2.53 FICD Eleanor Williams Tag watchlist tag was added to gene: FICD.
Neonatal diabetes v2.53 FICD Eleanor Williams Classified gene: FICD as Amber List (moderate evidence)
Neonatal diabetes v2.53 FICD Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with a watchlist tag added.
3 cases reported but all with the same variant and 2 families share a common haplotype. Some functional data. In addition the paper is still at the pre-print stage and so has not yet been peer reviewed.
Neonatal diabetes v2.53 FICD Eleanor Williams Gene: ficd has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.52 FICD Eleanor Williams Phenotypes for gene: FICD were changed from to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities.
Neonatal diabetes v2.51 FICD Eleanor Williams Mode of inheritance for gene: FICD was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.50 FICD Eleanor Williams commented on gene: FICD: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.
Neonatal diabetes v2.50 CNOT1 Eleanor Williams Tag Q3_22_NHS_review tag was added to gene: CNOT1.
Pituitary hormone deficiency v2.102 MAGEL2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: MAGEL2.
Congenital hyperinsulinism v2.29 MAGEL2 Sarah Leigh Added comment: Comment on phenotypes: Congenital hyperinsulinism with hypoglycaemia
Congenital hyperinsulinism v2.29 MAGEL2 Sarah Leigh Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, OMIM:615547; Schaaf-Yang syndrome, MONDO:0014243
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Classified gene: MAGEL2 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Gene: magel2 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.27 MAGEL2 Sarah Leigh Tag Q3_22_rating tag was added to gene: MAGEL2.
Tag Q3_22_MOI tag was added to gene: MAGEL2.
Tag Q3_22_NHS_review tag was added to gene: MAGEL2.
Congenital hyperinsulinism v2.27 NSD1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: NSD1.
Congenital hyperinsulinism v2.27 NSD1 Sarah Leigh Phenotypes for gene: NSD1 were changed from Sotos syndrome (OMIM#117550) to Sotos syndrome, OMIM:117550; Sotos syndrome 1, MONDO:0007299
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh changed review comment from: Comment on publications: this article is a preprint, the PMID will be added when avaiable; to: Comment on publications: this article is a preprint, the PMID will be added when available
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: HK1.
Tag Q3_22_rating tag was added to gene: HK1.
Tag Q3_22_MOI tag was added to gene: HK1.
Tag Q3_22_NHS_review tag was added to gene: HK1.
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh edited their review of gene: HK1: Changed rating: GREEN
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh changed review comment from: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism in the preprint https://doi.org/10.1101/2021.12.03.21267240; to: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism (Wakeling et al Nature Genetics 2022 (accepted for publication) medRxiv preprint doi: https://doi.org/10.1101/2021.12.03.21267240).
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh edited their review of gene: HK1: Added comment: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism in the preprint https://doi.org/10.1101/2021.12.03.21267240; Changed rating: AMBER
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Classified gene: HK1 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Gene: hk1 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.25 HK1 Sarah Leigh Phenotypes for gene: HK1 were changed from to Congenital hyperinsulinism
Congenital hyperinsulinism v2.24 HK1 Sarah Leigh Added comment: Comment on publications: this article is a preprint, the PMID will be added when avaiable
Congenital hyperinsulinism v2.24 HK1 Sarah Leigh Publications for gene: HK1 were set to
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Tag Q3_22_rating tag was added to gene: EIF2B1.
Tag Q3_22_NHS_review tag was added to gene: EIF2B1.
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Classified gene: EIF2B1 as Amber List (moderate evidence)
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Gene: eif2b1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Classified gene: EIF2B1 as Red List (low evidence)
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, but with a recommendation for green status.
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Gene: eif2b1 has been classified as Red List (Low Evidence).
Neonatal diabetes v2.48 EIF2B1 Eleanor Williams Phenotypes for gene: EIF2B1 were changed from to Permanent neonatal/early onset diabetes and transient liver dysfunction
Neonatal diabetes v2.47 EIF2B1 Eleanor Williams Publications for gene: EIF2B1 were set to
Neonatal diabetes v2.46 EIF2B1 Eleanor Williams Mode of inheritance for gene: EIF2B1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.45 EIF2B1 Eleanor Williams commented on gene: EIF2B1: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Tag Q3_22_rating tag was added to gene: CACNA1D.
