Table 1. Summary of human ZIC2 mutations.
| Mutation number | Base-pair alteration | Coding region alteration | Functional activity | Comments | Reference for report |
|---|---|---|---|---|---|
| 1 | -24C>T | N/A | N/A | 5′ non-coding region (immediately preceding the ATG) of unknown importance | GeneDx, this report |
| 2 | c.21delG | p.Gln8SerfsX33 | Predicted null | lacks homeodomain | Brown 2001 (#1) |
| 3 |
c.81_86delGGCGGC insTCGGT |
p.Ala28ArgfsX13 | Predicted null | lacks homeodomain | NIH, this report CLIA; GeneDx confirmed |
| 4 | c.107A>C | p.Gln36Pro | 170% | NH2-terminus | Dubourg 2004; Brown 2005 |
| 5 | c.109G>A | p.Asp37Asn | unknown | NH2-terminus. Also c.1059C>T (p.H353H) | NIH, this report CLIA; GeneDx confirmed |
| 6 | c.129_184dup56 | p.Leu62Argfs175 | Predicted null | NH2-terminus truncation | NIH, this report |
| 7 | c.136C>T | p.Gln46X | Predicted null | NH2-terminus truncation | Dubourg 2004; and GeneDx confirmed |
| 8 | c.172G>T | p.Gly58X | Predicted null | NH2-terminus truncation | Dubourg 2004 |
| 9 | c.177ins56 | p.Phe60GlnfsX176 | Predicted null | lacks homeodomain | Brown 1998 (#a) |
| 10 | c.191dupC | p.Ala66ArgfsX301 | Predicted null | lacks homeodomain | U. Rennes, this report |
| 11 | c.217C>T | p.Gln73X | Predicted null | lacks homeodomain | U. Rennes, this report |
| 12 | c.217delC | p.Gln73Argfs145 | Predicted null | lacks homeodomain | NIH, this report |
| 13 | c.367delA | p.Ser123AlafsX95 | Predicted null | lacks homeodomain | U. Rennes, this report |
| 14 | c.382G>A | p.Asp128Asn | unknown | Mis-sense | NIH, this report |
| 15 | c.386_392delCGGCGCC | p.Ser129TrpfsX87 | Predicted null | lacks homeodomain | NIH, this report |
| 16 | c.392_398del7 | p.Gly133SerfsX83 | Predicted null | lacks homeodomain | GeneDx, this report |
| 17 | c.454_455delinsTT | p.Asp152Phe | 60% | Mis-sense NH2-terminus | Brown 2001 (#3); Dubourg 2004 |
| 18 | c.479delC | p.Pro160ArgfsX58 | Predicted null | lacks homeodomain | Maastricht |
| 19 | c.490G>T | p.Glu164X | Predicted null | lacks homeodomain | NIH, this report; confirmed GeneDx |
| 20 | c.557_572dup16 | p.Glu192GlyfsX180 | Predicted null | lacks homeodomain | GeneDx, this report |
| 21 | c.577delC | p.Gln193AsnfsX25 | Predicted null | lacks homeodomain | GeneDx, this report |
| 22 | c.582C>A | p.Tyr194X | Predicted null | lacks homeodomain | U. Rennes, this report |
| 23 | c.612delC | p.Tyr205ThrfsX13 | Predicted null | lacks homeodomain | NIH, this report CLIA |
| 24 | c.659delA | p.Asn220ThrfsX4 | Predicted null | lacks homeodomain | U. Göttingen, this report |
| 25 | c.665_676dup12 | p.Gly222_Met225dup | unknown | unknown | U. Rennes, this report |
| 26 | c.710_718dupCACCACCAC | H12 variant | unknown | Observed length variation of 8 up to 12 H's | Brown 2001; and NIH, this report CLIA |
| 27 | c.716_718del | H8 variant | unknown | Observed length variation in controls | Dubourg 2004 |
| 28 | c.716_718dupACC | H10 variant | unknown | Observed length variation in controls | Brown 2001; Orioli 2001; Dubourg 2004 GeneDx, and NIH this report CLIA |
| 29 | c.748C>T | p.Gln250X | Predicted null | Truncation in ZF-NC; lacks homeodomain | NIH, this report |
| 30 | c.779G>A | p.Trp260X | Predicted null | Truncation in ZF#1 | U. Göttingen, this report |
