Table 2.
Rare variants unique to CDD probands
| Sex | Inheritance | Gene | AA change | Genomic coordinate (hg19) | Reference | Variant | Brain exp | PhyloPb | RVIS | PolyPhen2 | Gene-associated OMIM disorder (#, inheritance) | Variants identified in ID, ASD, EE, SCZ, DD: #, inheritance, variant type [reference] |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CDD03-03 | ||||||||||||
| M | Hemizygous | NRK | K336R | chrX:105150568 | A | G | Yes | 5.88 | n/a | 0.999 (Mis3) | n/a | ID: 1 DN, 7 n/a missense [42–44] |
| M | Hemizygous | TBC1D8B | L653I | chrX:106093374 | C | A | Yes | 4.84 | -1.15 | 0.999 (Mis3) | n/a | ASD: 1 DN missense [23]; ID: 1 DN, 2 n/a missense [42, 43] |
| M | Hemizygous | NKRF | K50R | chrX:118725239 | T | C | Yes | 1.39 | -0.54 | 0.005 (Mis1) | n/a | ID: 3 n/a missense [44] |
| M | Hemizygous | SAGE1 | A362V | chrX:134989926 | C | T | Yes | -0.03 | 0.01 | 0.000 (Mis1) | n/a | ASD: 1 DN missense [23]; ID: 4 n/a missense [42, 44] |
| CDD05-03 | ||||||||||||
| M | Homozygous | TCTEX1D2 | R110C | chr3:196022930 | G | A | Yes | 2.69 | 0.28 | 1.000 (Mis3) | n/a | SCZ: 1 DN, 20 n/a deletion [45, 46] |
| M | Hemizygous | USP26 | P683L | chrX:132160201 | G | A | No | -1.09 | 0.46 | 0.000 (Mis1) | n/a | ID: 4 n/a missense [42, 44] |
| CDD07-03 | ||||||||||||
| M | De novo | BBS9 | L376P | chr7:33376163 | T | C | Yes | 5.72 | 1.05 | 0.222 (Mis1) | Bardet-Biedl syndrome 9 (615986, AR) | Syndromic ID |
| M | De novo | TRRAP | P1781S | chr7:98548580 | C | T | Yes | 7.70 | -6.14 | 1.000 (Mis3) | n/a | ASD: 3 DN missense [23]; EE: 1 DN missense [47]; SCZ: 1 DN missense, 1 DN SS [48]; DD: 3 DN missense [49] |
| M | Homozygous | DNMT3B | A364T | chr20:31383238 | G | A | Yes | 0.31 | -1.70 | 0.000 (Mis1) | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (242860, AR) | Syndromic ID |
| M | Hemizygous | CDR1 | G161R | chrX:139866051 | C | T | Yes | 0.37 | 0.15 | 0.995 (Mis3) | n/a | ID: 2 n/a missense [42] |
| M | Hemizygous | FAM50A | E136K | chrX:153674872 | G | A | Yes | 6.75 | -0.01 | 0.010 (Mis1) | n/a | ID: 1 n/a missense [42]; EE: 1 DN missense [47] |
| CDD08-03 | ||||||||||||
| M | Hemizygous | CNGA2 | F385S | chrX:150912129 | T | C | No | 7.56 | 0.49 | 0.999 (Mis3) | n/a | ID: 5 n/a missense [42, 44] |
| CDD09-03 | ||||||||||||
| M | Homozygous | NOP9 | A161_E162insEE | chr14:24769850 | * | I:AGGAGG | Yes | 0.59 | 0.98 | n/a | n/a | DD: 1 DN indel [49] |
| M | Hemizygous | ZXDA | V264L | chrX:57936065 | C | A | Yes | -0.44 | n/a | 0.000 (Mis1) | n/a | ID: 1 DN, 1 n/a missense [42, 43] |
| M | Hemizygous | SPANXN2 | L41F | chrX:142795555 | C | A | No | -1.83 | 0.41 | 0.946 (Mis2) | n/a | ID: 1 n/a missense [42] |
| CDD10-03 | ||||||||||||
| M | De novo | NAV2 | R2046W | chr11:20122629 | C | T | Yes | 3.78 | -1.56 | 1.000 (Mis3) | n/a | ASD: 2 DN missense [23] |
| CDD12-03 | ||||||||||||
| F | Homozygous | ADAMTS18 | S660N | chr16:77359816 | C | T | Yes | 4.90 | -0.09 | 0.001 (Mis1) | Microcornea, myopic chorioretinal atrophy, and telecanthus (615458, AR) | |
