Table 2.
Pathogenic variants detected by multiplex PCR and NGS in 362 families (371 patients) with proteinuria and hematuria with an age of onset <25 in 11 genes that if mutated, cause AS, aHUS or TTP
| Family | Exon (Zygosity) | Nucleotide change | Amino acid change | dbSNP (rs #) | Conserved to | Poly- phen2 | SIFT | Mutation taster | Sex | Ethnicity (consan- guinity) | gnO-MAD general population | gnO-MAD closest ethnicity | Bio- base |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| COL4A3 | |||||||||||||
| A2041 | 4 (Het) | c.272G>A | p.Gly91Asp | − | Dr | 0.994 | Del | DC | m | Euro (N) | 1/30960 (0 hom) | 0/14998 (0 hom) | [30] |
| 48 (Het) | c.4421T>C | p.Leu1474Pro | 200302125 | Dr | 1 | Del | DC | 735/276998 (0 hom) | 620/126548 (0 hom) | [31, 32] | |||
| A1916 | 4 (Het) | c.279 + 6T>C | Splice | 770953670 | NA | −71% | −15.4% | −2.4% | f | Slavic (N) | 1/245742 (0 hom) | 0/30758 (0 hom) | Novel |
| A2490 | 23 (Het) | c.1504 + 6A>C | Splice | 760718271 | NA | +2.8% | +0.9% | +0.2% | f | Kazakh (N) | 1/246078 (0 hom) | 1/111616 (0 hom) | Novel |
| A1479 | 27 (Het) | c.1978C>A | p.Pro660Thr | 773674552 | Gg | 0.661 | Del | DC | f | Turk (Y) | 5/277150 (0 hom) | 5/126688 (0 hom) | Novel |
| A2358 | 29 (Hom) | c.2162del | p.Gly721Val*26 | − | NA | NA | NA | NA | m | Asian (Y) | 3/240354 (0 hom) | 2/29504 (0 hom) | Novel |
| A2609 | 49 (Het) | c.4487G>A | p.Arg1496Gln | 776086781 | Gg | 0.989 | Del | DC | m | Euro (N) | 11/276940 (0 hom) | 1/126550 (0 hom) | Novel |
| COL4A4 | |||||||||||||
| B789 | 2 (Hom) | c.71 + 1G>A | Splice | − | NA | −100% | −100% | −100% | f | Cauc (N) | − | − | [33] |
| COL4A5 | |||||||||||||
| A5192 | 3 (Hem) | c.231 + 3A>G | Splice | 376366035 | NA | −32.2% | −0.4% | −11.1% | m | Turk (Y) | 2/178120 (2 hem) | 2/79762 (2 hem) | Novel |
| A965 | 4 (Hem) | c.274_279del | p.Arg92_Gly93del | − | Dm | NA | NA | NA | m | Euro (Y) | − | − | Novel |
| A3676 | 6 (Hem) | c.322-1G>A | Splice | − | NA | −100% | −100% | −100% | m | Indian (Y) | − | − | [34] |
| A2917 | 20 (Hem) | c.1217del | p.Gly406Val*68 | − | NA | NA | NA | NA | m | Slavic (N) | − | − | Novel |
| A3933 | 24 (Hem) | c.1634G>A | p.Gly545Asp | − | Dm | 1 | Del | DC | m | Indian (N) | − | − | Novel |
| 24 (Hem) | c.1634G>A | p.Gly545Asp | − | Dm | 1 | Del | DC | m | Indian (N) | − | − | Novel | |
| B711 | 25 (Hem) | c.1781G>A | p.Gly594Asp | − | Dm | 0.355 | Del | DC | m | Euro (N) | − | − | [35] |
| A1963 | 25 (Hem) | c.1931G>A | p.Gly644Asp | − | Dm | 1 | Del | DC | m | Hisp (Y) | − | − | [11, 36] |
| B28 | 46 (Hem) | c.4063del | p.Glu1355Asn*22 | − | NA | NA | NA | NA | m | Arabic (Y) | − | − | Novel |
| A4926 | 48 (Hem) | c.4309C>G | p.Gln1437Glu | 143778018 | Dm | 0.407 | Del | DC | m | Filipino (N) | 19/197664 (3 hom) | 2/4713 (0 hom) | Novel |
| A169 | 49 (Hem) | c.4439del | p.Pro1480His*74 | − | NA | NA | NA | NA | m | Turk (Y) | − | – | Novel |
| 49 (Hem) | c.4439del | p.Pro1480His*74 | − | NA | NA | NA | NA | m | Turk (Y) | − | – | Novel | |
| CFH | |||||||||||||
| A4035 | 10 (Het) | c.1507C>G | p.Pro503Ala | 570523689 | Ci | 0.746 | Del | PMP | f | Euro (N) | 4/245456 (0 hom) | 4/111226 (0 hom) | [37]a |
| CFHR5 | |||||||||||||
| A4967 | 2 (Het) | c.232T>C | p.Ser78Pro | 146025130 | NA | 0.986 | Tol | PMP | m | African (N) | 32/277182 (0 hom) | 27/24038 (0 hom) | Novel |
| A2351 | 4 (Het) | c.486dup | p.Glu163Arg*35 | 565457964 | NA | NA | NA | NA | f | Cauc (N) | 564/276160 (0 hom) | 395/126014 (0 hom) | [38, 39] |
| A3422 | 10 (Het) | c.1615T>G | p.Phe539Val | 111989094 | NA | 0.998 | Del | DC | m | Arabic (?) | 5/277086 (0 hom) | 0/126608 (0 hom) | Novel |
| CFI | |||||||||||||
| A2336 | 13 (Het) | c.1558 + 5G>T | Splice | 1114013791 | NA | −21.2% | −11.9% | −12.3% | f | Asian (N) | 2400/276954 (19 hom) | 0/18862 (0 hom) | [40, 41] |
The genes sequenced were ADAMTS13, C3, CD46, CFH, CFHR5, CFI, COL4A3, COL4A4, COL4A5, DGKE and THBD.
Variant reported in Biobase for nonrenal disease. The splice site prediction scores were derived left to right from the MaxEnt, NNSPLICE and HSF prediction programs, respectively.
Cauc, Caucasian; Ci, Ciona intestinalis; DC, disease causing; Del, deleterious; Dm, Drosophila melanogaster; Dr, Danio rerio; dup, duplication; Euro, European; F, female; Gg, Gallus gallus; Hem, hemizygous; Het, heterozygous; Hisp, Hispanic; Hom, homozygous; M, male; N, no; NA, not applicable; PMP, polymorphism; Tol, tolerated; Turk, Turkish; Y, yes.