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Seizures, Cortical Blindness, Microcephaly Syndrome and Deafness, Autosomal Dominant 1 (DFNA1) via the DIAPH1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
3999 DIAPH1 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3999DIAPH181479 81479,81479 $990 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Testing run on PG-Select capture probes does not include exome-wide CNV analysis. Reflex is available to PGxome or an exome-based panel, or you can use this gene list to create a custom panel (click here).

Click here for costs to reflex to whole PGxome.

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the DIAPH1 gene involves autosomal dominant, fully penetrant, low-frequency deafness beginning at about 10 years of age and progressing to profound bilateral deafness involving all frequencies by 30 years of age (Lynch et al. 1997; Sloan-Heggen et al. 2016).

Pathogenic variants in DIAPH1 are also associated with seizures, cortical blindness, and microcephaly syndrome, an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, developmental delay, brain abnormalities and cortical blindness. Affected individuals may also show facial dysmorphism and overall poor growth with short stature, although hearing is normal (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015).

Genetics

The DIAPH1 gene is located on chromosome 5q31, spanning 108 kb and consisting of 28 coding exons that produce a 1272 amino acid protein. The DIAPH1 protein is ubiquitously expressed throughout the body, including the cochlea and brain, and is involved in actin polymerization and microtubule stabilization (Lynch et al. 1997; Ercan-Sencicek et al. 2015; Pan et al. 2014; Lin et al. 2015).

Pathogenic variants in DIAPH1 for nonsyndromic hearing loss are inherited in an autosomal dominant manner. Only one splicing variant thought to lead to partial loss of function and one missense variant have been described as pathogenic for DFNA1 (Lynch et al. 1997; Sloan-Heggen et al. 2016).

Pathogenic variants in DIAPH1 for seizures, cortical blindness, and microcephaly syndrome are inherited in an autosomal recessive manner. Only three nonsense variants have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015).

Clinical Sensitivity - Sequencing with CNV PG-Select

The clinical sensitivity of this sequencing test is not precisely known. In a study of 1,119 patients with hearing loss in which 440 patients received a genetic diagnosis, only one pathogenic variant in DIAPH1 was detected (Sloan-Heggen et al. 2016). Only three nonsense variants have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

In 79 patients with a clinical diagnosis of sensorineural hearing loss 15 deletion/duplication variants in DIAPH1 were detected (Ji et al. 2014). However, the pathogenicity of these variants was not fully evaluated and they were of a size (~100-150 bp) more likely to be detected by sequencing. No large deletion or duplication variants associated with DIAPH1 have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome.

Testing Strategy

This test provides full coverage of all coding exons of the DIAPH1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Nonsyndromic hearing loss and deafness due to variants in the DIAPH1 gene is suspected in individuals with the following: low-frequency to profound bilateral deafness; no related systemic findings identified by medical history and physical examination; and/or a family history of nonsyndromic hearing loss consistent with autosomal dominant inheritance.

Seizures, cortical blindness, and microcephaly syndrome due to variants in the DIAPH1 gene is suspected in individuals with the following: microcephaly, early-onset seizures, developmental delay, brain abnormalities, cortical blindness, facial dysmorphism, poor growth with short stature, normal hearing and a suspected autosomal recessive mode of inheritance. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in DIAPH1.

Gene

Official Gene Symbol OMIM ID
DIAPH1 602121
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Al-Maawali A. et al. 2016. American Journal of Medical Genetics. Part A. 170A: 435-40. PubMed ID: 26463574
  • Ciuman R.R. 2013. Medical Science Monitor. 19: 1195-210. PubMed ID: 24362017
  • Dodson K.M. et al. 2011. American Journal of Medical Genetics. Part A. 155A: 993-1000. PubMed ID: 21465647
  • Ercan-Sencicek A.G. et al. 2015. European Journal of Human Genetics. 23: 165-172. PubMed ID: 24781755
  • Hilgert N. et al. 2009. Mutation Research. 681: 189-96. PubMed ID: 18804553
  • Ji H. et al. 2014. Bmc Ear, Nose, and Throat Disorders. 14: 9. PubMed ID: 25342930
  • Lin Y.N. et al. 2015. Oncotarget. 6: 18577-89. PubMed ID: 26124177
  • Lynch E.D. et al. 1997. Science. 278: 1315-8. PubMed ID: 9360932
  • Pan J. et al. 2014. Blood. 124: 3967-77. PubMed ID: 25298036
  • Sloan-Heggen C.M. et al. 2016. Human Genetics. 135: 441-50. PubMed ID: 26969326
  • Van Camp G. et al. 1997. American Journal of Human Genetics. 60: 758-64. PubMed ID: 9106521
  • Yavarna T. et al. 2015. Human Genetics. 134: 967-80. PubMed ID: 26077850

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

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ORDER OPTIONS

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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