Table 5.
Compound heterozygous variants observed in exomes of seven ROHHAD cases (discovery cohort)
| Proband ID | Gene | Variant type | Selected transcript and variant effect | Inherited from | Polyphen-2 [22] Prediction (Probability) | CADD [21] Score (Phred-scaled | MAF (1000 genomes Project; EVS; ExAC)a | Total reads (% of reads supporting variant Allele) |
|---|---|---|---|---|---|---|---|---|
| 18 | MAST4 | Non-synonymous | MAST4:NM_001297651: | Mother | Deleterious (0.998) | 21.4 | Not found; Not found; 0.00004466 | 198 (40 %) |
| exon1:c.34C>T:p.L12F | ||||||||
| Non-synonymous | MAST4:NM_001297651: | Father | Deleterious (1.000) | 20.9 | Not found; Not found; 0.0002 | 92 (35 %) | ||
| exon26:c.4690C>T:p.L1564F | ||||||||
| OTOG | Non-synonymous | OTOG:NM_001277269: | Mother | Deleterious (1.000) | 20.1 | Not found; Not found; Not found | 31 (32 %) | |
| exon47:c.7907G>A:p.R2636H | ||||||||
| synonymous | OTOG:NM_001277269: | Father | N/A | 9.71 | Not found; Not found; Not found | 63 (48 %) | ||
| exon37:c.6381C>T:p.H2127H | ||||||||
| 25 | DNAH11 | synonymous | DNAH11:NM_001277115: | Father | N/A | 0.005 | 0.00159744; 0.0032; 0.003 | 177 (36 %) |
| exon16:c.3237T>C:p.L1079L | ||||||||
| synonymous | DNAH11:NM_001277115: | Mother | N/A | 0.002 | 0.000199681; 0.0027; 0.0024 | 53 (49 %) | ||
| exon57:c.9468T>C:p.D3156D | ||||||||
| DMXL2 | Non-synonymous | DMXL2:NM_001174117: | Mother | Neutral (0.029) | 14.65 | Not found; Not found; 0.0001 | 34 (32 %) | |
| exon39:c.6727G>C:p.V2243L | ||||||||
| synonymous | DMXL2:NM_001174116: | Father | N/A | 0.646 | Not found; 0.0004; 0.0005 | 126 (44 %) | ||
| exon8:c.861C>T:p.T287T | ||||||||
| 27 | SACS | Non-synonymous | SACS:NM_001278055: | Mother | Deleterious (0.999) | 21.8 | 0.000798722; 0.0035; 0.0028 | 87 (40 %) |
| exon8:c.7898T>G:p.F2633C | ||||||||
| Non-synonymous | SACS:NM_001278055: | Father | Deleterious (0.996) | 16.19 | Not found; Not found; Not found | 101 (45 %) | ||
| exon8:c.6009G>T:p.Q2003H | ||||||||
| ZNF44 | Non-synonymous | ZNF44:NM_016264: | Father | Deleterious (1.000) | 16.13 | Not found; Not found; 0.0002 | 123 (45 %) | |
| exon4:c.923C>T:p.P308L | ||||||||
| frameshift deletion | ZNF44:NM_016264: | Mother | N/A | 23.3 | Not found; Not found; 0.00008261 | 145 (43 %) | ||
| exon4:c.562_563del:p.M188fs | ||||||||
| 41 | C15orf39 | synonymous | C15orf39:NM_015492: | Father | N/A | 6.427 | 0.00139776; 0.0032; 0.0021 | 157 (38 %) |
| exon2:c.702C>T:p.Y234Y | ||||||||
| nonframeshift deletion | C15orf39:NM_015492:exon2: | Mother | N/A | 33 | Not found; 0.0026; 0.0001 | 56 (30 %) | ||
| c.2210_2221del:p.737_741del | ||||||||
| CD300LF | Non-synonymous | CD300LF:NM_001289083: | Mother | Neutral (0.278) | 0.265 | Not found; Not found; 0.0000249 | 37 (43 %) | |
| exon5:c.542T>C:p.I181T | ||||||||
| Non-synonymous | CD300LF:NM_001289083: | Father | Deleterious (0.746) | 13.19 | Not found; Not found; 0.000033 | 118 (43 %) | ||
| exon2:c.336A>C:p.K112N | ||||||||
| ZFHX4 | synonymous | ZFHX4:NM_024721: | Mother | N/A | 14.05 | 0.000199681; 0.0002; 0.000075 | 113 (36 %) | |
| exon3:c.3075G>A:p.A1025A | ||||||||
| Non-synonymous | ZFHX4:NM_024721: | Father | Neutral (0.000) | 1.699 | Not found; Not found; Not found | 171 (39 %) | ||
| exon10:c.7262C>T:p.P2421L | ||||||||
| synonymous | ZFHX4:NM_024721: | Mother | N/A | 3.092 | 0.00179712; 0.0019; 0.0025 | 125 (39 %) | ||
| exon11:c.9960A>G:p.Q3320Q | ||||||||
| 42 | DST | Non-synonymous | DST:NM_015548: | Mother | Deleterious (1.000) | 15.35 | Not found; Not found; Not found | 197 (43 %) |
| exon42:c.8467T>C:p.C2823R | ||||||||
| Non-synonymous | DST:NM_015548: | Father | Neutral (0.144) | 12.02 | Not found; Not found; Not found | 127 (39 %) | ||
| exon14:c.2124A>G:p.I708M | ||||||||
| EYS | Non-synonymous | EYS:NM_001142800: | Mother | Deleterious (1.000) | 14.25 | Not found; Not found; Not found | 183 (42 %) | |
| exon40:c.7792G>A:p.G2598S | ||||||||
| Non-synonymous | EYS:NM_001142800: | Father | Neutral (0.031) | 11.83 | Not found; Not found; 0.000008239 | 189 (38 %) | ||
| exon4:c.455T>C:p.M152T | ||||||||
| 45 | SPEG | Non-synonymous | SPEG:NM_005876: | Mother | Neutral (0.235) | 15.47 | Not found; Not found; Not found | 25 (24 %) |
| exon17:c.4181A>G:p.D1394G | ||||||||
| Non-synonymous | SPEG:NM_005876: | Father | Neutral (0.244) | 4.916 | Not found; 0.0003; 0.0003 | 17 (59 %) | ||
| exon30:c.6854C>T:p.P2285L | ||||||||
| 57 | ALS2CR11 | Non-synonymous | ALS2CR11:NM_001168221: | Father | Neutral (0.008) | 6.899 | Not found; Not found; Not found | 30 (47 %) |
| exon15:c.4114G>A:p.D1372N | ||||||||
| Non-synonymous | ALS2CR11:NM_001168221: | Mother | Neutral (0.125) | 16.49 | 0.000199681; Not found; Not found | 40 (55 %) | ||
| exon15:c.2216A>G:p.K739R | ||||||||
| SYNE1 | Non-synonymous | SYNE1:NM_033071: | Mother | Deleterious (0.982) | 25.8 | 0.000199681; 0.0006; 0.0005 | 214 (40 %) | |
| exon142:c.25607A>C:p.D8536A | ||||||||
| Non-synonymous | SYNE1:NM_033071: | Father | Deleterious (0.999) | 34 | Not found; 0.0002; 0.000008238 | 93 (51 %) | ||
| exon102:c.19015G>A:p.E6339K |
a1000 Genomes Project (http://www.1000genomes.org); EVS = Exome Variant Server (http://evs.gs.washington.edu/EVS/); ExAC = Exome Aggregation Consortium (http://exac.broadinstitute.org)