GRN

Inheritance Pattern: AD

Disease ID:MONDO:0011842

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013866

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013866

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011842

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0013866

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030923

Submitter: ClinGen

Variants in the *GRN* gene have been reported in relation to both autosomal dominant frontotemporal dementia and autosomal recessive neuronal ceroid lipofuscinosis (NCL) (PMID: 16862116, 16862115, 22608501). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability for these assertions. Therefore, these assertions have been split into the following disease entities: autosomal dominant Amyotrophic lateral Sclerosis (ALS) and/or Frontotemporal dementia (FTD) and autosomal recessive neuronal ceroid lipofuscinosis (NCL). This curation for autosomal dominant ALS, ALS-FTD and FTD does not include probands from autosomal recessive neuronal ceroid lipofuscinosis Heterozygous loss of function variants (frameshift or nonsense) in the *GRN* gene have been commonly reported in individuals with FTD, however occasionally, missense variants seen in signal sequence or initiator codon result in low or absent PGRN protein, consistent with a loss-of-function mechanism of disease (PMIDs: 17436289, 18184915, 23596077, 32772750, 17436289, 18184915, 23596077, 32772750, 16862116, 16862115, 17436289, 18183624). In all instances of literature when available, affected probands with *GRN* variants are identified to have low or absent PGRN consistent with a loss of function mechanism of disease – including the missense variant p.Ala9Asp. With the genetic evidence available in the literature, the score for genetic evidence for the ALS, ALS-FTD cases is 2.1, this is combined with the pure FTD cases to reach the maximum score for genetic evidence reached (12 points). It is emphasized that most of the evidence is from FTD but there are a handful of cases with MND phenotype. Evidence supporting this gene disease pair also includes experimental data from human cell lines and patient fibroblasts showing low expression of PGRN protein in addition to haploinsufficient FTD mouse model (PMID: 17984093, 29874572, 23063362, 23516300). In summary, *GRN* is definitively associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0013866

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0013866

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

Variants in the *GRN* gene have been reported in relation to both autosomal dominant frontotemporal dementia and autosomal recessive neuronal ceroid lipofuscinosis (NCL) (PMID:31855245). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability for these assertions. Therefore, these assertions have been split into the following disease entities: autosomal dominant frontotemporal dementia and autosomal recessive neuronal ceroid lipofuscinosis (NCL). This curation for autosomal recessive neuronal ceroid lipofuscinosis does not include probands with autosomal dominant frontotemporal dementia. NCL is a lysosomal storage disorder. Individuals with *GRN* related NCL present with a spectrum of features including seizures, cerebellar ataxia, retinitis pigmentosa and cognitive disorders. The presence and onset of these features is variable with some individuals presenting as early as childhood and others not presenting until late adulthood (PMIDs: 31855245, 31855245 respectively). Biallelic loss of function variants have been commonly reported in individuals with disease and seven variants reported across eight probands are included in this curation (PMIDs: 22608501, 24779634, 27021778, 28000352, 30922528, 31855245). In all instances of literature when available, affected probands with *GRN* variants are identified to have low or absent progranulin with normal levels found in unaffected family members, consistent with a loss of function mechanism of disease. More genetic evidence may be available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Evidence supporting this gene disease pair also includes experimental data. Supporting experimental data in knockout mice has demonstrated that variants in this gene result in the accumulation of lipofuscin which causes NCL (PMID:28404863). In summary, there is definitive evidence supporting the relationship between *GRN* and autosomal recessive neuronal ceroid lipofuscinosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Epilepsy GCEP on the meeting date January 3, 2023. As of January 24, 2023, this record underwent an administrative update to change the disease term to a gene-agnostic term and to make minimal edits to the evidence summary for clarity (SOP Version 9).