Table 1.
Molecular Diagnoses According to Expected Mode of Inheritance for 97 Patients with Dual Molecular Diagnoses.*
| Patient No. |
Genes with Pathogenic Variants | Modes of Inheritance (Gene A + Gene B) |
Class | Similarity Score† |
|
|---|---|---|---|---|---|
| Gene A | Gene B | ||||
| 1 | ADAR‡ | APOB | AD + AD | Distinct | 0.30 |
| 2§ | ANKRD11‡ | FLG | AD + AD | Distinct | 0.14 |
| 3§ | ANKRD11‡ | ARID1B‡ | AD + AD | Overlapping | 0.49 |
| 4 | ARID1B‡ | KMT2A‡ | AD + AD | Overlapping | 0.65 |
| 5§ | ASXL3 | ENG | AD + AD | Distinct | NA |
| 6 | CACNA1A‡ | SLC26A1‡ | AD + AD | Overlapping | NA |
| 7§ | CHD2‡ | PRRT2 | AD + AD | Overlapping | 0.43 |
| 8 | CHD8 | COL5A1 | AD + AD | Distinct | NA |
| 9 | COL4A1‡ | CRYGD | AD + AD | Overlapping | 0.71 |
| 10§ | CREBBP‡ | PRICKLE2‡ | AD + AD | Overlapping | 0.36 |
| 11 | DNM1‡ | PTEN‡ | AD + AD | Overlapping | NA |
| 12 | FBN1 | MYO1F‡ | AD + AD | Distinct | NA |
| 13§ | FLG | MEF2C‡ | AD + AD | Distinct | 0.08 |
| 14 | FLG | PACS1‡ | AD + AD | Distinct | NA |
| 15 | GDF6 | SOX10‡ | AD + AD | Overlapping | 0.24 |
| 16§ | GLI2 | IRF6 | AD + AD | Overlapping | 0.33 |
| 17 | GLI2‡ | SCN2A‡ | AD + AD | Overlapping | 0.29 |
| 18 | HBB | KANSL1 | AD + AD | Distinct | 0.37 |
| 19 | PTPN11‡ | SHH‡ | AD + AD | Distinct | 0.22 |
| 20§ | SCN1A‡ | SMARCA2‡ | AD + AD | Overlapping | 0.28 |
| 21 | KAT6A | 16p11.2 del | AD + AD | NA | NA |
| 22 | NOTCH1 | TTN | AD + AD | Distinct | 0.45 |
| 23 | KCNQ2‡ | PRRT2 | AD + AD | Overlapping | 0.47 |
| 24 | ANKRD11 | SLC6A1 | AD + AD | Overlapping | NA |
| 25 | PTCH1‡ | TCF12 | AD + AD | Distinct | 0.48 |
| 26 | COL11A1 | KRIT1 | AD + AD | Distinct | 0.16 |
| 27 | KCNQ2‡ | SCN8A | AD + AD | Overlapping | 0.63 |
| 28 | NF1‡ | SOX9 | AD + AD | Distinct | 0.35 |
| 29 | MYH2‡ | SMC1A | AD + AD | Distinct | 0.02 |
| 30 | SCN1A‡ | 16p13.11 del | AD + AD | NA | NA |
| 31 | CTNNB1‡ | 1q21.1q21.2 del | AD + AD | NA | NA |
| 32 | SOX11‡ | 17q11.2 dup | AD + AD | NA | NA |
| 33§ | SETBP1‡ | CLCN1 | AD + AD | Distinct | 0.23 |
| 34§ | KCNT1‡ | TTN | AD + AR | Distinct | 0.18 |
| 35§ | ABCC9 | RAPSN | AD + AR | Distinct | 0.01 |
| 36 | ACTG1‡ | WFS1 | AD + AR | Overlapping | 0.35 |
| 37§ | DES | CLCN1 | AD + AR | Overlapping | 0.33 |
| 38 | GATAD2B‡ | WWOX | AD + AR | Overlapping | 0.37 |
| 39 | GNAO1‡ | ACADM | AD + AR | Distinct | 0.21 |
| 40 | HBB | TJP2 | AD + AR | Distinct | 0.27 |
| 41§ | KIF5C‡ | NRXN1 | AD + AR | Overlapping | 0.17 |
| 42 | KMT2D‡ | HEXA | AD + AR | Overlapping | 0.27 |
| 43§ | NF1‡ | MEGF8 | AD + AR | Distinct | 0.26 |
| 44§ | NF1‡ | GALNT3 | AD + AR | Distinct | 0.17 |
| 45 | PUF60‡ | LOXHD1 | AD + AR | Distinct | 0.05 |
| 46 | SCN8A‡ | MAN2B1 | AD + AR | Overlapping | 0.32 |
| 47 | SLC2A9 | ETHE1 | AD + AR | Distinct | 0.28 |
| 48 | SPRED1‡ | MEGF10 | AD + AR | Distinct | 0.30 |
| 49§ | SYNGAP1‡ | MTFMT | AD + AR | Overlapping | 0.39 |
