ATN1 (aka DRPLA) Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note): CHEDDA syndrome (caused by de novo variants in exon 7). PMID: 34212383
Disease | Dentatorubral-pallidoluysian atrophy (aka DRPLA) |
|---|---|
Inheritance | Autosomal dominant |
Prevalence | 0.48:100,000 in Japanese population (highest known in the world) Source: PMID: 20301664 |
Rapid or full curation? | Rapid Full |
ClinGen - none. GenCC - supportive (orphanet). BabySeq - Moderate (7824105, 8929958, 20977674, 23263592) | |
Clinical Validity Scoring Notes and points | 7824105 - 12 families with DRPLA that included 38 affected individuals. Expanded alleles were present in all 38 affected individuals (26 segregations). Expanded alleles also detected in 5 individuals who were unaffected (ages 11-54). Normal alleles considered 7-23, expanded alleles ranged from 53-88. Patients with juvenile onset had significantly larger expansions than those with adult onset. Per fig 2, there were 17 different allele sizes in the affected individuals. These alleles are not present in gnomAD. The SOP doesn’t account for scoring triplet repeats, so I’m counting this as 0.5x17 alleles = 8.5 points for variants, 3 SEGREGATION POINTS, 8136826 (Nagafuchi 1994) - at least 13 affected segregations in 5 families in fig 1. But there is author overlap with above paper. 7951323 (Burke 1994) - A large African-American family with clinical features of DRPLA were found to have the same CAG expansion reported in the Japanese families previously reported. A LOD score of 5.52 was calculated. Six individuals were tested for the expansion, all found to have a repeat size of 63-68. I’ve already maxed out segregation, but would cite anyways since it adds to evidence. PMID: 10677044 (Schilling 1999) - DRPLA mouse model. Transgenic mice expressing full length human atrophin-1 with 65 repeats exhibit ataxia, tremors, abnormal movements, seizures and premature death. 2 POINTS - EXPERIMENTAL EVIDENCE ANIMAL MODEL 20589872 (Hasegawa 2010)- 183 patients genetically diagnosed with DRPLA. Larger repeats are associated with an earlier age of onset of clinical features. Counting as reproduced over time. Source: |
Clinical Validity Points Total | 13.5 Source: 7824105, 7951323, 10677044, 20589872 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive. Source: 7824105, 7951323, 10677044, 20589872 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function / Gain of function / Dominant Negative Repeat expansion - CAG repeats in exon 5
Literature notes: Gene Reviews PMID: 20301664 - Normal: 6-35; Full penetrance ≥48
Stripy - Normal 7-23, Full penetrance ≥49 gnomAD - Normal ≤ 23, Pathogenic ≥ 49. No alleles over 38 repeats. Many alleles between 23-30 repeats. Mayo clinic cWGS validation - Expanded: ≥49, Gray Zone: 36-48, cutoff 36 https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149 PMID: 7824105 (Komure 1995) - 38 affected individuals from 12 families. Normal alleles considered 7-23, expanded alleles ranged from 53-88 PMID: 8136826 (Nagafuchi 1994) - Five families were analyzed for the expansion in ATN1. In normal individuals the repeat size was 7-23, and expanded alleles in affected individuals was 49-75 repeats.
|
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | High Source: 20301664 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Pediatric to adulthood Source: 20301664 |
Severity Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. | Moderate to Severe Source: PMID: 20301664 |
Clinical Features | Progressive ataxia, myoclonus, epilepsy, intellectual deterioration, choreoathetosis, dementia. Sources: PMID: 20301664 |
HPO Terms |
|
Gene SOPs & Notes | Triplet repeat expansions, see molecular mechanism above |
Curation Summary - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited | The ATN1 gene is associated with autosomal dominant dentatorubral-pallidoluysian atrophy, which is characterized by progressive ataxia, myoclonus, epilepsy, intellectual deterioration, choreoathetosis, dementia. It is caused by a triplet repeat expansion of CAG in exon 5. The ATN1 gene has also been associated with autosomal dominant congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) syndrome, which is caused by de novo variants in exon 7. |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza. 09.08.2023 https://broadinstitute.atlassian.net/browse/BCL-168 |