Table 1.
List of All 28 Genes Discussed and Associated Evidence Supporting or Questioning Their Involvement in ID
| Gene (RefSeq Accession Number) | Listsa | Reason for Highlightb | Identification Methodc | ID Structural Variations | ID Point Mutations | Occurrence of Mutations in EVSd | Truncated Variants in EVS | dN/dS Ratio (#N/#S) | Protein Size | Implication in ID |
|---|---|---|---|---|---|---|---|---|---|---|
| AGTR2 (NM_000686.4) | L, R, G, E, A | T | 1 | (X; 7) translocation in a female19 | c.402del (p.Phe134Leufs∗5)19 | (see Table S4) | yes (1 F) | 0.731 (19/8) | 363 | highly questionable (already controversial)20–22 |
| c.62G>T (p.Gly21Val)19,23 | 10 M, 23 F (htz) | |||||||||
| c.971G>A (p.Arg324Gln)19 | 4 M, 24 F (htz) | |||||||||
| c.1009A>G (p.Ile337Val)19 | NF | |||||||||
| c.157A>T (p.Ile53Phe)24 | NF | |||||||||
| c.572G>A (p.Gly191Glu)23 | NF | |||||||||
| MAGT1 (IAP) (NM_032121.5) | L, R, G, E | T | 3 | - | c.1028T>G (p.Val311_343Gly)25 | 5 M, 8 F (htz) | yes (1 M) | 0.453 (15/10) | 367 | highly questionable |
| NXF5 (NM_032946.2) | L, R, G, A | T | 1 | inv(X)(p21.1;q22) in two males;26,27 deletion disrupting the NXF cluster;28,29 duplication at Xq22.1 disrupting30 and duplicating31NXF5 in one female and one male, respectively | - | - | yes (8 M) | 0.783 (30/11) | 365 | highly questionable |
| ZNF674 (NM_001039891.2) | L, R, E, A | T | 1 | deletion encompassing ZNF673, ZNF674, RP2, SLC9Z7, and CHST7 in one male;32 duplication encompassing ZNF673, ZNF674, and CHST733 | c.352G>T (p.Glu118∗)32 | NF | yes (19 M) | 0.750 (28/10) | 581 | highly questionable (already controversial)34 |
| c.1235C>A (p.Pro412Leu)32 | NF | |||||||||
| c.1028C>T (p.Met343Thr)32 | 49 M, 16 F (hmz), 223 F (htz) | |||||||||
| ZNF41 (NM_007130.2) | L, R, G, E, A | M | 1 | (X; 7) translocation disrupting ZNF4135 | c.332C>T (p.Pro111Leu)35 c.73−42A>C (p.?)35 | 2 M, 8 F (htz) | yes (1 M, 1 F) | 0.696 (45/17) | 779 | highly questionable |
| 5 M, 9 F (htz) | ||||||||||
| ZNF81 (NM_007137.3) | L, R, G, E, A | M | 1 | (X; 9) translocation in one female;36 1.3 Mb duplication encompassing >30 genes at Xp11.23–p11.3 in one male;37 335 kb microduplication bearing two other genes at Xp11.2–p11.3 in one male38 | c.536G>A (p.Ser179Asn)36 | NF | yes (1 M) | 0.595 (25/11) | 661 | questionable |
| ARHGEF6 (NM_004840.2) | L, R, G, E, A | M | 1 | (X; 21) translocation in one male39 | c.166−11T>C (p.?)39 | 5 M, 13 F (htz) | no | 0.456 (28/18) | 776 | questionable |
| ATP6AP2 (NM_005765.2) | L, R, G, E, A | T | 2 | - | c.321C>T (p.Asp107Asp) (affects splicing)40 | NF | yes (1 M) | 0.444 (14/10) | 350 | questionable |
| SRPX2 (NM_014467.2) | L, R, G, E, A | M | 2 | - | c.980A>G (p.Asn327Ser)41 | 3 M, 8 F (htz) | no | 0.728 (31/14) | 465 | questionable |
| c.215A>C (p.Tyr72Ser)41 | 1 M | |||||||||
| ZCCHC12 (SIZN1) (NM_173798.2) | E | M | 3 | - | c.19C>T (p.Arg7Cys)42 | 5 M, 28 F (htz) | no | 0.406 (19/14) | 402 | questionable |
| c.1031C>T (p.Thr344Ile)42 | NF | |||||||||
| IGBP1 (NM_001551.2) | L, G, E | I | 2 | - | 5′ UTR 2 bp substitution affecting IGBP1 expression43 | not covered | no | 0.487 (19/11) | 339 | never replicated |
| KIAA2022 (NM_001008537.2) | L, R, G, E, A | I | 1 | inv(X)(q13;p22) in two related males44 | - | NA | no | 0.441 (54/34) | 1,516 | never replicated |
| KLF8 (NM_007250.4) | L, R, G, E | I | 1 | (X; 21) translocation leading to a loss of KLF8 expression in a woman45 | - | NA | no | 0.831 (16/6) | 359 | never replicated |
| NLGN3 (NM_181303.1) | L, R, G, E, A | I | 3 | - | c.1411C>T (p.Arg451_471Cys) in two ASD brothers46 | NF | no | 0.209 (17/27) | 848 | never replicated |
| ZDHHC15 (NM_144969.2) | L, G, E | I | 1 | (X; 15) translocation leading to a loss of ZDHHC15 expression in a female47 | - | NA | no | 0.628 (17/8) | 337 | never replicated |
| ZNF261 (ZMYM3) (NM_201599.2) | R | I | 1 | (X; 13) translocation disrupting ZMYM3 in one female48 | - | NA | no | 0.232 (31/42) | 1,370 | never replicated |
