ScisGo-FcR/IGHG-v2

High resolution genotyping of FcR and IGHG for diagnostics and therapeutics with ScisGo-FcR/IGHG-v2

ScisGo-FcR-IGHG technology utilizes existing data sets at the IMGT and the NCBI genbank repository supplemented wit long range sequencing of 1000 genome samples from 25 populations providing a comprehensive database of FcR and IGHG polymorphism. This enhanced database allows the majority of variants detected by the short-read NGS assay to be phased accordingly through mapping back to the database. Our current targeting probes for the FcR genes include a panel of variants that have been previously characterized functionally (Table 1). The four IgG encoding genes are targeted at the CH1, CH2 and CH3 regions collected from 3 corresponding amplicons (Fig. 1) and phase between CH regions is determined through database lookup using enhanced long-read data sets from 1000 genomes samples. This FcR/IGHG short-read NGS multiplexing system uses the same technology as that currently deployed for HLA and post-transplant chimerism now in active use in clinical laboratories (ScisGo-HLA-v6, ScisGo-CHIM-v3).

Figure 1. Sequence diversity of the Human immunoglobulin constant heavy G chain (IGHG) (Fcγ) (GM) gene C1, C2, C3 regions. The IGHG gene is indicated to the left of each block of listed sequence variants with variable positions indicated.

Table 1. FcR polymorphisms detected with ScisGo-FcR-IGHG-v2

Gene	RS	Region	Position	DNA	Ref Seq	Position	Amino Acid	Ref Seq	Effect
FCGR2A	rs1801274	Exon	500	A>G	NM_001136219.1	167	His>Arg	NP_001129691.1	His(H)167: high affinity for IgG2
FCGR2B	rs1050501	Exon	695	T>C	NM_001002274.2	232	Ile>Thr	NP_001002274.1	Thr(T)232: decreased inhibitory activity
FCGR2C	rs759550223	Exon	169	C>T	NM_201563.5	57	Gln>Ter	NP_963857.3	Truncated non-functional protein
FCGR2B/C	rs3219018	Promoter	-386	G>C	NM_001002273.2				-386C: higher promoter activity
	rs780467580	Promoter	-120	T>A	NM_001002273.2				-120A: higher promoter activity
FCGR3A	rs396991	Exon	838	T>G	NM_001127592.2	280	Phe>Val	NP_001121064.2	Val(V)280: higher affinity for IgG1 and 3, binds IgG4
	rs200688856	Exon	108	C>G	NM_000570.4	36	Ser>Arg	NP_000561.3
	rs527909462	Exon	114	T>C	NM_000570.4	38	Leu>Leu	NP_000561.3
	rs448740	Exon	194	A>G	NM_000570.4	65	Asn>Ser	NP_000561.3
	rs5030738	Exon	233	C>A	NM_000570.4	78	Ala>Asp	NP_000561.3
	rs147574249	Exon	244	A>G	NM_000570.4	82	Asn>Asp	NP_000561.3
FCGR3B	rs2290834	Exon	2316	A>G	NM_000570.4	106	Ile>Val	NP_000561.3	FCGR3B*01 (NA1): higher affinity for IgG1 and 3
	Haplotype	108	114	194	233	244	316
	FCGR3B*01 (NA1)	G	C	A	C	G	G
	FCGR3B*02 (NA2)	C	T	G	C	A	A
	FCGR3B*03 (SH)	C	T	C	A	A	A
				VNTR (37bp)*
				VNTR1 (1 repeat)
				VNTR2 (2 repeats)
FCGRT (FcRn)		Intron	Intron1	VNTR3 (3 repeats)					VNTR3; High expression
				VNTR4 (4 repeats)
				VNTR5 (5 repeats)
FCER1A	rs2251746	Promoter	-36	T>C	NM_002001.3				-36T: higher promoter activity – additional GATA-1 binding site
	rs2427827	Promoter	-285	T>C	NM_002001.3				-285T: increased transcriptional activity – Sp1 site
MS4A2 (FCER1B)	rs1441586	Promoter	-211	T>C	NM_000139.4				-211T: unknown/higher receptor expression
	rs569108	Exon	710	A>G	NM_000139.4	237	Glu>Gly	NP_000130.1	Gly(G)237: associated with higher expression
FCER2	rs2228137	Exon	181	C>T	NM_001207019.2	61	Arg>Trp	NP_001193948.2	Trp(W)62: resistant to proteolytic cleavage
PIGR	rs291102	Exon	1739	C>T	NM_002644.3	580	Ala>Val	NP_002635.2	Val(V)580: near endoproteolytic cleavage site/reduced efficiency of IgA release?
	rs16986050	Exon	739	A>G	NM_133269.3	247	Ser>Gly	NP_579803.1	Gly(G)248: enhanced IgA-mediated responses; increased cytokine release
FCAR	rs3816051	Promoter	T>C	-142	NM_133269.3				-142 C; High expression
	rs12462181	Promoter	-311	T>C	NM_133269.3				-311 C; High expression

Bournazos et al. Clinical and Experimental Immunology. 2009. 157: 244–254, PMID: 19604264

Mkaddem et al. Front Immunol. April 2019. 10:811, PMID: 31057544

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