Table 2.
Summary of diagnosed conditions and causative variants in the cohort, classified by the mode of inheritance (see Fig 0.1)
| N | Patient ID | Gene | Codon and amino acid change | Effect on protein | Position on chromosome GRCh38.p13 |
Chromosome | Number of diagnosed cases | OMIM ID | Disorder |
|---|---|---|---|---|---|---|---|---|---|
| Autosomal dominant mode of inheritance (N = 41) | |||||||||
| 1 | 190 | ATP1A3 | c.2851G > A (p. Glu951Lys) | missense | 41,967,732 | 19q13.2 | 1 | 614,820 | Alternating hemiplegia of childhood 2 |
| 2 | 55 | C19ORF12 | c.204_214del (p. Gly69Argfs*10) | frameshift | 29,702,957–29,702,977 | 19q12 | 1 | 614,298 | Neurodegeneration with brain iron accumulation 4 |
| 3 | 147 | CHD1 |
c.206 C > G (p.Ser69Pro) |
missense | 98,904,946 | 5q15-q21.1 | 1 | 617,682 | Pilarowski-Bjornsson syndrome |
| 4 | 139 | CTBP1 | c.991 C > T(p.Arg331Trp) | missense | 1,213,028 | 4p16.3 | 1 | 617,915 | Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome |
| 5 | 278 | DEPDC5 | c.1325-1G > A | splice acceptor | 31,810,520 | 22q12.2-q12.3 | 1 | 604,364 | Epilepsy, familial focal, with variable foci 1 |
| 6 | 14 | DYRK1A | c.1294G > T | stop gained | 37,505,364 | 21q22.13 | 1 | 614,104 | Intellectual developmental disorder, autosomal dominant 7 |
| 7 | 101 | FOXG1 | c.701 C > T (p.Ser234Phe) | missense | 28,767,980 | 14q12 | 2 | 613,454 | Rett syndrome, congenital variant, FOXG1 syndrome |
| 8 | 392 | c.587 A > C (p.Gln196Pro) | missense | 28,767,866 | |||||
| 9 | 108 | GABRB3 | c.288G > T (p.Arg96Ser) | missense | 26,621,487 | 15q12 | 2 | 617,113 | Developmental and epileptic encephalopathy 43 |
| 10 | 23 | c.905 A > G (p.Tyr302Cys) | missense | 26,561,107 | |||||
| 11 | 314 | GLRA1 | c.381dup (p.Phe128Leufs*11) | frame shirt | 15,185,987 | 5q33.1 | 1 | 149,400 | Hyperekplexia 1 |
| 12 | 161 | GNB1 | c.239T > C (p.Ile80Thr) | missense | 1,806,503 | 1p36.33 | 1 | 616,973 | Intellectual developmental disorder, autosomal dominant 42 |
| 13 | 151 | KCNA2 | c.997T > C (p.Phe333Leu) | missense | 110,603,786 | 1p13.3 | 2 | 616,366 | Developmental and epileptic encephalopathy 32 |
| 14 | 376 | c.1219 C > T (p.Pro407Ser) | missense | 110,603,564 | |||||
| 15 | 65 | KCNQ2 | c.1639 C > T (p.Arg547Trp) | missense | 63,413,574 | 20q13.33 | 1 | 613,720 | Developmental and epileptic encephalopathy 7 |
| 16 | 237 | KCNT1 | c.1309 C > T (p.Leu437Phe) | missense | 135,765,732 | 9q34.3 | 2 | 614,959 | Developmental and epileptic encephalopathy 14 |
| 17 | 323 | c.784 C > T (p.Arg262Trp) | missense | 135,758,438 | |||||
| 18 | 131 | KDM1A |
c.2410dupA (p.Ser785Leufs*22) |
frame shift | 23,082,331 | 1p36.12 | 1 | 616,728 | Cleft palate, psychomotor retardation, and distinctive facial features |
| 19 | 68 | KMT2C | c.8965_8970delinsAGTACCTT (p.Val2989Serfs*44) | missense | 118,504,857 | 7q36.1 | 1 | 617,768 | Kleefstra syndrome 2 |
| 20 | 290 | KMT2D | c.14,710 C > T (p.Arg4904*) | stop gained | 49,027,256 | 12q13.13 | 1 | 147,920 | Kabuki syndrome 1 |
| 21 | 134 | MACF1 |
c.7661 A > G (p.Gln2554Arg) |
missense | 39,382,151 | 1p34.3 | 1 | 618,325 | Lissencephaly 9 with complex brainstem malformation |
| 22 | 44 | KMT2A | c.2968_2969insAGAG (p.Cys990*) | nonsense | 118,474,126 | 11q23.3 | 2 | 605,130 | Wiedemann-Steiner syndrome |
| 23 | 72 | c.1038del (p.Val347fs) | frame shift | 118,472,196 | |||||
| 24 | 172 | NPRL3 | Exon 2–6 deletion | truncating |
112,622 - 138,334 |
16p13.3 | 1 | 617,118 | Epilepsy, familial focal, with variable foci 3 |
| 25 | 182 | PAFAH1B1 | c.1159 + 2T > A | splice donor | 2,680,322 | 17p13.3 | 2 | 607,432 | Lissencephaly 1 |
| 26 | 284 |
c.656G > A (p.Trp219*) (mosaic) |
nonsense | 2,674,239 | |||||
| 27 | 150 | PTPN11 |
c.922 A > G (p.Asn308Asp) |
