Table 1.
Summary of the 26 candidate genes identified by research ES reanalysis in this study
| Cases | Candidate gene | Mode of inheritance | Variant (hg19) | PolyPhen2 | Mis-Z score | pLI | HSF | Cohort | Phenotype | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| 49 | HOXB9 | De novo |
chr17:g.46700492 G > A NM_024017.4:c.523 C > T NM_024017.4: p.(Pro175Ser) |
Deleterious | 1.59 | 0.10 | MCA without ID | Spondylocostal dysostosis | ||
| 50 | PCSK7 | De novo | chr11:g.117079626 G > C NM_004716.2:c.1678C > G NM_004716.2: p.(Arg560Gly) | Tolerated | 2.75 | 0.19 | MCA without ID | Pai syndrome | ||
| 51 | SMARCB1 | De novo |
chr22:g.24175842 C > G NM_003073.3:c.1070 C > G NM_003073.3: p.(Thr357Arg) |
Deleterious | 4.51 | 1.00 | MCA without ID |
Facial dysmorphism Deafness Cardiac defects Pectus excavatum Hypoplasia of the corpus callosum |
Retterer et al. [54] | |
| 52 | SLC25A24 | De novo |
chr1:g.108700103 C > T NM_013386.3:c.650 G > A NM_013386.3: p.(Arg217His) |
Deleterious | 0.21 | 0.00 | MCA without ID |
Cutis laxa Progeroid facial appearance |
||
| 53 | SBNO2 | De novo |
chr19:g.1122996 A > G NM_014963.2:c.677 T > C NM_014963.2: p.(Leu226Pro) |
Deleterious | 2.07 | 0.02 | MCA with ID | Syndromic poikiloderma | ||
| 54 | NUP50 | AR |
chr22:g.45564079_45564082delGAAG NM_007172.3:c.21_24delGAAG NM_007172.3: p.(Lys8Asnfs*2) chr22:g.45579309 A > G NM_007172.3:c.1112 A > G NM_007172.3: p.(Asn371Ser) |
NA tolerated |
2.11 | 0.24 | Isolated ID/EE | ID | ||
| 55 | CASZ1 | AR |
chr1:g.10707901 C > T NM_001079843.2:c.3454 G > A NM_001079843.2: p.(Ala1152Thr) chr1:g.10714261 G > A NM_001079843.2:c.1853C > T NM_001079843.2: p.(Thr618Ile) |
Deleterious | 4.04 | 1.00 | MCA without ID |
Hyperextensible skin Thoracolumbar scoliosis Myopathy |
||
| 56 | SCUBE2 | AR |
chr11:g.9051581 G > A NM_020974.1:c.2266 C > T NM_020974.1: p.(Pro756Ser) chr11:g.9068923 C > T NM_020974.1:c.1895G > A NM_020974.1: p.(Gly632Asp) |
Deleterious | 0.46 | 0.00 | MCA without ID | Holoprosencephaly | ||
| 57 | ACO2 | AR |
chr22:g.41895778 C > T NM_001098.2:c.85 C > T NM_001098.2: p.(Arg29Trp) chr22:g.41903904 C > T NM_001098.2:c.283 C > T NM_001098.2: p.(Arg95Cys) |
Deleterious | 3.27 | 0.45 | Isolated ID/EE | ID | ||
| 58 | GBP3 | AR | chr1:g.89476647_89476648delAA NM_018284.2:c.1301_1302delTT NM_018284.2: p.(Phe434Tyrfs*13) | NA | −1.33 | 0.00 | MCA without ID |
Ataxia Facial dysmorphism |
||
| 59 | ABCA2 | AR |
chr9:g.139907733_139907739delCGAGCTG NM_001606.4:c.4582_4588delCAGCTCG NM_001606.4: p.(Gln1528*) |
NA | 5.37 | 1.00 | Isolated ID/EE | ID | Maddirevula et al. [11] | |
| 60 | CYFIP2 | AR | chr5:g.156746779 A > G NM_001037333.1:c.1366 A > G NM_001037332.2: p.(Met456Val) | Deleterious | 6.15 | 1.00 | MCA with ID |
ID Facial dysmorphism |
||
| 60 | TMEM71 | AR | chr8:g.133764099 G > T NM_001145153.1:c.246 C > A NM_001145153.1: p.Cys82* | NA | −0.98 | 0.00 | MCA without ID | Syndromic neutropenia | ||