| 31 | c.793C>T | p.Gln265X | Predicted null | lacks homeodomain | GeneDx, this report |
| 32 | c.808_809ins17 | p.K270ThrfsX2 | Predicted null | Truncation in ZF#1 | Dubourg 2004 |
| 33 | c.815G>A | p.Ser272Asn | Predicted null | Mis-sense in ZF#1 | U. Rennes, this report |
| 34 | c.825_826delAA | p.Lys275AsnfsX91 | Predicted null | Fs in ZF#1; lacks homeodomain | GeneDx, this report |
| 35 | c.829_830dupTT | p.Thr279AlafsX7 | Predicted null | FS in ZF#1; lacks homeodomain | GeneDx, this report |
| 36 | c.862_863delTC | p.Ser288GlyfsX78 | Predicted null | Fs in ZF#1; lacks homeodomain | Orioli 2001 |
| 37 | c.857A>T | p.His286Leu | Predicted null | Invariant C2H2 structure ZF#1 | GeneDx, this report |
| 38 |
c.858C>G also c.1059C>T |
p.His286Gln also p.His353His | Predicted null also Common variant | Invariant C2H2 structure ZF#1; | NIH, this report; GeneDx confirmed |
| 39 | c.856C>T | p.His286Tyr | Predicted null | Invariant C2H2 structure ZF#1 | U. Rennes, this report |
| 40 | c.871C>T | p.His291Tyr | Predicted null | Invariant C2H2 structure ZF#1 | U. Rennes, this report |
| 41 | c.910T>A | p.Trp304Arg | Predicted null | ZF#2 | GeneDx, this report |
| 42 | c.912G>A | p.Trp304X | Predicted null | Truncation in ZF#2 | GeneDx and U. Rennes, this report |
| 43 | c.928G>T | p.Glu310X | Predicted null | ZF#2 truncation | NIH and U. Rennes, this report |
| 44 | c.932delG | p.Gly311AlafsX102 | Predicted null | ZF#2 frameshift | Brown 2001 (#4) |
| 45 | c.941T>G | p.Phe314Cys | Predicted null | Conserved ZF#2 | Rennes, this report |
| 46 | c.973C>A | p.Arg325Ser | Predicted null | Conserved ZF#2 | NIH, this report; GeneDx confirmed |
| 47 | c.974G>T | p.Arg325Leu | Predicted null | Conserved ZF#2 | U. Rennes, this report |
| 48 | c.979C>T | p.His327Tyr | Predicted null | ZF#2 invariant C2H2 motif | NIH, this report |
| 49 | c.1004G>T | p.Cys335Phe | Predicted null | ZF#3 invariant C2H2 motif | NIH, this report |
| 50 | c.1025_1026delAA | p.Lys342SerfsX24 | Predicted null | ZF#3 frameshift | Dubourg 2004 |
| 51 | c.1031_1032delTC | p.Phe344CysfsX22 | Predicted null | ZF#3 frameshift | Brown 2001 (#5) |
| 52 | c.1040_1046del | p.Glu348SerfsX63 | Predicted null | ZF#3 frameshift | Brown 1998 (#d) and NIH, this report |
| 53 | c.1051A>T | p.Lys351X | Predicted null | ZF#3 truncation | NIH, this report |
| 54 |
c.1052_1053insAAGGTT CACACAGAACCTCAA |
p.Lys351_Ile352ins7 | Predicted null | ZF#3 deletion/insertion | U. Rennes, this report |
| 55 |
c.1075+2T>A (IVS1+2T>A) |
Gly359fsX62 | Predicted null | Eliminates ZF#4 and 5 | U. Rennes, this report |
| 56 |
c.1076-1G>A (IVS1-1G>A) |
alternative splicing | Predicted null | ZF#1-3 intact; likely eliminates ZF#4-5 | NIH, this report; GeneDx confirmed |
|
c.1076-1G>A (IVS1-1G>A) |
alternative splicing | Predicted null | ZF#1-3 intact; likely eliminates ZF#4-5 | NIH, this report | |
|
c.1076-1G>A (IVS1-1G>A) |
alternative splicing | Predicted null | ZF#1-3 intact; likely eliminates ZF#4-5 | NIH, this report | |
| 57 |
c.1239+1G>C (IVS2+1G>C) |
Possible inclusion of intron 2 codons or alternative splicing | Predicted null | Disrupts ZF#5 | GeneDx, this report |
| 58 |
c.1240-2A>G (IVS2-2A>G) |
alternative splicing | Predicted null | ZF#1-3 intact; likely eliminates ZF#4-5 | NIH, this report |
