Test Directory

Test Code
2359
Test Name
Frontonasal Dysplasia, SIX2 Related
CPT Codes
81479
Expected Turnaround Time
Typically 2 to 4 weeks from receipt of a sample in the laboratory. All cases involving ongoing pregnancies will be expedited.
Clinical Utility
Genetic analysis to provide a molecular diagnosis of this disorder. Recommended for individuals with a personal and/or family history of this disorder to ensure appropriate treatment and establish recurrence risk for family members.
Specimen and Container Info

Non-Prenatal Specimens


Preferred/Alternate

Specimen Type

Containers

Volume

Preferred Specimen Type

Whole Blood

Lavender Top (EDTA)

3 mL

Alternate Specimen Type

Genomic DNA

1.5 mL Tube

3 µg (at a concentration of at least 30 ng/µl), preferably in TE solution.

Alternate Specimen Type

Fibroblasts

T-25 Flasks

2 confluent T-25 flasks, filled to capacity

Alternate Specimen Type

Saliva (Whole blood is recommended for CNV)

DNA Self-Collection Kit or Oragene Saliva Collection Kit for Young Children

Follow kit instructions (www.dnagenotek.com)


Prenatal Specimens

Either specimen type below is acceptable.


Specimen Type

Containers

Volume

Cultured cells

T-25 Flasks

2 confluent T-25 flasks derived from amnio or CVS samples.

Genomic DNA

1.5 mL Tube

3 µg (at a concentration of at least 30 ng/µl), preferably in TE solution.


NOTE: For specimens from outside of North America, the preferred specimen type is Genomic DNA. HNL Genomics does not recommend shipping whole blood or cultured cells from any location other than the United States, Canada, or Mexico.

Transport Instructions
  • Transport at room temperature within 24 hours.
  • If the specimen cannot be transported to the lab within 24 hours, refrigerate for up to 72 hours.
  • Do not freeze or expose to extreme temperatures, refrigerate for up to 72 hours if cannot be transported to lab within 24 hours. 
Stability Requirements

Room Temperature

24 hours

Refrigerated

72 hours

Causes for Rejection
  • Improperly labeled specimen (minimum of two patient identifiers)
  • Inappropriate specimen type
  • Incomplete or incorrect test request form
  • Insufficient volume
  • Specimen has leaked in transit
  • Specimen without a test order
Methodology
Next Generation Sequencing and Copy Number Variation Analysis
Performing Location
Genomics - Snowdrift
Alternate Names
SIX2
Description

Frontonasal dysplasia (FND) is a heterogeneous group of disorders characterized by hypertelorism, broad nasal tip and root, bifid nose and oral, palatal and facial clefting. Additional findings include microphthalmia, coloboma, and low-set, posteriorly rotated ears. FND1 (MIM 136760), FND2 (MIM 613451) and FND3 (MIM 613456) are autosomal recessive disorders caused by mutations in the ALX3, ALX4 and ALX1 genes. Patients with FND2 can also have skull defects, coronal craniosynostosis, cryptorchidism, agenesis of corpus callosum, total alopecia and mental retardation. Mutations in ALX4 also cause parietal foramina 2 (PFM2; MIM 609597), an autosomal dominant disorder characterized by symmetrical, oval parietal bone defects, cranium bifidum and scalp defect. Parietal foramina also occurs as part of the Potocki-Shaffer syndrome (PSS; MIM 601224), a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p12-p11.2 region, encompassing the ALX4 gene.  ALX1, ALX3 and ALX4 code for transcription regulators, homeobox protein aristaless-like 1, 3 and 4. Autosomal dominant FND is also recognized. This form is caused by mutations in the SIX2 gene (frontonasal dysplasia, SIX2 related).
Craniofrontonasal syndrome (CFNS; MIM 304110) shares clinical features with FND such as hypertelorism, broad nasal tip root, bifid nose, cleft lip and cleft palate. Other prominent features include longitudinal splitting of nails, clinodactyly, abnormal facial proportions, craniosynostosis, low implant of breasts, narrow shoulders, and frizzy and curly hair. CFNS is an X-linked dominant disorder caused by loss-of-function mutations is EFNB1. Paradoxically, CFNS displays greater severity in heterozygous females than in hemizygous males, who typically only have hypertelorism or no clear features at all. EFNB1 codes for ephrin-B1, a transmembrane ligand for Eph receptor tyrosine kinases. Because heterozygous females are uniquely mosaic due to random X-inactivation, individual cells either produce or do not produce functional protein. This random pattern of expression and non-expression causes abnormal sorting of cells. The cells of the hemizygous males are not able to produce a functional protein and thus the phenomenon cannot occur. A possible explanation for a few severely affected males can be mosaicism.

Testing Schedule
Monday-Friday
Genes
SIX2
Disease Group
Craniosynostosis and Craniofacial Disorders