| CDD13-03 and 04 (MZ twins)a | ||||||||||||
| F | De novo | BBS5 | I76M | chr2:170344335 | A | G | Yes | 1.29 | 0.04 | 0.82 (Mis2) | Bardet-Biedl syndrome 5 (615983, AR) | Syndromic ID |
| F | De novo | NSD1 | R964W | chr5:176639097 | C | T | Yes | 0.27 | -1.55 | 0.997 (Mis3) | Sotos syndrome 1 (117550, AD), Beckwith-Wiedemann syndrome (130650, AD) | Syndromic ID and ASD |
| F | De novo | OGDHL | 3′UTR deletion | chr10:50940935-50943068 | * | CNV: deletion | Yes | 5.43 | -0.54 | n/a | n/a | |
| F | Hemizygous | TUBGCP5 | T274S | chr15:22846945 | A | T (paternal allele deleted) | Yes | 8.29 | -0.77 | 0.891 (Mis2) | n/a | ASD: 1 DN missense [23]; ID: 1 inh deletion [50]; EE: 1 inh deletion [50]; SCZ: 1 inh deletion [50] |
| CDD15-03 | ||||||||||||
| M | De novo | ZNF236 | L1599H | chr18:74659496 | T | A | Yes | 5.43 | -1.53 | 0.999 (Mis3) | n/a | |
| M | Hemizygous | SUPT20HL2 | G472R | chrX:24330019 | C | T | No | 1.32 | n/a | 0.884 (Mis2) | n/a | |
| CDD16-03 | ||||||||||||
| M | Homozygous | PRKCSH | E314_E315del | chr19:11558343-11558348 | * | D:GGAGGA | Yes | 1.61 | -0.89 | n/a | Polycystic liver disease 1 (174050, AD) | |
| M | Hemizygous | SUPT20HL2 | P795A | chrX:24329050 | G | C | No | -0.55 | n/a | 0.047 (Mis1) | n/a | |
| M | Hemizygous | USP9X | A843G | chrX:41027363 | C | G | Yes | 7.62 | -1.62 | 0.102 (Mis1) | Mental retardation, X-linked 99 (300919, XLR and 300968, XLD) | Syndromic ID and EE |
| M | Hemizygous | GATA1 | A55T | chrX:48649679 | G | A | Yes | 1.06 | -0.60 | 0.993 (Mis3) | Anemia (300835, XLR); Thrombocytopenia (314050, XLR and 300367, XLR) | |
| M | Hemizygous | MTMR8 | N265K | chrX:63564995 | G | T | Yes | 4.00 | -0.77 | 1.000 (Mis3) | n/a | ASD: 1 DN missense [23], 1 hemizygous SS [51]; ID: 5 n/a missense [42, 44] |
| M | Hemizygous | DCX | M51V | chrX:110654052 | T | C | Yes | 0.66 | -0.10 | 0.002 (Mis1) | Lissencephaly, X-linked (300067, XL) | Syndromic ID and EE |
| M | Hemizygous | CT47B1 | L236P | chrX:120008818 | A | G | No | -1.15 | n/a | 0.001 (Mis1) | n/a | ASD: 1 DN missense [23]; ID: 2 n/a missense [44] |
| CDD17-03 | ||||||||||||
| M | Heterozygous | CLUL1 | 5′SS disruption | chr18:618107 | G | A (paternal) | Yes | 6.04 | 0.66 | n/a | n/a | |
| M | Hemizygous | BCOR | F1023L | chrX:39930395 | G | C | Yes | 8.97 | -3.03 | 0.999 (Mis3) | Microphthalmia, syndromic 2 (300166, XLD) | Syndromic ID |
| M | Hemizygous | BEX2 | Y97C | chrX:102564711 | T | C | Yes | 0.78 | 0.64 | 0.046 (Mis1) | n/a | ASD: 1 n/a missense [52]; ID: 1 n/a missense [42]; SCZ: 1 n/a missense [52] |
| M | Hemizygous | VSIG1 | Q88R | chrX:107304707 | A | G | Yes | 1.19 | -0.18 | 0.856 (Mis2) | n/a | ASD: 2 hemizygous SS [51]; ID: 1 n/a missense [44] |
| M | Hemizygous | SRPK3 | R619Q | chrX:153050929 | G | A | Yes | 7.69 | -0.33 | 1.000 (Mis3) | n/a | ID: 7 n/a missense [42, 44, 53] |
| M | Hemizygous | USP9Y | R122X | chrY:14837084 | C | T | Yes | 2.63 | n/a | n/a | Spermatogenic failure, Y-linked, 2 (415000, YL) | |
| CDD20-03a | ||||||||||||
