Table 2.

Diagnostic structural variants identified by GEM in the benchmarking cohort (20 out of 119 cases). Structural variants are ranked by GEM based on the genes harbored by the variant and presented alongside other ranked genes with coding SNVs or small indels based on the top scored gene. The asterisk indicates genes that in the literature are candidates for the phenotype of the diagnostic disease/syndrome (as described in OMIM). The results show that GEM can analyze both deletions (del) and duplications (dup) of sizes as small as 4 kb and up to entire chromosome arms, diverse modes of inheritance, pedigree structure, and from either WGS or WES assay data. GEM also automatically identified compound heterozygotes between SVs and SNV/indels (cases 1, 2, and 8). Input SV calls can include breakpoint-based calls (here “SV”), or imprecise CNV calls based on read depth analysis. Notably, GEM can also infer SVs directly from the small variant data when external SV calls are not provided (cases 2, 10, 15, and 17), and score them appropriately, identifying diagnostic variants that in the original cases were found by microarrays and not by sequencing

Case no.	Top scored gene(s)	Gene rank	GEM score	Variant(s) position	SV type	Length (kb)	Mode of Inheritance	Pedigree type	Assay type	SV calls in input	Diagnosis
252268	FANCA*	1	2.28	chr16:89847864-89863349; FANCA: c.3788_3790delTCT	Del	15	Recessive	Trio	WGS	SV	Fanconi anemia
223449	TANGO2*	1	2.13	chr22:20028937-20057143; TANGO2: c.605+1G>A	Del	28	Recessive	Trio	WGS	None	MECRCN
266523	BTRC*	1	2.05	chr10:102941001-103430600	Dup	490	Dominant	Duo	WGS	SV	Split hand/foot malformation type 3
267392	HIRA, TBX1*	1	2.05	chr22:18893883-21562619	Del	2669	Dominant	Single	WES	CNV	DiGeorge syndrome; velocardiofacial syndrome
267148	KMT2A	1	1.87	chr11:116691508-126432828; chr22:17038511-20307516	Dup	9741; 3269	Dominant	Trio	WES	CNV	Emanuel syndrome
253691	HIRA, TBX1*	1	1.73	chr22:18893883-20307516	Del	1414	Dominant	Single	WES	CNV	DiGeorge syndrome; velocardiofacial Syndrome
256943	MAGEL2*	1	1.64	chr15:22833478-28566610	Del	5733	Dominant	Single	WES	CNV	Prader Willi syndrome
254012	NDUFS3*	1	1.56	chr11:47605229-47609177; NDUFS3: c.374G>A	Del	4	Recessive	Trio	WGS	SV	Leigh syndrome
254728	EPHA4	2	1.46	chr2:220309089-224580863	Del	4272	Dominant	Single	WGS	SV	Pathogenic deletion in 2q35q36.1
44671	NPAP1	1	1.42	chr15 tetrasomy (broken in multiple dups)	Dup	4542; 991; 358; 158	Dominant	Trio	WGS	None	Isodicentric chromosome 15 syndrome
360547	FREM1	1	1.33	chr9:1-18477200	Del	18,437	Dominant	Trio	WGS	SV	Chromosome 9p deletion syndrome
259685	TYROBP	1	1.31	chr19:23158251-33502767	Dup	10,345	Dominant	Trio	WES	SV	Partial trisomy 19p12.q13.11
266700	TAB2	1	1.31	chr6:144951601-150260400	Del	5309	Dominant	Trio	WGS	SV	Chromsome 6q24-q25 Syndrome
244102	MAGEL2*	1	1.28	chr15:23684685-26108259	Del	2424	Dominant	Single	WES	CNV	Prader Willi syndrome
204560	JAG1*	2	1.21	chr20:10471400-13459333	Del	44	Dominant	Trio	WGS	None	Alagille syndrome
246146	HCN1	1	1.20	chr5:213101-46,270,700	Dup	44	Dominant	Single	WGS	SV	Trisomy 5p
45020	PCDH19*	1	1.15	chrX:92925011-99669272	Del	6744	X-linked dominant	Trio	WGS	None	Developmental and epileptic encephalopathy 9
248678	FANCC*	1	1.14	chr9:97998556-98009092	Del	11	Recessive	Single	WGS	SV	Fanconi Anemia
352726	THRA	1	1.00	chr17:32147833-79020944	Dup	46,873	Dominant	Proband	WGS	SV	Distal trisomy 17q
251355	TRIP11	4	0.58	chr14:84783523-96907490	Del	12,124	Dominant	Duo	WGS	SV	Chromosome 14q31.2q32.2 Syndrome