| 50 | TGFB2‡ | TYR1 | AD + AR | Distinct | 0.17 |
| 51 | GFAP‡ | MPZ | AD + AR | Distinct | 0.35 |
| 52 | ARHGEF1 | ECEL1 | AD + AR | Distinct | 0.01 |
| 53 | FLG | TECPR2 | AD + AR | Distinct | 0.15 |
| 54 | TUBB3‡ | ISCA2 | AD + AR | Overlapping | NA |
| 55 | NLRC4‡ | SERPINA1 | AD + AR | Distinct | 0.17 |
| 56 | CACNB4 | TANGO2 | AD + AR | Overlapping | NA |
| 57 | CPOX | ABCA1 | AD + AR | Overlapping | 0.33 |
| 58 | GLI2‡ | BLM | AD + AR | Distinct | 0.36 |
| 59 | CHD8‡ | BRWD3‡ | AD + XL | Overlapping | NA |
| 60§ | ARID1B‡ | GRIA3‡ | AD + XL | Overlapping | 0.39 |
| 61 | ARID1B‡ | G6PD | AD + XL | Distinct | 0 |
| 62 | CHD7‡ | DMD | AD + XL | Distinct | 0.27 |
| 63 | COL9A3 | PLP1 | AD + XL | Distinct | 0.12 |
| 64 | DNM1L‡ | PDHA1‡ | AD + XL | Overlapping | 0.37 |
| 65§ | EFHC1 | SMC1A‡ | AD + XL | Overlapping | 0.13 |
| 66 | GLI2 | KDM5C‡ | AD + XL | Overlapping | 0.44 |
| 67 | GLI3 | LAS1L‡ | AD + XL | Distinct | NA |
| 68 | GRIN2B‡ | SHOXY | AD + XL | Distinct | 0.05 |
| 69 | PAFAH1B1‡ | FGD1‡ | AD + XL | Distinct | 0.16 |
| 70 | SCN1A | PDHA1 | AD + XL | Overlapping | 0.35 |
| 71 | KIF5C | DMD | AD + XL | Distinct | 0.25 |
| 72 | MED13L‡ | HUWE1‡ | AD + XL | Distinct | 0.001 |
| 73 | COL7A1 | DDX3X | AD + XL | Distinct | NA |
| 74 | COL9A1 | ATRX | AD + XL | Distinct | 0.31 |
| 75 | AGL | PCCA | AR + AR | Distinct | 0.37 |
| 76 | HEXB | MCCC2 | AR + AR | Distinct | 0.22 |
| 77 | MTPAP | NPC1 | AR + AR | Overlapping | 0.40 |
| 78§ | RECQL4 | XPC | AR + AR | Overlapping | 0.56 |
| 79 | TPO | MMP2 | AR + AR | Distinct | 0.03 |
| 80 | AGL | LPAR6 | AR + AR | Distinct | 0.11 |
| 81§ | PAPSS2 | TRDN | AR + AR | Distinct | 0.06 |
| 82 | OTOF | SLC12A6 | AR + AR | Distinct | 0.31 |
| 83 | AGPAT2 | OBSL1 | AR + AR | Distinct | 0.21 |
| 84§ | BBS10 | PDHA1‡ | AR + XL | Distinct | 0.28 |
| 85 | F7 | MECP2‡ | AR + XL | Distinct | 0.21 |
| 86 | FANCG | G6PD | AR + XL | Distinct | 0.40 |
| 87 | TCF12 | SLC35A2 | AR + XL | Distinct | 0.33 |
| 88§ | TREX1 | PHEX | AR + XL | Distinct | 0.16 |
| 89 | PLA2G6 | BCAP31 | AR + XL | Overlapping | 0.53 |
| 90§ | CFTR | SMC1A‡ | AR + XL | Distinct | 0.07 |
| 91 | SLC45A2 | AVPR2 | AR + XL | Distinct | 0.06 |
| 92 | ALG6 | SHOX‡ | AR + XL | Distinct | 0.03 |
| 93 | IRX5 | HDAC8‡ | AR + XL | Overlapping | 0.53 |
| 94 | BCS1L | NLGN4X | AR + XL | Overlapping | 0.27 |
| 95 | KIAA2022 | PHF8 | XL + XL | Overlapping | 0.34 |
| 96 | SMC1A | DMD | XL + XL | Distinct | 0.21 |
| 97 | KIAA2022 | Xp22.31 del | XL + XL | NA | NA |
*
AD denotes autosomal dominant, AR autosomal recessive, NA not available, and XL X-linked.
†
The similarity score was calculated by the symmetric Resnik method (see Section S4 in the Supplementary Appendix), with higher scores indicating greater phenotypic similarity.
‡
The variant in this gene was a de novo variant.
§
Data for this patient have been reported previously.