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Limb disorders v1.52 GLI1 Eleanor Williams Publications for gene: GLI1 were set to 28973407; 28973407
Limb disorders v1.51 GLI1 Eleanor Williams Phenotypes for gene: GLI1 were changed from Polydactyly, postaxial, type A8, 618123); Polydactyly, preaxial I, 174400 to Polydactyly, postaxial, type A8, 618123; Polydactyly, preaxial I, 174400
Limb disorders v1.50 GLI1 Eleanor Williams Phenotypes for gene: GLI1 were changed from to Polydactyly, postaxial, type A8, 618123); Polydactyly, preaxial I, 174400
Limb disorders v1.49 GLI1 Eleanor Williams changed review comment from: Comment on list classification: >3 cases of variants in GLI1 in families with polydactyly; to: Comment on list classification: Changing rating from red to green. >3 cases of variants in GLI1 in families with polydactyly
Limb disorders v1.49 GLI1 Eleanor Williams Classified gene: GLI1 as Green List (high evidence)
Limb disorders v1.49 GLI1 Eleanor Williams Added comment: Comment on list classification: >3 cases of variants in GLI1 in families with polydactyly
Limb disorders v1.49 GLI1 Eleanor Williams Gene: gli1 has been classified as Green List (High Evidence).
Limb disorders v1.48 GLI1 Eleanor Williams changed review comment from: Associated with Polydactyly, postaxial, type A8 (#618123) and Polydactyly, preaxial I (#174400) in OMIM.

Postaxial Polydactyly Type A8:
PMID: 28973407 - Palencia-Campos et al. 2017- 3 cases. They report data from 3 families, 2 Turkish (1 consangineous),1 Pakistani (consangineous) with developmental defects overlapping with Ellis–van Creveld syndrome, including postaxial polydactyly of the hands and/or feet . Homozygous truncating mutations (NM_005269.2: c.2340G > A; p.Trp780*, NM_005269.2: c.1930C > T; p.Gln644*, NM_005269.2: c.337C > T; p.Arg113*) were identified in patients in all 3 families.
Note, in the extended members of family 1, one individual is reported with polydactyly but is heterozygous for the p.Trp780* variant and one individual with polydactyly but no p.Trp780* variant is reported (possible different homozygous genetic alteration not detectable by exome sequencing?).

Polydactyly, preaxial I:
PMID: 30620395 - Ullah et al. 2019 - 1 case. Pakistani family segregating autosomal recessive form of pre‐axial polydactyly. 2 individuals from two parts of the family were sequenced and a novel homozygous missense mutation identified c.1517T>A; p.Leu506Gln) in the GLI1. The variant segregated with the disease phenotype in the family.
It was not found in their in‐house exome sequence data from 70 additional unrelated Pakistani individuals with normal limb phenotypes but was found in heterozygous state in the gnomAD browser, with an allele frequency of 0.0002109, but not in homozygous state.; to: Associated with Polydactyly, postaxial, type A8 (#618123) and Polydactyly, preaxial I (#174400) in OMIM.

Postaxial Polydactyly Type A8:
PMID: 28973407 - Palencia-Campos et al. 2017- 3 cases. They report data from 3 families, 2 Turkish (1 consangineous),1 Pakistani (consangineous) with developmental defects overlapping with Ellis–van Creveld syndrome, including postaxial polydactyly of the hands and/or feet . Homozygous truncating mutations (NM_005269.2: c.2340G > A; p.Trp780*, NM_005269.2: c.1930C > T; p.Gln644*, NM_005269.2: c.337C > T; p.Arg113*) were identified in patients in all 3 families.
Note, in the extended members of family 1, one individual is reported with polydactyly but is heterozygous for the p.Trp780* variant (patient 3) and one individual with polydactyly but no p.Trp780* variant is reported (patient 4). Homozygosity mapping suggests that these results were consistent with GLI1-W780X being responsible for the phenotype of patients 1–2 and a different genetic variation or disease mechanism for the phenotypes of patients 3 and 4.

