Patient* | HPE type | DNA alteration (location) in SIX3 | Predicted protein alteration in SIX3 | Functional studies†47 | Gender | Proband/ relative | Ref. |
1 | Not specified | c.109G→T (NTD) | p.G37C | 0.5–0.9 | Female | Proband | NA |
2‡ | Lobar | c.109G→T (NTD) | p.G37C | 0.5–0.9 | Male | Proband | 42 |
3a‡ | MIHV | c.109G→T (NTD) | p.G37C | 0.5–0.9 | Female | Proband | NA |
3b‡ | None | c.109G→T (NTD) | p.G37C | 0.5–0.9 | Female | Mother | NA |
4a‡ | Alobar | c.206G→A (NTD) | c.G69D | >0.9 | Female | Proband | 48 |
c.406dupGC (SD) | FS | <0.5 | |||||
4b‡ | None | c.206G→A (NTD) | c.G69D | >0.9 | Male | Father | 4848 |
c.406dupGC (SD) | FS | <0.5 | |||||
4c | None | c.206G→A (NTD) | c.G69D | >0.9 | Female | Paternal grandmother | 48 |
c.406dupGC (SD) | FS | <0.5 | Female | 48 | |||
5a‡ | Alobar | c. 214G→C (NTD) | p.A72P | <0.5 | Female | Proband | 48 |
5b‡ | None | c. 214G→C (NTD) | p.A72P | <0.5 | Female | Mother | 48 |
6 | Alobar | c.235A→G (NTD) | p.M79V | Unknown | Not specified | Proband | 47 |
7a‡ | Alobar | Not specified (SD) | p.V92G | <0.5 | Male | Proband | 45 |
7b‡ | Alobar | Not specified (SD) | p.V92G | <0.5 | Male | Brother | 45 |
7c‡ | Alobar | Not specified (SD) | p.V92G | <0.5 | Male | Brother | 45 |
7d‡ | Microform | Not specified (SD) | p.V92G | <0.5 | Female | Mother | 45 |
8‡ | Semilobar | c.275T→G (SD) | p.V92G | <0.5 | Female | Proband | 43 |
9‡ | Semilobar | c.278C→A (SD) (PTCH1: c.1165G→A) | p.A93D (PTCH1: p.A393T) | <0.5 | Female | Proband | 22 42 |
10a‡ | Alobar | c.311A→G (SD) | p.D104G | 0.5–0.9 | Male | Proband | 48 |
10b‡ | None | c.311A→G (SD) | p.D104G | 0.5–0.9 | Male | Father | 48 |
11‡ | Not specified | c.313A→G (SD) | p.I105V | >0.9 | Not specified | Proband | 43 |
12‡ | Lobar | c.338G→A (SD) | p.W113X | <0.5 | Male | Proband | 42 |
13a‡ | Not specified | c.339G→A (SD) | p.W113X | <0.5 | Male | Proband | NA |
13b‡ | Not specified | Not tested | Not tested | Not tested | Male | Brother | NA |
13c‡ | Microform | c.339G→A (SD) | p.W113X | <0.5 | Female | Mother | NA |
14a‡ | Alobar | c.339G→T (SD) | p.W113C | <0.5 | Female | Proband | 42 |
14b‡ | Microform | c.339G→T (SD) | p.W113C | <0.5 | Female | Mother | 42 |
14c‡ | Microform | c.339G→T (SD) | p.W113C | <0.5 | Female | Maternal aunt | 42 |
14d‡ | Microform | c.339G→T (SD) | p.W113C | <0.5 | Male | Maternal uncle | 42 |
14e‡ | None | c.339G→T (SD) | p.W113C | <0.5 | Female | Maternal aunt | 42 |
14f‡ | Microform | c.339G→T (SD) | p.W113C | <0.5 | Female | Maternal grandmother | 42 |
14g‡ | Microform | Linkage only | Linkage only | Linkage only | Male | Maternal great uncle | 42 |
14h‡ | None | Linkage only | Linkage only | Linkage only | Female | Maternal first cousin | 42 |
14i‡ | Not specified | Linkage only | Linkage only | Linkage only | Female | Maternal half-sister | 42 |
14j | Not specified | Not tested | Not tested | Not tested | Female | Maternal first cousin | 42 |
14k‡ | Not specified | Not tested | Not tested | Not tested | Male | Maternal first cousin | 42 |