Tag Q3_22_NHS_review tag was added to gene: CACNA1D.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh edited their review of gene: CACNA1D: Added comment: Associated with phenotype in OMIM and as strong Gen2Phen gene for Primary aldosteronism, seizures, and neurologic abnormalities (OMIM:615474). Two variants have been reported in two unrelated cases of congenital hyperinsulinaemic hypoglycaemia; PMID: 28318089 reports: c.1319G>A (p.G403D) in a case who also has heart defects and severe hypotonia and PMID: 32336187 reports: c.812T>A (p.L271H) in a case who also has primary hyperaldosteronism and hypotonia. A third de novo case has been reported in the review provided by Eleanor Williams on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH.; Changed rating: GREEN
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Classified gene: CACNA1D as Amber List (moderate evidence)
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Gene: cacna1d has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.45 CNOT1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review.; to: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review, however the pancreatic agenesis is associated with one missense variant only.
Holoprosencephaly v2.30 CNOT1 Eleanor Williams Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis, 618500; pancreatic agenesis and holoprosencephaly syndrome to Holoprosencephaly 12, with or without pancreatic agenesis, OMIM:618500; holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Classified gene: CNOT1 as Amber List (moderate evidence)
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Amber for now, however an additional case with the same variant as other cases and a holoprosencephaly phenotype has been reported, and so the rating should reviewed by the GMS.
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.22 CACNA1D Sarah Leigh Publications for gene: CACNA1D were set to 28318089
Holoprosencephaly v2.28 CNOT1 Eleanor Williams Tag Q3_22_rating tag was added to gene: CNOT1.
Tag Q3_22_expert_review tag was added to gene: CNOT1.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Tag Q3_22_rating tag was added to gene: CNOT1.
Tag Q3_22_expert_review tag was added to gene: CNOT1.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Classified gene: CNOT1 as Amber List (moderate evidence)
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.44 CNOT1 Eleanor Williams Phenotypes for gene: CNOT1 were changed from to Holoprosencephaly 12, with or without pancreatic agenesis, OMIM:618500; holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787
Neonatal diabetes v2.43 CNOT1 Eleanor Williams Publications for gene: CNOT1 were set to
Neonatal diabetes v2.42 CNOT1 Eleanor Williams Added comment: Comment on mode of pathogenicity: Only one missense variant reported in all cases. All de novo.
Neonatal diabetes v2.42 CNOT1 Eleanor Williams Mode of pathogenicity for gene: CNOT1 was changed from to Other
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1C.
Neonatal diabetes v2.41 CNOT1 Eleanor Williams Mode of inheritance for gene: CNOT1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Holoprosencephaly v2.28 CNOT1 Eleanor Williams Publications for gene: CNOT1 were set to 31006513; 31006510
Holoprosencephaly v2.27 CNOT1 Eleanor Williams commented on gene: CNOT1
Neonatal diabetes v2.40 CNOT1 Eleanor Williams commented on gene: CNOT1: Associated with Holoprosencephaly 12, with or without pancreatic agenesis, 618500 (AD) in OMIM and HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS (strong) in Gene2Phenotype.

3 publications reporting 6 unrelated probands with the same de novo missense variant in CNOT and a holoprosencephaly phenotype. 5/6 also had pancreatic agenesis.

PMID:35481434 - Cospain et al 2022 - report a foetus with semi-lobar HPE diagnosed at ultrasound and total pancreas agenesis identified at general autopsy. WES found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo.

PMID:31006513 - de Franco et al 2019 - looked at an international cohort of 107 individuals diagnosed with pancreatic agenesis and identified 3 unrelated individuals with CNOT1 variant c.1603C>T [p.Arg535Cys]. In 2 patients it was confirmed as de novo (maternal DNA not available for the 3rd). 2 of the patients had definite holoprosencephaly and one had possible holoprosencephaly. They report that the DDD study5 has identified other de novo CNOT1 variants in three individuals with developmental delay (2 missense and 1 nonsense) but none of them had holoprosencephaly or diabetes. Mice heterozygous for p.Arg535Cys variant showed no phenotype, but homozygotes (embryonically lethal) were found to have significant reduction in the size of the pancreas and neurological abnormalities.

