WGS Multi-Region Joint Detection

Generated on 2026-05-11 Revised on 2026-06-07

Multi-Region Joint Detection

DRAGEN Multi-Region Joint Detection (MRJD) is a de novo germline small variant caller for paralogous regions. For standard short-read sequencing data, MRJD covers six clinically relevant genes: NEB, TTN, SMN1/2, PMS2, STRC, and IKBKG. MRJD is compatible with the hg38, hg19, and GRCh37 reference genomes. The table below lists the hg38 region coordinates covered by MRJD. For more information, refer to the DRAGEN user guide.

hg38 region coordinates covered by MRJD (click to expand)

Chromosome	Start	End	Description
chr2	151578759	151588523	NEB exon 98-105
chr2	151589318	151599076	NEB exon 90-97
chr2	151599871	151609628	NEB exon 82-89
chr2	178653238	178654995	TTN exon 172-180
chr2	178657498	178659255	TTN exon 181-189
chr2	178661759	178663516	TTN exon 190-198
chr5	70049522	70077596	SMN2
chr5	70924940	70953013	SMN1
chr7	5970924	5980896	PMS2 exon 13-15
chr7	5980968	5987689	PMS2 exon 11-12
chr7	6737007	6743712	PMS2CL exon 2-3
chr7	6743880	6753867	PMS2CL exon 4-6
chr15	43599563	43602630	STRC exon 24-29
chr15	43602982	43611000	STRC exon 14-23
chr15	43611040	43618800	STRC exon 1-13
chr15	43699379	43702452	STRCP1 exon 23-28
chr15	43702488	43710472	STRCP1 exon 13-22
chr15	43710502	43718262	STRCP1 exon 1-12
chrX	154555884	154565047	IKBKG exon 3-10
chrX	154639390	154648553	IKBKGP1

MRJD performance on cell line samples

We benchmarked MRJD variant calling performance in the PMS2 high-homology region using 147 cell line samples from the Illumina Polaris 1 diversity panel¹. Ground truth was established using orthogonal small variant calls derived from long-range PCR data. MRJD high sensitivity mode achieves aggregated recall of approximately 99.7% for SNVs and 97.1% for indels. The lower indel recall likely reflects the higher indel error rate of long-range PCR data. To address this limitation, we performed a concordance analysis against a long-read-based approach² using a separate set of 147 cell line samples representing diverse ancestries from the 1000 Genomes Project. Aggregated recall against the long-read-based approach exceeds 99% for both SNVs and indels.

The high recall of MRJD high sensitivity mode is achieved by reporting all possible variants across paralogous regions, which lowers precision. To measure the spurious call rate, we compared merged orthogonal variant calls in both PMS2 and PMS2CL against MRJD high sensitivity mode calls in PMS2 alone. The spurious call rate is below 0.7%, indicating that nearly all reported alleles are present in the samples but are reported at both locations by MRJD high sensitivity mode (ambiguous placement).

We further benchmarked MRJD performance across all six genes covered by MRJD. The results are shown in Figure 1. MRJD high sensitivity mode achieves aggregated recall between 96.5% and 100% for both SNVs and indels across all six genes, which is significantly higher than the recall from MRJD default mode.

MRJD performance on all six genes

Figure 1. Aggregated SNV and indel performance across the six genes covered by MRJD, comparing MRJD default mode and MRJD high sensitivity mode on more than 100 diverse cell line samples from the 1000 Genomes Project. Orthogonal small variant calls were derived from a long-read-based approach. Benchmark statistics were generated using RTG Tools ploidy-squash mode. All perfect homopolymers > 6 bp and imperfect homopolymers > 10 bp were excluded from the analysis.

For details on MRJD calling in high sensitivity mode, refer to the DRAGEN user guide.

Non-cell-line validation

We also validated MRJD performance on 22 non-cell-line samples from Broad Clinical Labs and Tempus AI. MRJD detected all expected clinically relevant small variants in these samples.

Non-cell-line validation

Table 1: MRJD high sensitivity mode results on 22 non-cell-line samples with potentially clinically relevant variants. All listed variants were orthogonally confirmed and localized to PMS2, PMS2CL, or NEB. Results were provided by Broad Clinical Labs and Tempus AI.

References

¹Gould GM, Gauman PV, Theilmann MR, et al. Detecting clinically actionable variants in the 3′ exons of PMS2 via a reflex workflow based on equivalent hybrid capture of the gene and its pseudogene. BMC Med Genet. 2018;19(1):176. doi:10.1186/s12881-018-0691-9

²Chen X, Harting J, Farrow E, et al. Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing. Am J Hum Genet. 2023;110(2):240-250. doi:10.1016/j.ajhg.2023.01.001