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Neonatal Respiratory Distress NGS Panel

Genes:
ABCA3;
FOXF1;
NKX2-1;
SFTPB;
SFTPC

Syndrome Information

Clinical Description

Neonatal respiratory distress (NRD) includes several diagnoses with an onset in the neonatal period.  Inherited forms of NRD covered by this panel are:

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) (FOXF1 gene):  Presents with respiratory distress in the neonatal period and pulmonary hypertension.  A significant number of affected children (75-80%) have involvement of another organ system (cardiac, vascular, genitourinary, gastrointestinal) or multiple congenital anomalies.  

Choreoathetosis, congenital hypothyroidism, neonatal respiratory distress syndrome (also known as Brain-Lung-Thyroid Syndrome) (NKX2-1 gene):  Pulmonary involvement occurs in approximately 49% of affected individuals.  Neonatal respiratory distress is a common presenting symptom, although childhood interstitial lung disease and pulmonary fibrosis can also be presenting diagnoses.  . 

Surfactant Protein C (SPC) Deficiency (SFTPC gene): SP-C Deficiency can present with various forms of interstitial lung disease including usual interstitial pneumonitis, pulmonary fibrosis, and cellular nonspecific interstital pneumonitis.  Although typical onset is in infancy or childhood, and some individuals are not diagnosed until adulthood, a small percentage of individuals with SPC deficiency present with neonatal respiratory distress.  

Surfactant Protein B (SPB) Deficiency (SFTPB gene): SP-B deficiency presents as severe respiratory distress in the neonatal period.  Histologic findings can include pulmonary alveolar proteinosis, desquamative interstitial pneumonitis, and pulmonary fibrosis. 

ABCA3-related Surfactant Deficiency (ABCA3 gene): ABCA3-deficiency typically presents as severe respiratory distress in the neonatal period, although some affected individuals present in infancy.  Histologic findings can include pulmonary alveolar proteinosis and desquamative interstitial pneumonitis  

Inheritance Pattern

Autosomal Recessive; Autosomal Dominant

Genotype-Phenotype Correlation

SFTPC: SP-C deficiency may present at an earlier age in individuals who also carry a deleterious ABCA3 mutation.  

FOXF1:  Deletions may be associated with more severe involvement of other organ systems.

Test Information

Test Method

Next Generation Sequencing (NGS) of the coding regions and intron-exon boundaries of the listed genesDeletion/Duplication:  Dosage analysis by normalization of NGS read depth for the listed genes (except SFTPC); Sanger sequencing for potential fill in / confirmation

Clinical Utility

Discrimination between multiple inherited disorders presenting with neonatal respiratory distress;  identification of causative mutations in known or highly suspicious cases; facilitation of targeted carrier or presymptomatic testing of relatives of proband and/or predictive prenatal testing.

Clinical Sensitivity

In a series of 337 children presenting with neonatal distress, 20% had mutations in SFTPBSFTPC, or ABCA3 (FOXF1 and NKX2-1 not tested). NKX2-1 mutations are identified in approximately 45% of patients with complete or partial choreoathetosis, congenital hypothyroidism, neonatal respiratory distress syndrome.  FOXF1 mutations are identified in approximately 70% of patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins.

Analytic Sensitivity

> 99% for inherited single nucleotide and small insertion/deletion variants for the nucleotides evaluated; >99% for multi-exon deletions and >98% for single exon deletions; >90% for multi-exon duplications and >75% for single exon duplications. Lower limit of detection for single nucleotide variants: 25% allele frequency (>99% sensitivity).

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests.

Turn Around Time

Approximately 3 weeks

Fee and CPT Codes

NGS Panel:  $3250 for routine testing
CPT Code:  81479 x 5

Special Considerations

Clinical and family history on affected individual is requested, as well as any BAL or biopsy results.

Click here to see other NGS panels for diffuse lung disease.

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.