| MAOA (NM_000240.3) | L, R, G, E, A | I | 1 | MAOA-MAOB-NDP deletion in subjects with severe ID49 | c.886C>T (p.Gln296∗)50 | NF | no | 0,359 (14/12) | 527 | never replicated |
| CCDC22 (NM_014008.3) | - | I | 3 | - | c.49A>G (p.Thr17Ala)51 | NF | no | 0.809 (40/17) | 627 | awaiting replication |
| CLIC2 (NM_001289.4) | - | I | 4 | - | c.303C>G (p.His101Gln)52 | NF | no | 0.346 (6/5) | 247 | awaiting replication |
| CNKSR2 (NM_014927.3) | - | I | 1 | partial deletion of CNKSR253 | - | NA | no | 0.340 (22/19) | 1,034 | awaiting replication |
| FRMPD4 (NM_014728.3) | - | I | 1 | partial duplication of FRMPD454 | - | NA | no | 0.383 (57/46) | 1,322 | awaiting replication |
| HCFC1 (NM_005334.2) | - | I | 2 | - | chrX: 152890455A>G55 | NA | no | 0.227 (50/80) | 2,035 | awaiting replication |
| c.674G>A (p.Ser225Asn)55 | NF | |||||||||
| NAA10 (NM_003491.2) | L | I | 4 | - | c.109T>C (p.Ser37Pro)56 | NF | no | 0.074 (2/8) | 235 | likely in Ogden syndrome but needs further replication in nonsyndromic ID |
| c.346C>T (p.Arg116Trp)13 | NF | |||||||||
| RPL10 (NM_006013.3) | L, R, G, E, A | I | 3 | - | c.616C>A (p.Leu206Met) (ASD)57 | NF | no | 0.154 (2/4) | 214 | awaiting replication |
| c.639C>G (p.His213Gln) (ASD)57,58 | NF | |||||||||
| SHROOM4 (NM_020717.3) | L, R, G, E, A | I | 1 | X-autosome translocations in two females;59 Xp11.22 deletion bearing SHROOM4 in one family54 | c.3266C>T (p.Ser1089Leu)59 | NF | yes (1 F) | 0.918 (86/28) | 1,493 | awaiting replication |
| c.1422A>G (p.Glu474Glu)59 | NF | |||||||||
| HUWE1 (NM_031407.5) | L, R, G, E, A | I | 1 | microduplications encompassing HSD17B10 and HUWE160,61 or HUWE1 alone62 in a total of 16 unrelated families | c.12037C>T (p.Arg4013Trp)61 | NF | no | 0.201 (67/105) | 4,374 | likely |
| c.8942G>A (p.Arg2981His)61 | NF | |||||||||
| c.12559C>T (p.Arg4187Cys)61 | NF | |||||||||
| c.2849T>A (p.Val950Asp) (ASD)63 | NF | |||||||||
| PTCHD1 (NM_173495.2) | L | M | 1 | 160 kb deletion leading to a null PTCHD1 in dizygotic ASD twin brothers;64 50–390 kb inherited deletions disrupting PTCHD1 in six ASD male probands;65 90 kb deletion disrupting PTCHD1 in three related ID males;60,66 200 kb deletion in two ID brothers67 | c.517A>G (p.Ile173Val)66 | 2 M, 2 F (htz) | no | 0.366 (29/25) | 888 | likely |
| c.583G>A (p.Val195Ile)66 | NF | |||||||||
| c.1008_1009delinsTA (p.MetLeu336_337IleIle)66 | NF | |||||||||
| c.217C>T (p.Leu73Phe)66 | 1 F (htz) | |||||||||
| c.1436A>G (p.Glu479Gly)66 | NF | |||||||||
| c.1409C>A (p.Ala470Asp)66 | NF | |||||||||
| c.1076A>G (p.His359Arg)66 | NF | |||||||||
| SYN 1 (NM_006950.3) | L, R, G, E, A | M | 2 | - | c.1067G>A (p.Trp356∗)68 | NF | no | 0.347 (12/12) | 705 | likely |
| c.1663C>T (p.Gln555∗)69 | not covered | |||||||||
| c.152C>G (p.Ala51Gly)69 | 11 M, 30 F (htz) | |||||||||
| c.1648G>A (p.Ala550Thr)69 | not covered | |||||||||
| c.1699A>G (p.Thr567Ala)69 | not covered |
Abbreviations are as follows: L, Lubs et al.;4 R, Ropers et al.;8 G, Greenwood Genetic Center (see Web Resources); E, Emory Genetics Laboratory (see Web Resources); A, Ambry Genetics (see Web Resources); T, truncating variants reported in EVS; M, ID mutations reported in EVS; I, one piece of evidence or study implicating this gene in ID; htz, heterozygous; hmz, homozygous; M, number of males carrying the mutation; F, number of females carrying the mutation; NF, not found; NA, not applicable; N, number of nonsynonymous variants; and S, number of silent variants.
a
Lists in which genes are included.
b
Reason why we discuss this gene in the paper.
c
Approach used for the initial identification, consistent with the information from the text: 1, positional candidate found through rearrangement or CNV; 2, positional candidate located in a linked region; 3, functional candidate; and 4, through exome or X-exome sequencing.
d
Occurrence of ID mutations in EVS.