14l‡ | Not specified | Not tested | Not tested | Not tested | Female | Maternal first cousin | 42 |
14m | Not specified | Not tested | Not tested | Not tested | Female | Maternal first cousin, once removed | 42 |
14n | Not specified | Not tested | Not tested | Not tested | Male | Maternal great uncle | 42 |
14o | Not specified | Not tested | Not tested | Not tested | Not specified | Maternal great-grandparent | 42 |
15‡ | Semilobar | c.341C→T (SD) | p.S114L | <0.5 | Female | Proband | 42 |
16a‡ | Lobar | c.385G→T (SD) | p.E129X | <0.5 | Male | Proband | 42 |
16b‡ | Alobar | c.385G→T (SD) | p.E129X | <0.5 | Female | Sister | 42 |
16c‡ | Microform | c.385G→T (SD) | p.E129X | <0.5 | Male | Father | 42 |
17 | Not specified | c.389C→A (SD) | p.S130X | <0.5 | Male | Proband | 42 |
18a‡ | Alobar | c.404G→C (SD) | p.R135P | <0.5 | Male | Proband | 48 |
18b‡ | None | c.404G→C (SD) | p.R135P | <0.5 | Female | Mother | 48 |
19 | Not specified | c.404_407dupGCGC (SD) | FS | <0.5 | Female | Proband | 42 |
20‡ | Semilobar | c.405_409CGCCG (SD) | FS | <0.5 | Male | Proband | 42 |
21a | Not specified | c.463_465delCAC (SD) | p.H155del | Unknown | Not specified | Proband | 47 |
21b | Not specified | c.463_465delCAC (SD) | p.H155del | Unknown | Female | Mother | 47 |
22‡ | Not specified | c.469T→A (SD) | p.F157I | <0.5 | Male | Proband | 42 |
23a‡ | Alobar | c.507delG (SD) | FS | <0.5 | Female | Proband | 48 |
23b‡ | None | c.507delG (SD) | FS | <0.5 | Male | Father | 48 |
24a‡ | Lobar | c.515C→T (SD) | p.A172V | 0.5–0.9 | Male | Proband | 42 |
24b‡ | Semilobar | Not tested | Not tested | Not tested | Female | Sister | 42 |
24c‡ | Not specified | Not tested | Not tested | Not tested | Female | Mother | 42 |
25a | Alobar | c.518A→C (SD) | p.H173P | 0.5–0.9 | Female | Proband | 45 |
25b | None | c.518A→C (SD) | p.H173P | 0.5–0.9 | Female | Mother | 45 |
26a | Semilobar | c.518A→C (SD) | p.H173P | 0.5–0.9 | Female | Proband | 43 |
26b | None | c.518A→C (SD) | p.H173P | 0.5–0.9 | Female | Mother | 43 |
26c | None | c.518A→C (SD) | p.H173P | 0.5–0.9 | Female | Maternal aunt | 43 |
26d | Not specified | Not tested | Not tested | Not tested | Not specified | Maternal first cousin | 43 |
26e | Not specified | Not tested | Not tested | Not tested | Not specified | Maternal first cousin | 43 |
26f | Not specified | Not tested | Not tested | Not tested | Not specified | Maternal first cousin | 43 |
27‡ | Not specified | c.520T→C (SD) | p.Y174H | 0.5–0.9 | Female | Proband | 42 |
28a‡ | Alobar | c.542_576dup (SD) | FS | Unknown | Female | Proband | 43 45 |
28b‡ | None | c.542_576dup (SD) | FS | Unknown | Male | Father | 43 45 |
29‡ | Semilobar | c.551delC (SD) | FS | <0.5 | Female | Proband | 42 |
30a‡ | Alobar | c.556_557dupGG (SD) | FS | <0.5 | Female | Proband | 44 45 |
30b‡ | Alobar | c.556_557dupGG (SD) | FS | <0.5 | Male | Brother | 44 45 |
30c‡ | Alobar | c.556_557dupGG (SD) | FS | <0.5 | Female | Sister | 44 45 |
30d‡ | Not specified | c.556_557dupGG (SD) | FS | <0.5 | Female | Sister | 44 45 |
