Early onset or syndromic epilepsy

Gene: PARP6

Comment on list classification: New gene added by Zornitza Stark. At least 3 individuals with heterozygous PARP6 variants and a relevant phenotype have been reported (PMID: 34067418) - however, segregation analysis has only been complete for one of these cases. Furthermore, identification of two sibs with biallelic variants and unaffected parents who were heterozygous carriers arises possibility of incomplete penetrance or role of variants in other genes.

Overall there is not enough evidence to add this gene as diagnostic grade, so rating Amber with watchlist tag.

Created: 13 Sep 2021, 3:08 p.m. | Last Modified: 13 Sep 2021, 3:08 p.m.

Panel Version: 3.1263

Vermehren-Schmaedick et al., 2021 (PMID: 34067418) describe four unrelated individuals with heterozygous variants in this gene, but without complete segregation studies in at least two of these families. Seizures and mild to severe GDD since early infancy with speech delay and learning disabilities were noted in 3/4 individuals, of which two had ID. Notably, one patient had normal psychomotor development. Furthermore, two sibs with compound het variants inherited from unaffected parents were also identified displaying GDD, epilepsy and various anomalies on brain imaging. Studies in primary rat hippocampal neurons of two variants, both located in the catalytic domain of PARP6, demonstrated opposite effects on dendritic complexity - with one variant increasing and the other decreasing complexity compared to controls.

This gene-disease association is described in OMIM but is currently pending confirmation. PARP6 is not yet listed in G2P and no further reports linking variants in this gene with disease have been published to date.

Created: 13 Sep 2021, 2:39 p.m. | Last Modified: 13 Sep 2021, 2:39 p.m.

Panel Version: 3.1262

Publications

• 34067418

Green List (high evidence)

Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature

Created: 11 Jun 2021, 9:38 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; Epilepsy; Microcephaly

Publications

• 34067418