| 59 | c.1090C>T | p.Gln364X | Predicted null | Eliminates all of ZF#4-5 | Maastricht |
| 60 | c.1091_1092delAG | p.Gln364LeufsX2 | Predicted null | Eliminates all of ZF#4-5 | Dubourg 2004 |
| 61 | c.1095_1096delTG | p.Cys365X | Predicted null | Eliminates all of ZF#4-5 | NIH, this report (case #1) |
| c.1095_1096delTG | p.Cys365X | Predicted null | Eliminates all of ZF#4-5 | NIH, this report (apparently unrelated case #2) | |
| 62 | c.1097_1098delAG | p.Glu366Valfs2 | Predicted null | ZF#4 truncation | NIH, this report; GeneDx confirmed; Brown 2001 (#7) |
| 63 | c.1119_1120delCT | p.Phe374ArgfsX17 | Predicted null | ZF#4 frameshift | NIH, this report |
| 64 | c.1118G>C | p.Arg373Pro | Predicted null | ZF#4 conserved | GeneDx, this report |
| 65 | c.1206C>G | p.Tyr402X | Predicated null | ZF #5 truncation | NIH, this report CLIA |
| 66 | c.1204T>A | p.Tyr402Asn | Predicted null | ZF#5 core sequence | NIH, this report; GeneDx confirmed |
| 67 | c. 1208C>A | p.Thr403Lys | Predicted null | ZF#5 core sequence | NIH, this report; GeneDx confirmed |
| 68 | c.1211A>G | p.His404Arg | Predicted null | ZF#5 core sequence | GeneDx, this report |
| 69 | c.1225C>T | p.Arg409Trp | Predicted null | ZF#5 core sequence | NIH, this report |
| 70 | c.1245T>G | p.His415Gln | Predicted null | Invariant C2H2 structure ZF#5 | U. Rennes, this report |
| 71 | c.1277delC | p.Pro426ArgfsX129 | Predicted null | Intact ZF#1-5 | NIH, this report; GeneDx confirmed |
| 72 | c.1313dupC | p.Leu440AlafsX90 | Predicted null | Intact ZF#1-5 | Brown 1998 (#b) |
| 73 | c.1323dupG | p.Ser442Valfs88 | 2% | Intact ZF#1-5 | NIH, this report; Brown 2001 (#8) and 2005 |
| 74 | c.1330_1365del | p.444_455del In frame deletion | 60% | Intact ZF#1-5 and intact polyalanine tract | Brown 2001 (#9) and 2005 |
| 75 | c.1377_1406dup30 | p.Ala461_470dup In frame duplication | 5% with reduced DNA binding | 25 alanine variant | Brown 1998 (#c) and 2001 (#10-16) and 2005; NIH, this report CLIA; Maastricht, this report (one case maternal and one de novo). |
| 76 | c.1392_1406del | In frame deletion | Predicted null | 10 alanine variant | NIH, this report; GeneDx confirmed |
| 77 | c.1377_1406del | In frame deletion | Predicted null | 5 alanine variant | U. Rennes, this report |
| 78 |
c.[1420-1427dup; 1428-1433delinsCG] |
p.Gly477CysfsX54 | Predicted null | Novel COOH terminus | U. Rennes, this report |
| 79 | c.1445_1461del17 | p.Ser482ArgfsX42 | Predicted null | Novel COOH-terminus | NIH, this report; GeneDx confirmed |
| 80 | c.1452_1456delCGCGG | p.Ala485ArgfsX43 | Predicted null | Novel COOH terminus | U. Rennes, this report |
| 81 | c.1455_1461delinsCG | p.Gly487LeufsX41 | Predicted null | Novel COOH terminus | U. Rennes, this report |
| 82 |
c.1508_1520delGCGGCGG GGGCGG |
p.Gly503AlafsX48 | Predicted null | Novel COOH terminus | Maastricht |
| 83 | c.1559delA | p.His520ProfsX35 | Predicted null | Novel COOH terminus | U. Rennes, this report |
1
Sequence variant numbering is based on ZIC2 cDNA sequence (GenBank NM_007129.2). Nucleotide numbering uses the A of the ATG translation initiation site as nucleotide +1 and the 5′ untranslated variant is numbered on this basis, rather than by its genomic position.