Table 2.
Examples of mutations in the same genes causing different diseases, highlighting the role of NGS in uncovering pleiotropic events in neurodegenerative disorders
| Gene | Initially described in disease(s) | Type of mutation | Also found in | Type of mutation | Refs. |
|---|---|---|---|---|---|
| ATP13A2* | Kufor Rakeb syndrome (KRS, OMIM #606693) | Frameshift homozygous | Neuronal ceroid-lipofuscinosis (NCL) | Missense homozygous | (20,21) |
| NOTCH3* | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) | Missense heterozygous changing a cysteine residue in the protein | Alzheimer's disease (AD, OMIM #104300) | Missense heterozygous changing a cysteine residue in the protein | (22,23) |
| C9ORF72 | Frontotemporal dementia (FTD, OMIM #600274) and/or amyotrophic lateral sclerosis (ALS, OMIM #105400) | GGGGCC hexanucleotide intronic expansion | (17,18) | ||
| SQSTM1 | Paget disease of the bone (PDB, OMIM #602080) | Missense heterozygous; frameshift; affecting splice site | FTD and ALS | Missense heterozygous; affecting splice site | (24–27) |
| GRN* | FTD | Heterozygous null | Neuronal ceroid lipofuscinosis (CLN11, OMIM #614706) | Homozygous null | (28–30) |
| VCP* | Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD, OMIM #167320) | Heterozygous missense | ALS and hereditary spastic paraplegia | Heterozygous missense | (19,31,32) |
| PLA2G6 | Neurodegeneration with Brain Iron Accumulation 2A and 2B and Karak Syndrome (INAD, NBIA2A, OMIM # 256600 and NBIA2B, OMIM # 610217) | Missense, nonsense, splice-site, deletions, large intragenic deletions, homozygous or compound heterozygous | Adult-onset dystonia-parkinsonism (PARK14, OMIM 612953) | Homozygous and compound heterozygous missense and frameshift | (33,34) |
| PSEN1 | AD | Missense, small insertions, heterozygous | Acne inversa (ACNINV3, OMIM #613737) | Frameshift deletion | (35,36) |
| TRPV4 | Scapuloperoneal spinal muscular atrophy (SPSMA, OMIM #181405) | Missense heterozygous | Charcot-Marie-Tooth disease type 2C (HMSN2C, #606071) | Missense heterozygous | (37) |
| TPP1* | Late-infantile Neuronal Ceroid Lipofuscinosis 2 (CLN2, OMIM #204500) | Missense, nonsense, splice-site affecting, deletions, insertions and deletion–insertion homozygous or compound heterozygous | Autosomal recessive spinocerebellar ataxia 7 (SCAR7, OMIM %609270) | Compound heterozygous | (38–40) |
*Second association found by exome sequencing. Refs., references associated with the original descriptions in the different diseases.