PMID:31006510 - Kruszka et al 2019 - 2 unrelated individuals with semilobar holoprosencephaly with de novo variants in CNOT1 (c.1603C>T [p.Arg535Cys]) identified by WES. Both probands also presented with hearing loss and global developmental delay. Proband 1 also had diabetes insipidus, neonatal diabetes mellitus requiring insulin, pancreatic exocrine insufficiency requiring enzyme therapy.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Tag Q3_22_rating tag was added to gene: CACNA1C.
Tag Q3_22_NHS_review tag was added to gene: CACNA1C.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Classified gene: CACNA1C as Amber List (moderate evidence)
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.20 CACNA1C Sarah Leigh edited their review of gene: CACNA1C: Added comment: Associated with in OMIM and as definitive Gen2Phen gene for Timothy syndrome (OMIM:601005). At least two CACNA1C variants have been reported in numerous cases of Timothy syndrome.
PMID: 35897673 reports novel heterozygous CACNA1C variant in a patient with congenital hyperinsulinism (CHI), which appears to have gain-of-function and loss-of-function effects at the electrophysiological level, explaining the hyperinsulinism and resulting hypoglycemia in the patient reported. It appeared that c.1679T>C, p.L566P (NM_000719.6) reported in this patient has a minor effects on the cardiac action potential in an in silico model, in contrast to c.1216G>T, p.G406R (NM_000719.6) which is associated with the Long QT in Timothy syndrome (OMIM:601005). Therefore the authors conclude that this represents a novel congeital non-syndromic hyperinsulinism.
Hypoglycemia is also seen in Timothy syndrome patients with c.1216G>T, p.G406R (Table S3, PMID: 35897673), it would therefore be appropriate to screen other patients with hyperinsulinism / hypoglycemia for CACNA1C variants.; Changed rating: GREEN
Congenital hyperinsulinism v2.20 CACNA1C Sarah Leigh Phenotypes for gene: CACNA1C were changed from non-syndromic congeital hyperinsulinism to non-syndromic congeital hyperinsulinism; Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979
Congenital hyperinsulinism v2.19 CACNA1C Sarah Leigh Added comment: Comment on mode of pathogenicity: In vitro studies show that c.1679T>C, p.Leu566Pro (NM_000719.6) appears to have loss-of-function effects by altering current amplitudes in mutant channels and a gain-of-function effect by slowing the voltage-dependent inactivation (PMID: 35897673).
Congenital hyperinsulinism v2.19 CACNA1C Sarah Leigh Mode of pathogenicity for gene: CACNA1C was changed from to Other
Congenital hyperinsulinism v2.18 CACNA1C Sarah Leigh Phenotypes for gene: CACNA1C were changed from to non-syndromic congeital hyperinsulinism
Nephrocalcinosis or nephrolithiasis v2.36 RRAGD Detlef Bockenhauer gene: RRAGD was added
gene: RRAGD was added to Nephrocalcinosis or nephrolithiasis. Sources: Other
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to hypomagnesaemia, nephrocalcinosis, salt wasting, cardiomyopathy
Penetrance for gene: RRAGD were set to Complete
Mode of pathogenicity for gene: RRAGD 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: RRAGD was set to GREEN
Added comment: so far only a single paper, but with 9 patients/families
Sources: Other
Congenital hyperinsulinism v2.17 MAGEL2 Sarah Leigh Mode of inheritance for gene: MAGEL2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Congenital hyperinsulinism v2.16 MAGEL2 Sarah Leigh Publications for gene: MAGEL2 were set to
Congenital hyperinsulinism v2.15 HK1 Sarah Leigh Mode of inheritance for gene: HK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.14 CACNA1C Sarah Leigh Publications for gene: CACNA1C were set to
Congenital hyperinsulinism v2.13 CACNA1C Sarah Leigh Mode of inheritance for gene: CACNA1C was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Tag Q3_22_rating tag was added to gene: TBC1D32.
Tag Q3_22_NHS_review tag was added to gene: TBC1D32.
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Classified gene: TBC1D32 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v1.18 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Neurological ciliopathies v1.32 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Ophthalmological ciliopathies v1.31 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556
Rare multisystem ciliopathy disorders v1.164 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Structural eye disease v1.149 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 24285566
Fetal anomalies v1.973 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556
Malformations of cortical development v2.149 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Hydrocephalus v2.132 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566