Background
Methods
Results
Mutation group | Nucleotide change (cDNA) | Protein change | Exon/intron | Individuals (gender) | Reported mutation | Reported individual |
---|---|---|---|---|---|---|
No functional protein | c.-253-?_-163 + ?del | p.(0) | 1 | 2 (F) | Yes | Yes
[4] |
No functional protein | c.-253-?_-163 + ?del | p.(0?) | 1 | 1 (F) | Yes | Yes
[4] |
No functional protein | c.-253-?_99 + ?del | p.(0) | 1–3 | 1 (F) | Yes | Yes
[4] |
No functional protein | c.64 + 2 T > C | p.(0) | 2 | 1 (F) | Yes | No |
No functional protein | c.64 + 1G > A | p.(0) | 2 | 1 (F) | Yes | Yes
[4] |
No functional protein | c.-162-?_99 + ?del | p.(0) | 2–3 | 1 (F) | Yes | Yes
[4] |
No functional protein | c.-162-?_99 + ? | p.(0) | 2–3 | 1 (F) | No | No |
No functional protein | c.-253-?_*1085del | p.(0) | 1–21+ | 1 (F) | No | No |
No functional protein | c.-253-?_*1085del | p.(0) | 1–21 | 3(F) | No | No |
No functional protein | c.-253-?_*1085del | p.(0) | 1–21+ | 1 (F) | No | No |
No functional protein | c.-253-?_*1085del | p.(0) | 1–21+ | 1 (F) | Yes | Yes
[4] |
No functional protein | c.-253-?_*1085del | p.(0) | 1–21+ | 1 (F) | No | No |
No functional protein | c.65-?_99 + ?del | p.(Ala23Asnfs*3) | 3 | 2 (F and M) | Yes | Yes
[4] |
No functional protein | c.99 + 5G > A | p.Ala23Asnfs*3 | 3 | 1 (F) | Yes | |
No functional protein | c.100-?_*1085del | p.(?) | 4–21+ | 1 (F) | No | No |
No functional protein | c.146-1G > A | p.(Asn50Tyrfs*15) | 5 | 1 (M) | No | No |
No functional protein | c.146-6 T > G | p.(Glu49Valfs*2) | 5 | 1 (F) | No | No |
No functional protein | c.146-?_282 + ?del | p.(Asn50Tyrfs*15) | 5 | 1 (F) | Yes | Yes
[4] |
No functional protein | c.163_166delGAAA | p.Glu55Argfs*20 | 5 | 1 (F) | Yes | No |
No functional protein | c.175C > T | p.Arg59* | 5 | 5 (4 and 1 M) | Yes | |
No functional protein | c.183delT | p.Met63Cysfs*13 | 5 | 2 (F, twins) | Yes | Yes
[4] |
No functional protein | c.220G > T | p.Glu74* | 5 | 1 (F) | No | No |
No functional protein | c.282 + 3_282 + 6delAAGT | p.(Asn50Tyrfs*15) | 5 | 2 (F) | Yes | Yes
[4] |
No functional protein | c.283-3_290del | p.(Asn95Ilefs*2) | 5 | 2 (F, sisters) | Yes | |
No functional protein | c.339ins1 | p.? | 6 | 1 (F) | No | No |
No functional protein | c.351 T > A | p.Tyr117* | 6 | 1 (M) | No | No |
No functional protein | c.400C > T | p.Arg134* | 6 | 2 (F and M) | Yes | |
No functional protein | c.456_457delTG | p.Cys152* | 7 | 1 (F) | No | No |
No functional protein | c.464-2A > G | p.Gly155Alafs*43 | 7 | 1 (M) | Yes | No |
No functional protein | c.506_507delAC | p.Thr168Argfs*36 | 8 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.38 T > C | p.Phe13Ser | 2 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.58G > C | p.Gly20Arg | 2 | 1 (F) | Yes | |
Missense/in-frame mutation within catalytic domain | c.100-9_100-3delCCCTTGCinsGCAGA | p.(Lys33dup) | 4 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.119C > T | p.Ala40Val | 4 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.191 T > C | p.Leu64Pro | 5 | 1 (M) | Yes | |
Missense/in-frame mutation within catalytic domain | c.214_216del | p. Ile72del | 5 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.215 T > C | p.Ile72Thr | 5 | 1 (F) | Yes | No |
Missense/in-frame mutation within catalytic domain | c.364G > A | p.Ala122Thr | 6 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.377G > A | p.Cys126Tyr | 6 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.395 T > G | p.Val132Gly | 6 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.404A > G | p.(Asp135_Phe154del) | 7 | 1 (M) | No | No |
