Caution about AR expansions esp. interruptions

data/STRchive-database.csv

@@ -2,7 +2,7 @@ chrom,start_hg38,stop_hg38,start_hg19,stop_hg19,start_t2t,stop_t2t,notes_t2t,id,
 chr1,94418422,94418444,94883978,94884000,94266545,94266567,,OPDM_ABCD3,OPDM,+,GCC,GCC,CCG,,,,,Oculopharyngodistal myopathy,ABCD3,,(GCC)*,AD,5' UTR,,3-44,3.0,44.0,,,,118-694,118.0,694.0,7.7,3,Typical: 24-30; Range: 10-50 (doi.org/10.1101/2023.10.09.23296582),10,50,,,,,,,https://doi.org/10.1101/2023.10.09.23296582,,,,,,Unknown,,,,2023.0
 chrX,148500605,148500753,147582125,147582273,146765191,146765342,(GCC)51.3,FRAXE_AFF2,FRAXE,+,GCC,GCC,CCG,,,,,"Fragile X syndrome, FRAXE type",AFF2,,(GCC)*,XR,5' UTR,5’ Region,4-39,4.0,39.0,,,,200-2000,200.0,2000.0,50.3,3,Typical: 2-10; Range: 1-10 (developmental delays without physical features can make onset difficult to detect until schooling),1,10,2.0,10.0,ref,"LOF, reduced gene expression",Loss of function via transcriptional silencing,(doi.org/10.1038/nrg1691) (doi.org/10.1007/s11604-022-01343-5),"Mirkin 2007, OMIM, GeneReviews NBK535148",,,148.0,309548,2/50000,"1-4/100,000 males (https://medlineplus.gov/genetics/condition/fragile-xe-syndrome); 1/50-100,000 males, more than 50 families (PMID: 11246464)",AFF2,AFF2,NBK535148,1993.0
 chr2,100104799,100104824,100721261,100721286,100563686,100563738,(GCC)17.7,FRA2A_AFF3,FRA2A,-,GCC,GCC,CGG,,,,,Intellectual disability associated with fragile site FRA2A,AFF3,,(GCC)*,AD,Intronic,Intron ,3-20,3.0,20.0,,,,300,300.0,300.0,8.7,3,Early childhood (small sample size) (PMID: 24763282),1,7,,,ref,"Decreased gene expression, methylation","""silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene""",malacard,"https://doi.org/10.1038/s41580-021-00382-6, PMC3998887","Path threshold may actually be higher than 300, assay was not sensitive enough",,25.0,601464,,1/862 (1/654-1266) population prevalence of methylated AFF3 expansions (mild cognitive disability) https://www.medrxiv.org/content/10.1101/2023.05.03.23289461v1.full.pdf,,,,2014.0
-chrX,67545317,67545419,66765159,66765261,65975148,65975250,(GCA)33.3,SBMA_AR,SBMA,+,GCA,GCA,AGC,,,,,"Spinal and bulbar muscular atrophy, Kennedy Disease",AR,,(GCA)*,XR,Coding,Exon 1,9–34,9.0,34.0,36-37,36.0,37.0,38–68,38.0,68.0,34.0,3,"Typical: 20-49 (OMIM), Range: 8(PMID: 15851746)-78 (PMID: 19227892)",8,78,20.0,49.0,ref,Polyglutamine,Polyglutamine,(doi.org/10.1038/nrg.2017.115) (doi.org/10.1007/s11604-022-01343-5),"Hannan 2018, Mirkin 2007, GeneReviews NBK535148, s40478-021-01201-x, doi.org/10.1016/j.neurol.2017.03.019, doi.org/10.1016/j.pneurobio.2012.05.007, doi.org/10.1111/odi.12121, DOI: 10.1007/s00415-018-8968-7, DOI: 10.1007/s12031-015-0684-5",Possibility that contractions may play a role in disease (PMID: 10398229). May be subclinical in females (PMID: 34922802). Interruptions are not found and thus appear not to play a role in disease (PMID: 24041967). Can be clinically heterogeneous even within the same family (PMID: 20184516); may present with clinical heterogeneity.,First triplet disease to be discovered (doi:10.1001/archneur.61.8.1324),102.0,313200,1/30000,"1-2/100,000 (population-specific, higher in Finnish population, Canadian population) (PMID: 37628685); 1/30,000  (Orphanet) ; mutation frequency of 1:3182 10x more frequent than reported disease prevalence of 1 in 30,000 (PMID: 36797998); Tang et al., 2017: 0.67-2.5/100,000",AR,AR,NBK1333,1991.0
