Table 2.

The phenotype of patients carrying rare variants (MAF <0.1%) in complement genes or FHAAs^a

Case no.	Sex/age, yr	Creatinine, μmol/L	MAHA	Platelets, ×109/L	Treatment	Outcome	Gene/FHAA	Variant	Protein	MAF, %	In vitro	Significance
C-TMA and no coexisting conditions (i.e., primary aHUS)
M00018	F/3	92	+	12	PEX, Ecu	CR, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
							CFI	c.392T>G	L131R	<0.01	LOF48	Pathogenic
M11317	M/65	372	+	44	PEX	CR	CFHR5	c.1412G>A	G471E	<0.07	Unknown	VUS
M00016	M/4	311	+	28	PEX, CS	CR	FHAA	c.CFHR1/3 del	p.CFHR1/3 del	N/A	N/A	N/A
M01609	M/20	287	+	345	PEX	CR	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
M03103	F/12	339	+	264	PEX	ESKD, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
M00004	F/49	800	+	<150	PEX	ESKD, Rec.	CFI	c.1420C>T	R474∗	<0.01	LOF49	Pathogenic
B12	F/31	359	–	23	PEX, Ecu	CR	CFH	c.3486delA	K1162Nfs∗7	0	Unknown	Pathogenic
B27	M/53	441	+	53	PEX, Ecu	CKD G3b	CD46	c.478G>T	V160F	0	Unknown	VUS
B39	M/25	469	+	7	PEX	CR	C3	c.3125G>A	R1042Q	0	Unknown	VUS
C–TMA and coexisting hypertensive emergency
M99917	M/47	1980	–	272	Ecu	CKD G3b	CFI	c.148C>G	P50A	<0.02	LOF50	Pathogenic
							THBD	c.1433C>T	T478I	<0.01	Unknown	VUS
M02715	F/28	1065	–	228	PEX	ESKD	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
M01715	F/41	334	–	291	PEX, Ecu	CKD G4	CFI	c.452A>G	N151S	<0.01	LOF50	Pathogenic
M04010	F/32	1138	+	142	PEX	ESKD, Rec.	CFH	c.2558G>A	C853Y	0	LOF51	Pathogenic
M03307	M/37	586	+	100	PEX	ESKD, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
M04306	M/40	1195	+	158	PEX	ESKD, Rec.	CD46	c.811_816delGACAT	D271/S272	0	LOF52	Pathogenic
M00105	F/38	1730	+	228	–	ESKD, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
M05486	M/39	1089	–	101	–	ESKD, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
C-TMA and coexisting pregnancy (i.e., pregnancy-associated atypical HUS)
M00503	F/32	1388	+	212	PEX, CS	ESKD, Rec.	C3	c.481C>T	R161W	<0.01	GOF47	Pathogenic
B46	F/31	557	+	77	PEX, Ecu	ESKD	CFI	c.772G>A	A258T	0.01-0.03	LOF48	Pathogenic
C-TMA and coexisting kidney transplantation (i.e., de novo TMA after kidney transplantation)
B33	M/24	309	–	252	PEX, Ecu	CKD G4/T	CFI	c.148C>G	P50A	<0.02	LOF50	Pathogenic

aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; CR, complete renal remission; CS, corticosteroids; Ecu, eculizumab; ESKD, end-stage kidney disease; F, female; FHAA, factor H autoantibody; GOF, gain of function; LOF, loss of function; M, male; MAF, minor allele frequency in the European American population according to the Exome Variant Server and Genome Aggregation Database; MAHA, microangiopathic hemolytic anemia; PEX, plasma therapy; Rec, recurrence; TMA, thrombotic microangiopathy; VUS, variant of uncertain significance.

Case numbers beginning with a B are from the Brussels cohort, and case numbers beginning with an M are from the Maastricht cohort.

^aRare variants in complement genes/FHAAs were found in 9 of 13 (69%) patients with primary aHUS, 8 of 30 (27%) patients with coexisting hypertensive emergency, 2 of 8 (25%) patients with coexisting pregnancy, and 1 (20%) patient with de novo TMA after kidney transplantation.