missense | 112,477,719 | 12q24.13 | 1 | 163,950 | Noonan syndrome 1 |
| 28 | 389 | SCN1A | c.4073G > T (p.Trp1358Leu) | missense | 166,002,683 | 2q24.3 | 2 | 607,208 | Dravet syndrome |
| 29 | 403 | c.4265 A > G (p.Tyr1422Cys) | missense | 166,002,491 | |||||
| 30 | 306 | SCN2A | c.2552 C > A (p.Ser851*) | nonsense | 65,342,459 | 2q24.3 | 2 | 613,721 | Developmental and epileptic encephalopathy 11 |
| 31 | 283 | Exon 17 deletion | |||||||
| 32 | 311 | KCNC1 | c.22G > T(p. .Glu8Ter) | missense | 17,736,024 | 11p15.1 | 1 | 616,187 | Epilepsy, progressive myoclonic 7 |
| 33 | 130 | STXBP1 | c.1606delC | 127,682,459 | 9q34.11 | 2 | 612,164 | Developmental and epileptic encephalopathy 4 | |
| 34 | 224 | c.175G > A (p.Glu59Lys) | missense | 127,658,380 | |||||
| 35 | 257 | SYNGAP1 | c.1564del (p.Glu522Lysfs*5) | frame shirt | 33,438,273 | 6p21.32 | 2 | 612,621 | Developmental disorder, autosomal Intellectual dominant 5 |
| 36 | 126 | c.1534G > T (p.Glu512Ter) | stop gained | 33,438,777 | |||||
| 37 | 142 | TGFBR1 |
c.844T > C (p.Tyr282His) |
missense | 99,142,574 | 9q22.33 | 1 | 609,192 | Loeys-Dietz syndrome 1 |
| 38 | 116 | TLK2 |
c.754 C > T (p.Gln252Ter) |
stop gained | 62,560,049 | 17q23.2 | 1 | 618,050 | Intellectual developmental disorder, autosomal dominant 57 |
| 39 | 186 | TREX1 | c.341G > A (p.Arg114His) | missense | 48,466,996 | 3p21.31 | 2 | 225,750 | Aicardi-Goutieres syndrome 1 |
| 40 | 378 | c.341G > A (p.Arg114His) | missense | 48,466,996 | |||||
| 41 | 145 | TRRAP | c.6653 A > C (p.Glu823Ala) | missense | 98,967,697 | 7q22.11 | 1 | 618,454 | Developmental delay with or without dysmorphic facies and autism |
| Autosomal recessive mode of inheritance (N = 4) | |||||||||
| 42 | 16 | ARSA | c.465 + 1G > A | splice donor | 50,627,165 | 22q13.33 | 1 | 250,100 | Metachromatic leukodystrophy |
| c.542T > G (p.Ile181Ser) | stop gained | 50,626,976 | |||||||
| 43 | 180 | FBXL4 |
c.45T > G (p.Tyr15*) c.627_633del (p.Asn210Leufs*9) |
frame shift | 98,926,944 | 6q16.1-16.2 | 1 | 615,471 | Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) |
| 44 | 56 | NPC1 | c.2861 C > T (p.Ser954Leu) | missense | 23,539,405 | 18q11.2 | 1 | 257,220 | Niemann-Pick disease, type C1 |
| c.1026G > A (p.Trp342*) | nonsense | 23,556,543 | |||||||
| 45 | 332 | PAH | c.1222 C > T (p.Arg408Trp) | missense | 102,840,493 | 12q23.2 | 1 | 261,600 | Phenylketonuria |
| c.473G > A (p.Arg158Gln) | missense | 102,866,632 | |||||||
| X-linked dominant (N = 9) | |||||||||
| 46 | 42 | CDKL5 | c.372_385del (p.His124Glnfs*2) | frame shift | 18,579,937 | Xp22.13 | 1 | 300,672 | Developmental and epileptic encephalopathy 2 |
| 47 | 251 | MECP2 | c.397 C > T (p.Arg133Cys) | missense | 154,031,431 | Xq28 | 5 | 312,750 | Rett syndrome |
| 48 | 83 | c.806del (p.Gly269Alafs*20) | frame shift | 154,031,025 | |||||
| 49 | 414 | c.1084_1216del (p.Pro362Argfs*3) | frame shift | 154,030,743 | |||||
| 50 | 106 | c.844del (p.Arg282fs) | frame shift | 154,031,020 | |||||
| 51 | 95 | c.1115 C > A (p.Ser372Ter) | stop gained | 154,030,749 | |||||
| 52 | 157 | SLC35A2 |
c.845G > A (p.Gly221Glu) |
missense | 48,905,064 | Xp11.23 | 1 | 300,896 | Congenital disorder of glycosylation, type IIm |
| 53 | 60 | WDR45 | c.1013_1014del (p.Phe338Tyrfs*3) | frame shift | 49,074,874 | Xp11.23 | 2 | 300,894 | Neurodegeneration with brain iron accumulation 5 |
| 54 | 61 | c.64del (p.Cys22Alafs*16) | frame shift | 49,077,902 | |||||
| X-linked recessive (N = 2) | |||||||||
| 55 | 400 | ATP7A | c.2938 C > T (p.Arg980Ter) | stop gained | 78,029,271 | Xq21.1 | 1 | 309,400 | Menkes disease |
| 56 | 200 | ARX | c.1058 C > T (p.Pro353Leu) | missense | 25,012,937 | Xp21.3 | 1 | 308,350 | Developmental and epileptic encephalopathy 1 |