Table 3.
Causative variants and variants of uncertain significance (VUS) identified in genes previously known to be associated with neurological phenotypes.
| Family code | Inheritance pattern | Gene | Variant | ACMG class for point mutations / Conclusion from other criteria | ACMG criteria |
|---|---|---|---|---|---|
| Families in which the candidate variant explains the disease in all the patients | |||||
| F8 | AR homozygous | SIL1 | NM_001037633.2:c.767 + 1 G > A (splice-site) | Pathogenic | PVS1, PM2, PP1, PP4 |
| F27 | AR compound heterozygous | ERCC8 | NM_000082.4:c.523 T > C (p.Ser175Pro) / NM_000082.4:c.572_574del (p.Ala191del) | Likely pathogenic/likely pathogenic | PM2, PP1, PP3, PP4 / PM2, PP1, PP3, PP4, BP3 |
| F31 | AR homozygous | VLDLR | NM_003383.5:c.2144 G > A (p.Cys715Tyr) | Likely pathogenic | PP1 (moderate), PM2, PP3, PP4 |
| F38 | AR homozygous | FXN | GAA repeat expansion (a single patient tested but phenotype compatible in other patients) | Not applicable/Toxic expansion | |
| F49 | AD | ATXN3 | CAG repeat expansion (73 + /−3 CAG) | Not applicable/Toxic expansion | _ |
| F53 | AR compound heterozygous | SPG11 | NM_025137.4:c.2399del (p.Tyr800Phefs*19) / NM_025137.4:c.6739_6742del (p.Glu2247Leufs*14) | Pathogenic/pathogenic | PVS1, PM2, PM3, PP1/ PVS1, PM2, PP1, PP5 |
| F57 | AR homozygous | SACS | NM_014363.6:c.10444_10447del (p.Leu3482Glnfs*12) | Pathogenic | PVS1, PM2, PP1 |
| F59 | AR homozygous | NT5C2 | NM_001351171.2:c.175 + 1 G > A (splice-site) | Pathogenic | PVS1, PM2, PP1, PP5 |
| F61 | AR homozygous | FA2H | NM_024306.5:c.674 T > C (p.Leu225Pro) | Likely pathogenic | PP1 (strong), PM2, PP3, PP4 |
| F62 | AR homozygous | ERCC6 | NM_000124.4:c.4063–1 G > C (splice-site) | Pathogenic | PVS1, PM2, PP1, PP4, PP5 |
| F63 | AR homozygous | ADAT3 | NM_138422.4:c.430 G > A (p.Val144Met) | Pathogenic | PM2, PP1 (strong), PS3, PP3, PP4, PP5 |
| F66 | AR homozygous | DMXL2 | NM_001174116.3:c.5020 A > C (p.Lys1674Gln) | VUS | PM2, PP1, PP3, BP1 |
| F67 | AR homozygous | MFSD8 | NM_152778.3:c.753 A > G (p.Glu251Glu) (splice site) | VUS | PM2 |
| F68 | AR homozygous | FA2H | NM_024306.5:c.674 T > C (p.Leu225Pro) | Likely pathogenic | PP1 (strong), PM2, PP3, PP4 |
| F76 | AR homozygous | DDHD2 | NM_015214.3:c.985 C > T (p.Arg329*) | Pathogenic | PVS1, PM2, PP5, PP1, PP3 |
| F78 | AR homozygous | ZFYVE26 | NM_015346.4:c.1254dup (p.Cys419Valfs*61) | Pathogenic | PVS1, PM2, PP1, PP3 |
| F79 | AR homozygous / X-linked | HERC2/ATP2B3 | NM_004667.6:c.10855 C > T (p.Pro3619Ser)/ NM_021949.3:c.2086 C > T (p.Arg696Cys) | VUS/VUS | PM2, PP3 / PM2, PP3 |
| F81 | AR homozygous | CCDC82 | NM_001318736.2:c.535 C > T (p.Arg179*) | Pathogenic | PVS1, PM2, PP1 |
| F82 | X-linked (likely de novo) | HUWE1 | NM_031407.7:c.12639 G > A (p.Met4213Ile) | Likely pathogenic | PM1, PM2 |
| F83 | AD (likely de novo) | CCDC88C | NM_001080414.4:c.1993G > A (p.Glu665Lys) | Likely pathogenic | PS3, PM2, PP3 |
| F84 | AR homozygous | MCOLN1 | NM_020533.3:c.514 C > T (p.Arg172*) | Pathogenic | PVS1, PP5, PM2, PP1 |
| FM3 | AR homozygous | PRUNE1 | NM_021222.3:c.132 + 2 T > C (splice-site) | Pathogenic | PVS1, PM2, PP1 |
| FM6 | AR compound heterozygous | DARS2 | NM_018122.5:c.1762C > G (p.Leu588Val) / NM_018122.5:c.563 G > A (p.Arg188Gln) | Likely pathogenic/likely pathogenic | PM2, PP1 (moderate), PP3, PP4, PP5 / PM2, PP1 (moderate), PP3, PP4 |
| Families in which the candidate variant explains the disease only in a proportion of the patients | |||||
| F41 | AD (likely de novo) | NF1 | NM_001042492.3:c.187_188del (p.Lys63Glufs*3) | Pathogenic | PVS1, PM2, PM6 |
| F54 | AR homozygous | AP5Z1 | NM_014855.3:c.1132 G > A (p.Gly378Arg) (splice-site) | Likely pathogenic | PVS1, PM2 |
| F70 | AR homozygous | POLR3A | NM_007055.4:c.1771–7 C > G (splice-site) | Likely pathogenic | PP1 (strong), PS3, PM2, PP5 |
| F80 | AR homozygous | NT5C2 | NM_001134373.3:c.629del (p.Tyr210Serfs*17) | Pathogenic | PVS1, PM2, PP3 |
| F85 | AR homozygous | PTPRQ | NM_001145026.2:c.5893 C > A (p.Pro1965Thr) | VUS | PM2, PP3 |
AR Autosomal recessive, AD Autosomal dominant, PVS1 null variant in a gene where loss of function is a known disease mechanism, PS3 well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product, PM1 located in a mutational hot spot or well-established critical protein domain without benign variation, PM2 absent or have low frequency in gnomAD public database, PM3 detected in trans with a pathogenic variant, PM6 assumed de novo, PP1 cosegregate with disease in multiple affected family members, PP3 multiple lines of computational evidence support a deleterious effect, PP4 Patients’ phenotype or family history is highly specific for a disease with a single genetic etiology, PP5 reported as deleterious by a reputable source.