30e‡ | Microform | c.556_557dupGG (SD) | FS | <0.5 | Male | Father | 44 45 |
31a‡ | Alobar | Not tested | Not tested | Not tested | Female | Proband | 42 |
31b‡ | Semilobar | c.582dup C (SD) | FS | <0.5 | Female | Sister | 42 |
31c‡ | Microform | c.582dup C (SD) | FS | <0.5 | Male | Father | 42 |
32a‡ | Semilobar | c.605C→T (SD) | p.T202I | <0.5 | Female | Proband | 43 45 |
32b‡ | None | c.605C→T (SD) | p.T202I | <0.5 | Female | Mother | 43 45 |
33a‡ | Semilobar | c.619G→T (HD) | p.E207X | <0.5 | Male | Proband | 42 |
33b‡ | Alobar | c.619G→T (HD) | p.E207X | <0.5 | Female | Sister | 42 |
34 | Not specified | c.637T→G (HD) | p.F213V | <0.5 | Male | Proband | 42 |
35‡ | Lobar | c.652C→T (HD) | p.R218W | 0.5–0.9 | Female | Proband | 42 |
36‡ | Not specified | c. 653G→C (HD) | p.R218P | <0.5 | Female | Proband | 42 |
37‡ | Not specified | c.676C→G (HD) | p.L226V | >0.9 | Female | Proband | 19 52 |
38 | Not specified | c.680A→C (HD) | p.Q227P | 0.5–0.9 | Not specified | Proband | 42 |
39‡ | Microform | c.686C→T (HD) | p.P229L | Unknown | Male | Proband | 46 |
40‡ | Alobar | c.692C→G (HD) | p.P231R | <0.5 | Female | Proband | 45 |
41‡ | Alobar | c.698_706del (HD) | p.N233_S235del | <0.5 | Female | Proband | 19 39 |
42 | Not specified | c.GC718_719AA (HD) | p.A240K | <0.5 | Not specified | Proband | 42 |
43a‡ | Not specified | c.721C→T (HD) | p.Q241X | Unknown | Male | Proband | 42 |
43b | Not specified | Not tested | Not tested | Unknown | Not specified | Sibling | 42 |
43c‡ | None | c.721C→T (HD) | p.Q241X | Unknown | Female | Mother | 42 |
44 | Not specified | c.730G→T (HD) | p.G244C | <0.5 | Not specified | Proband | 42 |
45 | Not specified | c.736delA (HD) | FS | Unknown | Not specified | Proband | 47 |
46 | Not specified | c.743_745delCAG (HD) (TGIF: c.478C→T) | p.248K delQ (TGIF: p.160S) | Unknown | Female | Proband | NA |
47a‡ | Microform | c.749T→C (HD) | p.V250A | 0.5–0.9 | Male | Proband | 19 |
47b‡ | None | c.749T→C (HD) | p.V250A | 0.5–0.9 | Female | Mother | 19 |
47c‡ | None | c.749T→C (HD) | p.V250A | 0.5–0.9 | Female | Maternal aunt | 19 |
47d‡ | Alobar | c.749T→C (HD) | p.V250A | 0.5–0.9 | Not specified | Sibling | 19 |
47e‡ | Alobar | c.749T→C (HD) | p.V250A | 0.5–0.9 | Not specified | Sibling | 19 |
47f | Alobar | c.749T→C (HD) | p.V250A | 0.5–0.9 | Not specified | Sibling | 19 |
48 | Not specified | c.762T→A (HD) | p.F254L | 0.5–0.9 | Male | Proband | 42 |
49‡ | Not specified | c.769C→T (HD) | p.R257W | <0.5 | Female | Proband | 42 |
50a | Semilobar | c. 769C→T (HD) | p.R257W | <0.5 | Female | Proband | 43 45 |
50b | Alobar | Not tested | Not tested | Not tested | Male | Brother | 43 45 |
50c‡ | None | c. 769C→T (HD) | p.R257W | <0.5 | Male | Father | 43 45 |
51a | Lobar | c. 769C→G (HD) | p.R257G | Unknown | Not specified | Proband | 47 |
51b | Not specified | c. 769C→G (HD) | p.R257G | Unknown | Male | Father | 47 |
52‡ | Semilobar | c.770G→C (HD) | p.R257P | >0.9 | Female | Proband | 19 52 |