Missense/in-frame mutation within catalytic domain | c.404-3C > A | p.(Asp135_Phe154del) | 7 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.428 T > A | p. Ile143Asn | 7 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.458A > T | p. Asp153Val | 7 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.463 + 1G > A | p.Asp135_Phe154del | 7 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.473G > C | p.Arg158Pro | 8 | 1 (M) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.514G > A | p.Val172Ile | 8 | 1 (M) | No | No |
Missense/in-frame mutation within catalytic domain | c.526 T > C | p.Trp176Arg | 8 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.532C > T | p.Arg178Trp | 8 | 2 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.536C > T | p. Ser179Phe | 8 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.577G > C | p.Asp193His | 9 | 1 (F) | No | No |
Missense/in-frame mutation within catalytic domain | c.587C > T | p.Ser196Leu | 9 | 5 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.595 T > C | p.Cys199Arg | 9 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.620G > A | p.Gly207Glu | 9 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.656A > C | p.Gln219Pro | 9 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.680 T > C | p.Leu227Pro | 9 | 1 (F) | Yes | Yes
[4] |
Missense/in-frame mutation within catalytic domain | c.872G > A | p.Cys291Tyr | 11 | 1 (F) | Yes | No |
Truncation occurring between aa 172 and 781 | c.670C > T | p.Gln224* | 9 | 1 (M) | No | No |
Truncation occurring between aa 172 and 781 | c.556_557delGC | p.Ala186Serfs*19 | 9 | 1 (M) | No | No |
Truncation occurring between aa 172 and 781 | c.745-?_977 + ?del | p.(Phe249Lysfs*16) | 10–11 | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.801_802delAT | p.Asn267Lysfs*5 | 11 | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.857dupA | p.Tyr286* | 11 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.859_868del10 | p.Leu287Serfs*3 | 11 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.978-?_2980 + ?del | p.? | 12+ | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.1039C > T | p.Gln347* | 12 | 1 (F) | Yes | No |
Truncation occurring between aa 172 and 781 | c.1371dupA | p.Leu458Thrfs*5 | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1375C > T | p.Gln459* | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1446delC | p.Tyr482* | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1470_1471delGG | p.Ala491Thrfs*3 | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1499ins4 | p.? | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1547_1554del8 | p.Tyr516Phefs*2 | 12 | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.1581del | p.Pro527fs | 12 | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.1648C > T | p.Arg550* | 12 | 4 (F) | Yes | Yes (1 child
[4]) |
Truncation occurring between aa 172 and 781 | c.1671dupA | p.Arg558Thrfs*9 | 12 | 1 (F) | Yes | No |
Truncation occurring between aa 172 and 781 | c.1675C > T | p.Arg559* | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1782 T > G | p.Tyr594* | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.1791delC | p.Tyr598Thrfs*18 | 12 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.2038A > T | p.Lys680* | 13 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.2047-1G > A | p.Gly683Valfs*101 | 13 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.2047-2A > G | p.Gly683Cysfs*66 | 13 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.2072_2073delCT | p.Ser691* | 14 | 1 (F) | Yes | Yes
[4] |
Truncation occurring between aa 172 and 781 | c.2258_2259delAA | p.Gln753Profs*10 | 15 | 1 (F) | No | No |
Truncation occurring between aa 172 and 781 | c.2376 + 5G > A | p.(Lys760Tyrfs*10) | 16 | 1 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2374dupA | p.Thr792Asnfs*9 | 16 | 1 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2377-8 T > A | p.(Val793Leufs*2) | 16 | 1 (F) | No | No |