| M | Homozygous | KIAA2018 | Q1472del | chr3:113376112-113376114 | * | D:GCT | Yes | 3.58 | -0.71 | n/a | n/a | ASD: 1 DN nonsense, 4 n/a missense [22]; EE: 1 DN missense [47]; SCZ: 1 DN missense [54] |
| M | Homozygous | BRIP1 | V193I | chr17:59924512 | C | T | Yes | -0.69 | -0.64 | 0.000 (Mis1) | Breast cancer, early-onset (114480, AD); Fanconi anemia, complementation group J (609054, AR) | |
| M | Hemizygous | PDK3 | K410Q | chrX:24557261 | A | C | Yes | 2.44 | 0.13 | 0.001 (Mis1) | Charcot-Marie-Tooth disease, 6 (300905, XLD) | |
| M | Hemizygous | ARSF | R386Q | chrX:3021857 | G | A | Yes | 6.00 | 0.36 | 0.999 (Mis3) | n/a | ASD: 1 n/a nonsense [51]; ID: 4 n/a missense, 3 n/a indel, 2 n/a SS [42, 44] |
| M | Hemizygous | ALAS2 | V193I | chrX:55047546 | C | T | Yes | 3.26 | 0.13 | 0.803 (Mis2) | Anemia, sideroblastic, 1 (300751, XLR); Protoporphyria, erythropoietic (300752, XLD) | |
| M | Hemizygous | STARD8 | 3 bp deletion | chrX:67938303-67938305 | * | D:AAG | Yes | 3.59 | 0.74 | n/a | n/a | ID: 2 n/a missense, 1 n/a indel [42, 44] |
| M | Hemizygous | CXorf57 | R545T | chrX:105882817 | G | C | Yes | 6.24 | -0.40 | 1.000 (Mis3) | n/a | ID: 2 n/a missense [42, 44] |
| M | Hemizygous | ALG13 | S891F | chrX:110980084 | C | T | Yes | 4.77 | -1.00 | 0.986 (Mis3) | Epileptic encephalopathy, early infantile, 36 (300884, XLD) | Syndromic ID and EE |
| CDD21-03 | ||||||||||||
| F | Homozygous | RAD51C | T287A | chr17:56798128 | A | G | Yes | 5.16 | 0.11 | 0.988 (Mis3) | Fanconi anemia, complementation group O (613390, AR) | |
| F | Homozygous | SHANK3 | G277R | chr22:51117800 | G | A | Yes | 1.95 | n/a | 0.002 (Mis1) | Phelan-McDermid syndrome (606232, DN); Schizophrenia 15 (613950, DN) | Syndromic ID, ASD, EE, SCZ |
| CDD22-03 | ||||||||||||
| M | Homozygous | DAP3 | G5E | chr1:155679584 | G | A | Yes | 1.86 | -0.22 | 0.890 (Mis2) | n/a | ASD: 1 DN missense [23] |
| M | Hemizygous | ENOX2 | E12K | chrX:129843232 | C | T | Yes | -0.35 | -0.43 | 0.000 (Mis1) | n/a | ID: 1 hemizygous, 1 n/a missense [42, 55] |
Abbreviations: AA amino acid, AD autosomal dominant, AR autosomal recessive, ASD autism spectrum disorder, CDD childhood disintegrative disorder, CNV copy number variant, DD developmental disorders, DN de novo, EE epilepsy/epileptic encephalopathy, F female, indel insertion/deletion, inh inherited, ID intellectual disability, M male, Mis1 Missense1 (benign), Mis2 Missense2 (possibly damaging), Mis3 Missense3 (probably damaging), MZ monozygotic, OMIM Online Mendelian Inheritance in Man, PhyloP phylogenetic P-value, PolyPhen-2 polymorphism phenotyping v2, RVIS Residual Variation Intolerance Score, SCZ schizophrenia/childhood-onset schizophrenia, SS splice site, XL X-linked, XLD X-linked dominant, XLR X-linked recessive, YL Y-linked
aNo discordant variants were confirmed between monozygotic twin girls CDD13-03 and 04 (CDD) and between monozygotic twin boys CDD20-03 (CDD) and 04 (ASD)
bPhyloP scores for indels and CNVs were calculated by averaging the PhyloP scores for all positions affected
*wild-type sequence