53 | Not specified | c.773G→C (HD) | p.R258L | <0.5 | Not specified | Proband | 42 |
54 | Not specified | c.785G→A (HD) | p.R262H | 0.5–0.9 | Not specified | Proband | 42 |
55a | Not specified | Not tested | Not tested | Unknown | Not specified | Proband | 47 |
55b | None | Not tested | Not tested | Unknown | Not specified | Obligate carrier | 47 |
55c | Not specified | c.806G→C (CTD) | p.R269T | Unknown | Male | Grandfather | 47 |
56a‡ | Semilobar | c.806G→T (CTD) | p.R269M | Unknown | Female | Proband | 47 51 |
56b‡ | Alobar | Not tested | Not tested | Unknown | Male | Sibling | 47 |
56c‡ | Lobar | c.806G→T (CTD) | p.R269M | Unknown | Male | Sibling | 47 |
56d‡ | Microform | c.806G→T (CTD) | p.R269M | Unknown | Female | Mother | 47 51 |
57 | Semilobar | c.806+1G→T (CTD) | Splice | Unknown | Not specified | Proband | 47 |
58‡ | Not specified | c.G807C (CTD) | p.R269S | 0.5–0.9 | Male | Proband | 42 |
59 | Not specified | c.820_832delinsCTGGACCT (CTD) | p.A274X | Unknown | Male | Proband | NA |
60 | Semilobar | c.850G→C (CTD) (ZIC2: c.910T→C) | p.A284P (ZIC2: p.W304R) | Unknown | Female | Proband | NA |
61‡ | Semilobar | c.890C→T (CTD) | p.P297L | 0.5–0.9 | Female | Proband | 42 |
62‡ | Semilobar | c.944C→T (CTD) | p.T315I | Unknown | Female | Proband | 48 |
63 | Not specified | Deletion | NA | Unknown | Not specified | Proband | 47 |
64 | Not specified | Microdeletion by qPCR | NA | Unknown | Not specified | Proband | 40 41 |
65 | Not specified | Microdeletion by qPCR | NA | Unknown | Not specified | Proband | 40 41 |
66 | Not specified | Microdeletion by qPCR | NA | Unknown | Not specified | Proband | 41 |
67 | Not specified | Microdeletion by qPCR | NA | Unknown | Female | Proband | 41 |
68‡ | Semilobar | del(2)(p2101p2109) | NA | Unknown | Female | Proband | 38 49 |
69‡ | None | del(2)(p21) | NA | Unknown | Male | Proband | 38 |
70‡ | Semilobar | del(2)(p21p23) | NA | Unknown | Male | Proband | 38 |
71‡ | Semilobar | del(2)(p16p22) | NA | Unknown | Female | Proband | 38 |
72 | Lobar | del(2)(p21p22.2) | NA | Unknown | Female | Proband | 38 50 |
73‡ | Alobar | del(2)(p21p22.1) | NA | Unknown | Male | Proband | 38 |
74‡ | Semilobar | inv ins(2)(p21q24q13) | NA | Unknown | Female | Proband | 38 |
75‡ | Semilobar | t(1;2)(p21;p21) | NA | Unknown | Male | Proband | 38 |
76 | Alobar | t(1;2)(p22.3;p21) | NA | Unknown | Male | Proband | 38 |
77‡ | Lobar | del(2)(p16.3p21)§ | NA | Unknown | Male | Proband | NA |
CTD, C-terminal domain; HD, homeodomain; HPE, holoprosencephaly; MIHV, middle interhemispheric variant; NA, not applicable (unpublished when seeming in the Reference column); NTD, N-terminal domain; qPCR, quantitative PCR: SD, SIX domain.
*Each kindred is numbered separately; within a kindred, individual members have separate letter identifier.
†Protein Activity Index.
‡Clinical information available.
§Complex rearrangement additionally resulting in chromosome 2 inversion, translocation involving chromosomes 7, 13 and 18 and deletions of regions of chromosomes 7 and 18.