+chrX,67545317,67545419,66765159,66765261,65975148,65975250,(GCA)33.3,SBMA_AR,SBMA,+,GCA,GCA,AGC,,,,,"Spinal and bulbar muscular atrophy, Kennedy Disease",AR,,(GCA)*,XR,Coding,Exon 1,9–34,9.0,34.0,36-37,36.0,37.0,38–68,38.0,68.0,34.0,3,"Typical: 20-49 (OMIM), Range: 8(PMID: 15851746)-78 (PMID: 19227892)",8,78,20.0,49.0,ref,Polyglutamine,Polyglutamine,(doi.org/10.1038/nrg.2017.115) (doi.org/10.1007/s11604-022-01343-5),"Hannan 2018, Mirkin 2007, GeneReviews NBK535148, s40478-021-01201-x, doi.org/10.1016/j.neurol.2017.03.019, doi.org/10.1016/j.pneurobio.2012.05.007, doi.org/10.1111/odi.12121, DOI: 10.1007/s00415-018-8968-7, DOI: 10.1007/s12031-015-0684-5",Possibility that contractions may play a role in disease (PMID: 10398229). May be subclinical in females (PMID: 34922802). Interruptions are not found and thus appear not to play a role in disease (PMID: 24041967). Can be clinically heterogeneous even within the same family (PMID: 20184516); may present with clinical heterogeneity.,Expansions larger than the pathogenic threshold in the AR gene should be evaluated carefully. Interruptions have not been observed in patient cases and it has been proposed that longer alleles with interruptions may not be pathogenic (PMID: 24041967). Expansions are also detected ten-fold more often in a general population than would be expected by disease prevalence  (PMID: 36797998). Clinical evaluation and phenotypic matching may be necessary to determine diagnosis even in the presence of a pure expanded allele. AR was the first triplet disease to be discovered (doi:10.1001/archneur.61.8.1324),102.0,313200,1/30000,"1-2/100,000 (population-specific, higher in Finnish population, Canadian population) (PMID: 37628685); 1/30,000  (Orphanet) ; mutation frequency of 1:3182 10x more frequent than reported disease prevalence of 1 in 30,000 (PMID: 36797998); Tang et al., 2017: 0.67-2.5/100,000",AR,AR,NBK1333,1991.0
 chrX,25013649,25013697,25031766,25031814,24597886,24597934,(GCC)14.7,EIEE1_ARX,EIEE1,-,NGC,NGC,CNG,,,,,Early-infantile epileptic encephalopathy,ARX,,(NGC)*,XR,Coding,Exon 2,10-16,10.0,16.0,,,,17-27,17.0,27.0,14.7,3,"Typical: 0 (PMID: 21204215, PMID: 9307258, OMIM); Range: 0-4 (Childhood epilepsy, cognitive disability,  ∼70% of cases infantile spasms -->  seizures by 3 or 4 years re: PMID: 19587282)",0,4,0.0,0.0,ref,Polyalanine,Polyalanine,(doi.org/10.1038/nature05977) (doi.org/10.1007/s11604-022-01343-5),"GeneReviews NBK535148, OMIM",Exon 2 aa 110-115,"ARX expansions result in a range of phenotypes such as Partington syndrome (OMIM 309510), Early Infantile Epileptic Encephalopathy (OMIM 308350), Agenesis of Corpus Callosum with Abnormal Genitalia (OMIM 300004), and X-Linked Lissencephaly with Ambiguous Genitalia (OMIM 300215) as described in 10.1002/mgg3.133 and 10.1002/humu.21288",43.0,308350; 300419; 300215,,Unknown,ARX_1,ARX_1,NBK535148,