Polydactyly, preaxial I:
PMID: 30620395 - Ullah et al. 2019 - 1 case. Pakistani family segregating autosomal recessive form of pre‐axial polydactyly. 2 individuals from two parts of the family were sequenced and a novel homozygous missense mutation identified c.1517T>A; p.Leu506Gln) in the GLI1. The variant segregated with the disease phenotype in the family. It was not found in their in‐house exome sequence data from 70 additional unrelated Pakistani individuals with normal limb phenotypes but was found in heterozygous state in the gnomAD browser, with an allele frequency of 0.0002109, but not in homozygous state.
Limb disorders v1.48 GLI1 Eleanor Williams commented on gene: GLI1: Associated with Polydactyly, postaxial, type A8 (#618123) and Polydactyly, preaxial I (#174400) in OMIM.

Postaxial Polydactyly Type A8:
PMID: 28973407 - Palencia-Campos et al. 2017- 3 cases. They report data from 3 families, 2 Turkish (1 consangineous),1 Pakistani (consangineous) with developmental defects overlapping with Ellis–van Creveld syndrome, including postaxial polydactyly of the hands and/or feet . Homozygous truncating mutations (NM_005269.2: c.2340G > A; p.Trp780*, NM_005269.2: c.1930C > T; p.Gln644*, NM_005269.2: c.337C > T; p.Arg113*) were identified in patients in all 3 families.
Note, in the extended members of family 1, one individual is reported with polydactyly but is heterozygous for the p.Trp780* variant and one individual with polydactyly but no p.Trp780* variant is reported (possible different homozygous genetic alteration not detectable by exome sequencing?).

Polydactyly, preaxial I:
PMID: 30620395 - Ullah et al. 2019 - 1 case. Pakistani family segregating autosomal recessive form of pre‐axial polydactyly. 2 individuals from two parts of the family were sequenced and a novel homozygous missense mutation identified c.1517T>A; p.Leu506Gln) in the GLI1. The variant segregated with the disease phenotype in the family.
It was not found in their in‐house exome sequence data from 70 additional unrelated Pakistani individuals with normal limb phenotypes but was found in heterozygous state in the gnomAD browser, with an allele frequency of 0.0002109, but not in homozygous state.
Limb disorders v1.46 GLI1 Eleanor Williams gene: GLI1 was added
gene: GLI1 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: GLI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLI1 were set to 28973407; 28973407
Review for gene: GLI1 was set to AMBER
Added comment: Gene listed in Table 1 in PMID: 30945277 as associated with polydactyly.
Sources: Literature
Limb disorders v1.39 SUFU Eleanor Williams commented on gene: SUFU: Associated with Joubert syndrome 32 (#617757) in OMIM and Joubert Syndrome with Cranio-facial and Skeletal Defects in Gene2Phenotype (probable).

PMID: 28965847 - Mori et al 2017 - 2 cases. They report four children from two unrelated consanguineous families (from Italy and Egypt) carrying homozygous missense variants (c.1217T>C,p.Ile406Thr and c.1218C>G,p.Ile406Met) in SUFU. The children presented with congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and 3 had postaxial polydactyly.
In family 1, the two affected siblings also had a homozygous missense variant in CDHR1 but is expressed only in the outer nuclear layer of the retina and pathogenic variants of this gene are known to cause an autosomal-recessive form of cone-rod dystrophy with onset in the late second decade of life (older than the probands).
Functional studies on fibroblasts and cell lines showed that the mutant proteins were less stable and more rapidly degraded than SUFU WT and had impaired ability to bind GLI3 and promote its cleavage into the repressor form GLI3R, while they maintained unaltered ability to bind GLI1. These findings suggest that both variants are hypomorphic alleles, resulting only in a partial loss of the normal gene function.