Tertiary analysis of STR variants

Short tandem repeats (STRs) are genomic regions composed of repeated short DNA sequences. When STRs expand beyond the normal range, they can cause mutations known as repeat expansions, which may alter gene expression or function.

Expansion of these sequences in certain genes is the underlying mechanism for a group of inherited conditions called repeat expansion disorders. These disorders primarily affect the nervous and muscular systems, leading to diseases such as Fragile X syndrome, amyotrophic lateral sclerosis and Huntington’s disease.

The platform shows repeat counts per allele and highlights values that fall in normal, intermediate or pathogenic ranges (where known).

STR loci filtering and prioritization

STR variants outside the genomic regions specified in the DRAGEN v4.2 expanded variant catalog are excluded before tertiary analysis. This applies regardless of whether DRAGEN (internal or external) or another pipeline was used for the secondary analysis and irrespective of the DRAGEN version.

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Variant calling reliability and availability of meaningful annotations for STR loci can vary. To reduce noise and ensure high-confidence calls, only a curated subset of STR loci is included in AI Shortlist analysis (Table 1). STR loci were curated by Emedgene based on strict criteria to ensure technical accuracy:

• Validated genotype–phenotype associations and established pathogenicity. Loci must have well-documented links to disease and specific phenotypes. This avoids reporting variants with unclear implications.

• Reliable calling performance. STR calling is technically challenging. Some loci are prone to false positives or inaccurate sizing. The subset includes loci that DRAGEN-STR can call consistently and accurately. This avoids reporting low-quality variants.

• Expansion thresholds. Loci with defined pathogenic thresholds (e.g., number of repeats linked to disease) are prioritized. This avoids reporting variants that lack clear interpretation guidelines.

STRs that are not tagged by AI Shortlist are still included in the analysis. This means they will not be automatically prioritized or tagged as Most Likely or Candidate by the AI. However, these loci remain available for manual review and tagging.

Table 1. STR loci considered by AI Shortlist

№

STR locus

Genomic region (hg38)

Associated condition(s)

Inheritance mode

Repeat unit

1	AR	X:67545316-67545385	Spinal and bulbar muscular atrophy (SBMA)	XR	GCA
2	ATN1	12:6936716-6936773	Dentatorubral-pallidoluysian atrophy (DRPLA)	AD	CAG
3	ATN1	12:6923960-6923977			TG
4	ATN1	12:6925117-6925140			GT
5	ATN1	12:6930800-6930827			AATA
6	ATXN1	6:16327633-16327723	Spinocerebellar ataxia 1 (SCA1)	AD	TGC
7	ATXN10	22:45795354-45795424	Spinocerebellar ataxia 10 (SCA10)	AD	ATTCT
8	ATXN2	12:111598949-111599018	Spinocerebellar ataxia 2 (SCA2)	AD	GCT
9	ATXN2	12:111461472-111461481			AAAAT
10	ATXN2	12:111464247-111464282			GT
11	ATXN2	12:111483194-111483237			AC
12	ATXN2	12:111487453-111487472			TTTA
13	ATXN2	12:111568991-111569015			TTTTG
14	ATXN2	12:111577256-111577279			TTAT
15	ATXN2	12:111588188-111588219			AAAT
16	ATXN2	12:111591364-111591375			TAAAAA
17	ATXN2	12:111591756-111591773			TTG
18	ATXN2	12:111596205-111596244			AC
19	ATXN2	12:111596373-111596388			CA
20	ATXN2	12:111600935-111600958			AAAT
21	ATXN2	12:111604087-111604106			AT
22	ATXN3	14:92071009-92071041	Spinocerebellar ataxia 3 (SCA3)	AD	GCT
23	ATXN3	14:92059829-92059848			AAAG
24	ATXN3	14:92065889-92065900			AAT
25	ATXN3	14:92078361-92078376			TTAT
26	ATXN7	3:63912684-63912714	Spinocerebellar ataxia 7 (SCA7)	AD	GCA
27	ATXN7	3:63912714-63912725			GCC
28	ATXN8OS	13:70139383-70139428			CTG
29	ATXN8OS	13:70139353-70139382	Spinocerebellar ataxia 8 (SCA8)	AD	CTA
30	ATXN8OS	13:70115027-70115046			GT
31	ATXN8OS	13:70126607-70126620			TA
32	ATXN8OS	13:70129375-70129402			TG
33	C9ORF72	9:27573528-27573546	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1)	AD	GGCCCC
34	CACNA1A	19:13207858-13207897	Spinocerebellar ataxia 6 (SCA6)	AD	CTG
35	CNBP	3:129172576-129172656			CAGA
36	DMPK	19:45770204-45770264	Myotonic dystrophy 1 (DM1)	AD	CAG
37	FMR1	X:147912050-147912110	Fragile X syndrome (FXS)	XD	CGG
38	FXN	9:69037286-69037304			GAA
39	FXN	9:69037261-69037285	Friedreich ataxia (FRDA)	AR	A
40	HTT	4:3074876-3074933	Huntington disease (HD)	AD	CAG
41	HTT	4:3074939-3074965			CCG
42	JPH3	16:87604287-87604329	Huntington disease-like 2 (HDL2)	AD	CTG
43	NOP56	20:2652733-2652757	Spinocerebellar ataxia 36 (SCA36)	AD	GGCCTG
44	NOP56	20:2652757-2652774			CGCCTG
45	PPP2R2B	5:146878727-146878757	Spinocerebellar ataxia 12 (SCA12)	AD	GCT
46	TBP	6:170561906-170562017	Spinocerebellar ataxia 17 (SCA17)	AD	GCA