 chrX,25013530,25013565,25031647,25031682,24597767,24597799,(GGCCGCGGCGGCCGC)2.2,PRTS_ARX,PRTS,-,NGC,NGC,CNG,,,,,Partington syndrome,ARX,,(NGC)*,XR,Coding,Exon 2,12,12.0,12.0,,,,20,20.0,20.0,12.0,3,Typical: 1-3; Range: 0-4 (OMIM); Mildness can make diagnosis difficult (particularly mild/absent in females) ,0,4,,,ref,Polyalanine,Polyalanine,(OMIM) (doi.org/10.1007/s11604-022-01343-5),"GeneReviews NBK535148, OMIM","Novel, Exon 2 aa 144-155","ARX expansions result in a range of phenotypes such as Partington syndrome (OMIM 309510), Early Infantile Epileptic Encephalopathy (OMIM 308350), Agenesis of Corpus Callosum with Abnormal Genitalia (OMIM 300004), and X-Linked Lissencephaly with Ambiguous Genitalia (OMIM 300215) as described in 10.1002/mgg3.133 and 10.1002/humu.21288",35.0,309510,,Unknown,ARX_2,ARX_2,NBK535148,
 chr12,6936717,6936775,7045880,7045938,6947904,6947941,(CAG)12.7,DRPLA_ATN1,DRPLA,+,CAG,CAG,AGC,,,,,Dentatorubral-Pallidoluysian Atrophy,ATN1,,(CAG)*,AD,Coding,Exon 5,3–35,3.0,35.0,,,,48-93,48.0,93.0,19.0,3,"Typical: 20-40 (PMID: 6808417, NBK1491); Range: 0 (PMID: 11160976) - 72 (NBK1491)",0,72,20.0,40.0,ref,Polyglutamine,Polyglutamine,(doi.org/10.1038/nrg.2017.115) (doi.org/10.1007/s11604-022-01343-5),"Hannan 2018, Mirkin 2007, GeneReviews NBK535148, s40478-021-01201-x",Interruptions: CAA (PMID: 35245110),,58.0,125370,4.5/1000000,"2-7/1,000,000",ATN1,ATN1,NBK1491,1994.0

data/STRchive-database.json

@@ -221,7 +221,7 @@
         "Mechanism_source":"(doi.org\/10.1038\/nrg.2017.115) (doi.org\/10.1007\/s11604-022-01343-5)",
         "source":"Hannan 2018, Mirkin 2007, GeneReviews NBK535148, s40478-021-01201-x, doi.org\/10.1016\/j.neurol.2017.03.019, doi.org\/10.1016\/j.pneurobio.2012.05.007, doi.org\/10.1111\/odi.12121, DOI: 10.1007\/s00415-018-8968-7, DOI: 10.1007\/s12031-015-0684-5",
         "notes":"Possibility that contractions may play a role in disease (PMID: 10398229). May be subclinical in females (PMID: 34922802). Interruptions are not found and thus appear not to play a role in disease (PMID: 24041967). Can be clinically heterogeneous even within the same family (PMID: 20184516); may present with clinical heterogeneity.",
-        "details":"First triplet disease to be discovered (doi:10.1001\/archneur.61.8.1324)",
+        "details":"Expansions larger than the pathogenic threshold in the AR gene should be evaluated carefully. Interruptions have not been observed in patient cases and it has been proposed that longer alleles with interruptions may not be pathogenic (PMID: 24041967). Expansions are also detected ten-fold more often in a general population than would be expected by disease prevalence  (PMID: 36797998). Clinical evaluation and phenotypic matching may be necessary to determine diagnosis even in the presence of a pure expanded allele. AR was the first triplet disease to be discovered (doi:10.1001\/archneur.61.8.1324)",
         "width":102.0,
         "OMIM":"313200",
         "Prevalence":"1\/30000",