Late truncation after aa 781 | c.2413C > T | p.Gln805* | 17 | 1 (M) | No | No |
Late truncation after aa 781 | c.2420_2430del | p.Ser807Cysfs*2 | 17 | 1 (M) | No | No |
Late truncation after aa 781 | c.2504delC | p.Pro835Hisfs*2 | 17 | 1 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2477-?_2713 + ?del | p.(Ser833Thrfs*22) | 17 | 2 (F) | No | No |
Late truncation after aa 781 | c.2564C > G | p.Ser855* | 18 | 2 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2572delC | p.Arg858Alafs*5 | 18 | 1 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2635_2636delCT | p.Leu879Glufs*30 | 18 | 2 (F) | Yes | Yes
[4] |
Late truncation after aa 781 | c.2711delC | p.Pro904Glnfs*23 | 18 | 1 (F) | Yes | Yes
[4] |
Mutations not grouped
| ||||||
c.1612A > G | p.Thr538Ala | 1 | 1 (M) | No | No | |
c.2684C > T | p.Pro895Leu | 18 | 1 (F) | No | No | |
c.65-?_1944 + ?dup | p.(?) | 3–12 | 1 (M) | No | No | |
c.146-?_463 + ?dup | p.(?) | 5–7 | 1 (F) | No | No | |
(Position uncertain) | p.(?) | 1–3 | 1 (M) | Yes | Yes
[4] | |
c.745-2A > G | p.(Phe249_Lys275del) | 10 | 1 (F) | Yes | Yes
[4] | |
c.825 + 1G > A | p.(Phe249_Lys275del) | 10 | 1 (F) | Yes | Yes
[4] | |
c.825 + 1G > T | p.(Phe249_Lys275del) | 10 | 1 (F) | Yes | No | |
c.1030_1031insGAC | p.Lys344delinsArgGln | 12 | 1 (F) | Yes | Yes
[4] | |
c.2276 + 1G > A | p.(Val718_Trp759delinsGly) | 15 | 1 (F) | Yes | Yes
[4] |
Nucleotide change (cDNA) | Protein change | SIFT (score 1–0) | MutationTaster (pvalue 0–1) | PolyPhen2 (score 0–1) | Align GVGD (Class C0–C65) |
---|---|---|---|---|---|
c.38 T > C | p.Phe13Ser | Deleterious (0) | Disease-causing (0.999) | Probably damaging (0.999) | Benign (C0) |
c.58G > C | p.Gly20Arg | Deleterious (0) | Disease-causing (1) | Probably damaging (0.985) | Benign (C0) |
c.119C > T | p.Ala40Val | Tolerated (0.12) | Disease-causing (0.999) | Probably damaging (0.999) | Benign (C0) |
c.191 T > C | p.Leu64Pro | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Benign (C0) |
c.364G > A | p.Ala122Thr | Deleterious (0) | Disease-causing (1) | Probably damaging (0.999) | Likely pathogenic (C55) |
c.377G > A | p.Cys126Tyr | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Pathogenic (C65) |
c.395 T > G | p.Val132Gly | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Pathogenic (C65) |
c.428 T > A | p. Ile143Asn | Deleterious (0) | Disease-causing (1) | Possibly damaging (0.9) | Benign (C0) |
c.458A > T | p. Asp153Val | Deleterious (0) | Disease-causing (1) | Benign (0.07) | Benign (C0) |
c.473G > C | p.Arg158Pro | Deleterious (0) | Disease-causing (1) | Probably damaging (0.999) | Benign (C0) |
c.514G > A | p.Val172le | Deleterious (0) | Disease-causing (1) | Probably damaging (0.995) | Benign (C0) |
c.526 T > C | p. Trp176Arg | Deleterious (0) | Disease-causing (1) | Probably damaging (0.999) | Benign (C0) |
c.532C > T | p.Arg178Trp | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Benign (C0) |
c.536C > T | p. Ser179Phe | Deleterious (0) | Disease-causing (1) | Probably damaging (0.999) | Likely benign (C15) |
c.577G > C | p.Asp193His | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Pathogenic (C65) |
c.587C > T | p.Ser196Leu | Deleterious (0) | Disease-causing (1) | Probably damaging (0.976) | Pathogenic (C65) |
c.595 T > C | p.Cys199Arg | Deleterious (0) | Disease-causing (1) | Probably damaging (0.999) | Pathogenic (C65) |
c.620G > A | p.Gly207Glu | Deleterious (0) | Disease-causing (1) | Probably damaging (1) | Pathogenic (C65) |
c.656A > C | p.Gln219Pro | Deleterious (0) | Disease-causing (1) | Probably damaging (0.996) | Pathogenic (C65) |
