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Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to X-linked: hemizygous mutation in males, monallelic mutations in females after advice from the Genomics England clinical team. There are 5 reported relevant cases in females.
Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Non-syndromic familial congenital anorectal malformations v1.7 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as biallelic in females just now but noting that a few female cases have been reported, mainly with skewed x-chromosome inactivation.
Non-syndromic familial congenital anorectal malformations v1.7 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams changed review comment from: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and 1 additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.; to: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and one of the three additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams commented on gene: MED12: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and 1 additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.
Non-syndromic familial congenital anorectal malformations v0.108 MED12 Eleanor Williams Marked gene: MED12 as ready
Non-syndromic familial congenital anorectal malformations v0.108 MED12 Eleanor Williams Gene: med12 has been classified as Green List (High Evidence).
Non-syndromic familial congenital anorectal malformations v0.108 MED12 Eleanor Williams commented on gene: MED12: Note that in Gene2Phenotype the Mutation consequence summary is "uncertain".
Non-syndromic familial congenital anorectal malformations v0.103 MED12 Charles Shaw-Smith reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: FG syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Non-syndromic familial congenital anorectal malformations v0.103 MED12 Charles Shaw-Smith reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Mode of inheritance:
Non-syndromic familial congenital anorectal malformations v0.78 MED12 Eleanor Williams Phenotypes for gene: MED12 were changed from anorectal malformation to anorectal malformation; Opitz-Kaveggia syndrome 305450; FG SYNDROME 1; FG SYNDROME
Non-syndromic familial congenital anorectal malformations v0.77 MED12 Eleanor Williams Publications for gene: MED12 were set to
Non-syndromic familial congenital anorectal malformations v0.76 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Non-syndromic familial congenital anorectal malformations v0.75 MED12 Eleanor Williams Classified gene: MED12 as Green List (high evidence)
Non-syndromic familial congenital anorectal malformations v0.75 MED12 Eleanor Williams Added comment: Comment on list classification: Rated green as more than 3 families with the R961W variant show a relevant phenotype.
Non-syndromic familial congenital anorectal malformations v0.75 MED12 Eleanor Williams Gene: med12 has been classified as Green List (High Evidence).
Non-syndromic familial congenital anorectal malformations v0.74 MED12 Eleanor Williams commented on gene: MED12: MED12 is associated with Opitz-Kaveggia syndrome (also known as FG syndrome and FG syndrome 1) in OMIM and Gene2Phenotype (confirmed). Opitz-Kaveggia syndrome (OKS) is an X-linked recessive mental retardation syndrome characterized by dysmorphic features, but phenotypes relevant to this panel also include anal stenosis, imperforate anus anteriorly placed anus and constipation.

As stated in OMIM Risheg et al 2007 (PMID: 17334363) reported that the original family from which the designation FG was derived and 5 other families had a recurrent mutation in the MED12 gene, R961W. Imperforate anus, wide flat thumbs, and wide great toes were present in 7 of 10 cases. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor.

Ding et al. (2008) (PMID: 18691967) showed that the R961W substitution disrupt the REST corepressor function of MED12.

Other variants in MED12 are linked to other syndromes such as LUJAN-FRYNS SYNDROME and OHDO SYNDROME, X-LINKED.
Non-syndromic familial congenital anorectal malformations v0.53 MED12 Eleanor Williams Classified gene: MED12 as Amber List (moderate evidence)
Non-syndromic familial congenital anorectal malformations v0.53 MED12 Eleanor Williams Added comment: Comment on list classification: Rated gene amber as is on expert list
Non-syndromic familial congenital anorectal malformations v0.53 MED12 Eleanor Williams Gene: med12 has been classified as Amber List (Moderate Evidence).
Non-syndromic familial congenital anorectal malformations v0.52 MED12 Eleanor Williams commented on gene: MED12
Non-syndromic familial congenital anorectal malformations v0.48 MED12 Eleanor Williams Added phenotypes anorectal malformation for gene: MED12
Non-syndromic familial congenital anorectal malformations v0.47 MED12 Eleanor Williams gene: MED12 was added
gene: MED12 was added to Non-syndromic familial congenital anorectal malformations. Sources: Expert list
Mode of inheritance for gene: MED12 was set to
Phenotypes for gene: MED12 were set to anorectal malformation