| 61 | GPATCH11 | AR | chr2:g.37317866 G > T NM_174931.2:c.316 + 1 G > T | NA | −1.19 | 0.00 | Splice defect | MCA without ID | Syndromic neutropenia | |
| 62 | FAT4 | AR |
chr4:g.126238090 G > T NM_024582.4:c.524 G > T NM_024582.4: p.(Arg175Leu) chr4:g.126239320 C > A NM_024582.4:c.1754C > A NM_024582.4: p.(Pro585Gln) |
Deleterious Tolerated | −0.32 | 1.00 | MCA without ID | Severe arthrogryposis | ||
| 63 | SARS | AR |
chr1:g.109774299 G > T NM_006513.3:c.638 G > T NM_006513.3: p.(Arg213Leu) |
Deleterious | 3.13 | 1.00 | Isolated ID/EE | EE | ||
| 64 | CADPS | AR | chr3:g.62543079 C > A NM_003716.3:c.1753 + 1 G > T | NA | 3.41 | 0.05 | Splice defect | MCA with ID |
Musculoskeletal defects Facial dysmorphism Seizure |
|
| 65 | RFT1 | AR |
chr3:g.53126558 C > T NM_052859.3:c.1285 G > A NM_052859.3: p.(Val429Met) chr3:g.53156410 G > A NM_052859.3:c.436 C > T NM_052859.3: p.(His146Tyr) |
Deleterious | −0.35 | 0.00 | MCA with ID |
ID Facial dysmorphism Hyperextensible skin Hypotonia |
||
| 66a | ARHGAP6 | X-linked |
chrX:g.11160407 A > G NM_013427.2:c.2203 T > C NM_013427.2: p.(Trp735Arg) |
Deleterious | 1.99 | 0.99 | Isolated ID/EE | ID | ||
| 66a | CHIC1 | X-linked | chrX:g.72783341 G > C NM_001039840.2:c.221 G > C NM_001039840.2: p.(Arg74Pro) | Deleterious | 1.71 | 0.68 | Isolated ID/EE | ID | ||
| 67 | MAGED1 | X-linked | chrX:g.51638620 G > A NM_001005332.1:c.517 G > A NM_001005332.1: p.(Ala173Thr) | Deleterious | 1.42 | 0.98 | MCA with ID |
ID Facial dysmorphism Autism |
||
| 68 | PLXNA1 | AD | chr3:g.126733621 C > T NM_032242.3:c.2824 C > T NM_032242.3:p.(Arg942Trp) | Deleterious | 5.15 | 1.00 | MCA with ID |
Facial dysmorphism Eye abnormality Seizure |
||
| 69 | PLCB4 | AD |
chr20:g.9389801 A > T NM_000933.2:c.1936A > T NM_000933.3: p.(Met646Leu) |
Deleterious | 2.78 | 0.27 | MCA without ID |
Anodontia Facial dysmorphism |
||
| 70 | ACTN2 | NA |
chr1:g.236881186 T > G NM_001103.3:c.155 T > G NM_001103.3: p.(Leu52Arg) |
Tolerated | 1.76 | 1.00 | MCA without ID | Myopathy | ||
| 71 | FEZF2 | NA |
chr3:g.62355766 G > A NM_018008.3:c.1372 C > T NM_018008.3: p.(Gln458*) |
NA | 3.73 | 0.90 | MCA without ID |
Facial dysmorphism Deafness |
Anazi et al. 2017 | |
| 72 | MTOR | NA | chr1:g.11227521_11227522delinsAA NM_004958.3:c.4306_4307delinsTT NM_004958.3: p.(Ala1436Phe) | Deleterious | 7.89 | 1.00 | MCA with ID |
Macrocephaly Facial dysmorphism Cardiac defects Hypotonia EE Splenomegaly Hepatomegaly |
OMIM 616638 |
NA not available, AR autosomal recessive, AD autosomal dominant, HSF human splice finding, PP2 PolyPhen2 score, Mis-Zscore Z-score for missense (constraint metrics from GnomAD), pLI probability of loss-of-function intolerance (constraint metrics from GnomAD)
aTwo candidate genes in the same case. A detailed phenotype is available upon request. Candidate genes included unknown disease-causing genes and known disease-causing genes inconclusive in our patients because of the absence of parental segregation or atypical phenotype. One year or more has passed since the initial cES analysis and this reanalysis