c.680 T > C | p.Leu227Pro | Deleterious (0) | Disease-causing (1) | Probably damaging (0.996) | Pathogenic (C65) |
c.2684C > T | p.Pro895Leu | Deleterious (0.03) | Disease causing (1) | Possibly damaging (0.578) | Benign (C0) |
c.872G > A | p.Cys291Tyr | Deleterious (0.01) | Disease causing (1) | Probably damaging (0.930) | Benign (C0) |
c.215 T > C | p.Ile72Thr | Deleterious (0) | Disease-causing (1) | Possibly damaging (0.578) | Benign (C0) |
c.1612A > G | p.Thr538Ala | Deleterious (0.04) | Polymorphism (1) | Benign (0.009) | Benign (C0) |
c.526 T > C | p.Trp167Arg | Deleterious (0) | Disease causing (1) | Probably damaging (0.999) | Benign (C0) |
Time-to-event analysis of attainment of developmental milestones
Age at completion of questionnaire | ||||||||
---|---|---|---|---|---|---|---|---|
1.5 years and under | 1.5–7 years | 7–13 years | 13 years and over | |||||
Developmental skill | Females (n = 11) | Males (n = 1) | Females (n = 50) | Males (n = 10) | Females (n = 32) | Males (n = 5) | Females (n = 16) | Males (n = 2) |
Gross motor
| ||||||||
Roll front to back | 4 (36.4) | 1 (100) | 46 (92) | 5 (50) | 27 (84) | 2 (40) | 14 (88) | 1 (50) |
Roll back to front | 5 (45) | 1 (100) | 47 (94) | 5 (50) | 26 (81) | 2 (40) | 14 (88) | 1 (50) |
Transition from sitting to crawling position | 1 (9) | 1 (100) | 23 (46) | 3 (30) | 16 (50) | 0 (0) | 5 (31) | 1 (50) |
Crawl | 1 (9) | 0 (0) | 12 (24) | 2 (20) | 10 (31) | 0 (0) | 4 (25) | 1 (50) |
Stand with support | 2 (18) | 1 (100) | 37 (74) | 3 (30) | 22 (69) | 1 (20) | 10 (63) | 1 (50) |
Pull to stand | 1 (9) | 0 (0) | 13 (26) | 2 (20) | 14 (44) | 1 (20) | 6 (38) | 1 (50) |
Walk with support | 1 (9) | 0 (0) | 24 (48) | 1 (10) | 16 (50) | 1 (20) | 8 (50) | 1 (50) |
Fine motor
| ||||||||
Transfer from hand to hand | 3 (27) | 1 (100) | 25 (50) | 2 (20) | 18 (56) | 0 (0) | 8 (50) | 0 (0) |
Play with blocks | 0 (0) | 0 (0) | 8 (16) | 1 (10) | 8 (25) | 0 (0) | 2 (13) | 0 (0) |
Social and communication
| ||||||||
Social smile | 8 (73) | 1 (100) | 38 (76) | 7 (70) | 18 (56) | 1 (20) | 9 (56) | 0 (0)a
|
Fix and follow | 3 (30.0)a
| 1 (100) | 39 (78) | 4 (40) | 23 (72) | 1 (20) | 10 (67)a
| 1 (100)a
|
Wave goodbye | 0 (0.0) | 0 (0) | 11 (22) | 1 (10) | 4 (13) | 0 (0) | 1 (6) | 0 (0) |
Respond to own name | 4 (36) | 1 (100) | 33 (66) | 3 (33.3)a
| 20 (63) | 2 (40) | 9 (56) | 0 (0) |
Point to things that he/she wants | 0 (0.0) | 0 (0) | 6 (12) | 1 (10) | 8 (26)a
| 0 (0) | 2 (13) | 0 (0) |
Respond to others emotions | 4 (36) | 1 (100) | 23 (47)a
| 4 (40) | 11 (34) | 1 (20) | 4 (25) | 1 (50) |
Respond to ‘no’ | 2 (18) | 0 (0) | 16 (32) | 2 (25)a
| 13 (41) | 0 (0) | 4 (25) | 0 (0) |
Phrases | 0 (0.0) | 0 (0) | 3 (6) | 0 (0) | 3 (9) | 0 (0) | 1 (6) | 0 (0) |
Relationship between genotype and attainment of developmental milestones for females
Milestone | No functional protein | Missense/in-frame mutation within catalytic domain | Truncation between aa 172 and aa 781 inclusive | Truncation after aa 781 | ||||
---|---|---|---|---|---|---|---|---|
Number (%) | Median age skill attained (years) | Number (%) | Median age skill attained (years) | Number (%) | Median age skill attained (years) | Number (%) | Median age skill attained (years) | |
Sitting | 17/33 (52) | 2 | 18/27 (67) | 3 | 10/26 (38) | - | 10/12 (83) | 1.2 |
Standing | 6/32 (19) | - | 5/28 (18) | - | 8/28 (29) | - | 5/10 (50) | 5 |
Walking | 6/34 (18) | - | 4/28 (14) | - | 6/28 (21) | - | 5/12 (42) | |
Babble | 13/29 (45) | - | 13/27 (48) | 6 | 12/25 (44) | - | 4/8 (50) | 1 |
Single words | 4/32 (13) | - | 3/28 (11) | - | 6/28 (21) | - | 3/10 (30) | |
Raking grasp | 12/29 (44) | 7 | 16/25 (64) | 4 | 8/22 (36) | 12 | 7/9 (78) | 2 |
Pincer grasp | 3/32 (9) | - | 2/28 (7) | - | 2/28 (7) | - | 4/10 (40) | - |