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Intellectual disability v2.718 CCDC47 Louise Daugherty Classified gene: CCDC47 as Green List (high evidence)
Intellectual disability v2.718 CCDC47 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Intellectual disability v2.718 CCDC47 Louise Daugherty Gene: ccdc47 has been classified as Green List (High Evidence).
Intellectual disability v2.717 CCDC47 Louise Daugherty commented on gene: CCDC47: Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto el al., 2018)
Intellectual disability v2.717 CCDC47 Louise Daugherty Added comment: Comment on phenotypes: Added OMIM phenotype and MIMid
Intellectual disability v2.717 CCDC47 Louise Daugherty Phenotypes for gene: CCDC47 were changed from Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability; Trichohepatoneurodevelopmental syndrome, 618268
Intellectual disability v2.583 CCDC47 Konstantinos Varvagiannis gene: CCDC47 was added
gene: CCDC47 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC47 were set to 30401460
Phenotypes for gene: CCDC47 were set to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability
Penetrance for gene: CCDC47 were set to Complete
Review for gene: CCDC47 was set to GREEN
Added comment: Morimoto el al. (PMID: 30401460) report on 4 individuals from 4 unrelated families with biallelic LoF variants in CCDC47. The phenotype consisted of abnormal (woolly) hair, liver dysfunction, common facial features as well as DD/ID.

The patients were found to harbor the variants in compound heterozygous or more commonly in homozygous state (due to consanguinity and/or common ancestry). 4 loss-of-function variants are reported in total (using NM_020198.2 as a reference):
- c.811C>T or p.(Arg271*) [consanguineous family of Turkish origin]
- c.1145delT or p.(Leu382Argfs*2) [probably a founder mutation in Amish]
- c.1165delT or p.(Ser389Leufs*25)
- c.1189C>T or p.(Arg397*)

Decreased mRNA levels in fibroblasts/lymphoblastoid cells were shown as well as absence of the protein upon Western blot using antibodies recognizing the N and C terminus (thus suggesting NMD).

Localization of CCDC47 in the ER was demonstrated with perturbed Ca+2 homeostasis and signalling in the ER.

Ccdc47-knockout mice present features similar to the human phenotypes eg. growth, neurological as well as heart anomalies. In mice embryonic/neonatal lethality was noted in some cases which might be associated with recurrent miscarriages reported in 3 patient families.

CCDC47 is not associated with any phenotype in G2P or OMIM.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature