TABLE I.
Frequency of stop-gain and splice site variants in DOCK6 and other autosomal recessive disease genes, observed in 1000 Genomes, the Exome Variant Server, and other databases, as mined by Kaviar (http://db.systemsbiology.net/kaviar/). A theoretical incidence for each disorder, based on the frequency of these variants, has been calculated and then compared to the clinically observed incidence. Disorders with greater than expected ratios of theoretical incidence to the observed incidences have been highlighted in the final column.
| Disease | Observed incidence per 100,000 | Gene | % of disease caused by gene | Frequency of truncating mutations (%) | Theoretical disease incidence per 100,000 | Ratio of theoretical to observed incidence |
|---|---|---|---|---|---|---|
| Alstrom syndrome | 0.14 | ALMS1 | 50% | 0.1575 | 0.248 | 1.772 |
| GM1 gangliosidosis | 0.5 (1) | GLB1 | 100% | 0.1344 | 0.181 | 0.361 |
| Alkaptonuria | 0.5 | HGD | 100% | 0.0068 | 0.0005 | 0.001 |
| Hurler syndrome | 0.57 | IDUA | 100% | 0.171 | 0.292 | 0.513 |
| Wolfram syndrome | 0.57 | WFS1 | >90% | 0.0962 | 0.093 | 0.162 |
| Netherton syndrome | 0.5 | SPINK5 | 100% | 0.0805 | 0.065 | 0.130 |
| Argininosuccinic aciduria | 0.45 | ASL | 100% | 0.0623 | 0.039 | 0.086 |
| Shwachman- Diamond syndrome | 0.55 | SBDS | >90% | 0.2924 | 0.855 | 1.555 |
| Werner syndrome | 0.45 | WRN | 90% | 0.2116 | 0.448 | 0.995 |
| Jervell and Lange-Nielson syndrome | 0.3 | KCNQ1 | 90% | 0.0136 | 0.002 | 0.006 |
| Niemann Pick A/B disease | 0.4 | SMPD1 | 100% | 0.034 | 0.012 | 0.029 |
| Bardet-Biedl syndrome | 0.7 | BBS1 | 23% | 0.0407 | 0.017 | 0.024 |
| AR malignant osteopetrosis | 0.75 | TCIRG1 | 50% | 0.1077 | 0.116 | 0.155 |
| Ataxia telangiectasia | 1 | ATM | 100% | 0.1558 | 0.243 | 0.243 |
| Congenital factor VII deficiency | 0.33 | F7 | 100% | 0.014 | 0.002 | 0.006 |
| Krabbe disease | 1 (2) | GALC | 100% | 0.3572 | 1.276 | 1.276 |
| Tyrosinemia | 0.8 (3) | FAH | 100% | 0.2227 | 0.496 | 0.620 |
| PMM2-CDG | 0.64 | PMM2 | 100% | 0.0676 | 0.046 | 0.071 |
| Cystinosis | 0.5 | CTNS | 100% | 0.0476 | 0.023 | 0.045 |
| Blackfan-Diamond anemia | 0.67 | RPS19 | 25% | 0.0772 | 0.060 | 0.089 |
| Adams-Oliver syndrome | 0.44 (4) | DOCK6 | <10%* | 0.1836 | 0.337 | 0.766 |
Incidences as reported in Orphanet, June 2013 Report, unless otherwise specifically cited. 1) Suzuki et al., 2008 2) Wenger, 2011 3) Mitchell et al., 2001 4) Martínez-Frías et al., 1996. AR - autosomal recessive.
From the authors’ experience in a genome-sequenced cohort of 13 probands (data not shown).