Duane-Radial Ray Syndrome and Acro-Renal-Ocular Syndrome via the SALL4 Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8459 | SALL4 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Duane-radial ray syndrome (DRRS, aka Okihiro syndrome; OMIM#607323) is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication preaxial polydactyly. Acro-renal-ocular syndrome (AROS; OMIM#102490) is characterized by radial ray malformations, renal abnormalities, ocular coloboma, and Duane anomaly. DRRS and AROS are allelic disorders, both caused by variants in the SALL4 gene. Rarely, SALL4 variants may also cause clinically typical Holt-Oram syndrome (i.e. radial ray malformations and cardiac malformations without additional features). Additional clinical features in patients with a SALL4 variant include sensorineural and/or conductive deafness (Kohlhase GeneReviews 2008).
Genetics
Duane-radial ray syndrome (DRRS) and acro-renal-ocular syndrome (AROS) are inherited in an autosomal dominant manner with ~95% penetrance. SALL4 is the only gene known to be associated with these two disorders; about half of cases are caused by de novo variants. SALL4 encodes sal-like protein 4, a C2H2 zinc finger transcription factor of the SAL type (Kohlhase et al. Hum Mol Genet 11:2979–2987, 2002). Sal-like protein 4 appears to be an essential developmental regulator. SALL4 cooperates with SALL1 in anorectal, heart, brain, and kidney development (Sakaki-Yumoto et al. Development 133:3005–3013, 2006). It is regulated by TBX5 in patterning and morphogenesis of the first digit of the upper limbs (Koshiba-Takeuchi et al. Nat Genet 38:175–183, 2006). The majority of variants in SALL4 are nonsense and frameshift variants leading to haploinsufficiency of sal-like protein 4.
Clinical Sensitivity - Sequencing with CNV PGxome
Sequencing of SALL4 is predicted to detect disease variants in up to 80% of individuals with a clinical diagnosis of DRRS and AROS (Al-Baradie et al. Am J Hum Genet 71:1195–1199, 2002; Kohlhase et al. Hum Mol Genet 11:2979–2987, 2002; Kohlhase et al. J Med Genet 40:473–478, 2003; Borozdin et al. J Med Genet 41:e102, 2004; Kohlhase et al. Hum Mutat 26:176–83, 2005). Large deletions involving single or multiple exons have been reported to account for 10-15% cases (Borozdin et al. J Med Genet 41:e113, 2004; Borozdin et al. Hum Mutat 28:830, 2007); such deletions would not generally be detected by sequence analysis alone.
Testing Strategy
This test provides full coverage of all coding exons of the SALL4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).
Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).
Indications for Test
Candidates for this test are patients with clinical and radiographic features consistent with DRRS or AROS, patients with typical Holt-Oran syndrome but who tested negative for a causative variant in the TBX5 gene, those with some features of Townes-Brocks syndrome but who tested negative for a causative variant in the SALL1 gene, and family members of patients who have known SALL4 variants.
Candidates for this test are patients with clinical and radiographic features consistent with DRRS or AROS, patients with typical Holt-Oran syndrome but who tested negative for a causative variant in the TBX5 gene, those with some features of Townes-Brocks syndrome but who tested negative for a causative variant in the SALL1 gene, and family members of patients who have known SALL4 variants.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| SALL4 | 607343 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Duane-Radial Ray Syndrome | AD | 607323 |
| Ivic Syndrome | AD | 147750 |
Related Test
| Name |
|---|
| Comprehensive Cardiology Panel |
Citations
- Al-Baradie, R., et.al. (2002). "Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family." Am J Hum Genet 71(5): 1195-9. PubMed ID: 12395297
- Borozdin, W., et.al. (2004). "Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum." J Med Genet 41(8): e102. PubMed ID: 15286162
- Borozdin, W., et.al. (2004). "SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism." J Med Genet 41(9): e113. PubMed ID: 15342710
- Borozdin, W., et.al. (2007). "Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay." Hum Mutat 28(8): 830. PubMed ID: 17623483
- Jürgen Kohlhase (2008). "SALL4-Related Disorders."
- Kohlhase, J., et.al. (2002). "Okihiro syndrome is caused by SALL4 mutations." Hum Mol Genet 11(23): 2979-87. PubMed ID: 12393809
- Kohlhase, J., et.al. (2003). "Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy." J Med Genet 40(7): 473-8. PubMed ID: 12843316
- Kohlhase, J., et.al. (2005). "SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders." Hum Mutat 26(3): 176-83. PubMed ID: 16086360
- Koshiba-Takeuchi, K., et.al. (2006). "Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart." Nat Genet 38(2): 175-83. PubMed ID: 16380715
- Sakaki-Yumoto, M., et.al. (2006). "The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development." Development 133(15): 3005-13. PubMed ID: 16790473
Ordering/Specimens
Ordering Options
We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.
myPrevent - Online Ordering
- The test can be added to your online orders in the Summary and Pricing section.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
Requisition Form
- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
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