Neonatal Respiratory Distress – Surfactant Dysfunction Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: PU0501

The Blueprint Genetics Neonatal Respiratory Distress – Surfactant Dysfunction Panel is a five gene test for genetic diagnostics of patients with clinical suspicion of alveolar capillary with vein misalignment, chronic respiratory distress with surfactant metabolism deficiency, congenital alveolar capillary dysplasia or infant acute respiratory distress syndrome.

Pathogenic germline mutations in several genes involved in surfactant metabolism can cause clinical features of respiratory distress syndrome (RDS) in term neonates, children and adults, disorders referred to as 'surfactant metabolism dysfunction'. Chronic respiratory distress with surfactant metabolism deficiency has autosomal dominant inheritance. Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is caused by autosomal dominant mutations in FOXF1 and leads to neonatal respiratory distress and is thus included in the panel.

About Neonatal Respiratory Distress – Surfactant Dysfunction

The main cause of RDS in premature infants is a developmental deficiency of pulmonary surfactant. The symptoms usually appear shortly after birth and may include tachypnea, tachycardia, chest wall retractions (recession), expiratory grunting, nasal flaring and cyanosis during breathing efforts. The frequency of RDS is inversely proportional to gestational age. Disorders of surfactant metabolism can cause RDS in neonates of all gestational ages. The severity of the disease is dependent on the mutation type. In general surfactant protein B deficiency cause a severe and often fatal lung disease but problems from surfactant protein C deficiency can occur as late as in adulthood. ACDMPV have been found to be caused by two broad types of genetic abnormality: a mutation of the FOXF1 gene or other genetic abnormalities such as deletions in areas of chromosome 16 that regulate the expression of the FOXF1 gene. These abnormalities are estimated to be found in around 80-90% of infants with confirmed ACDMPV. Alveolar capillary dysplasia (ACD, also congenital alveolar dysplasia) is a very rare congenital malformation involving abnormal development of the capillary vascular system around the alveoli of the lungs. It is a rare cause of persistent pulmonary hypertension in infants and may also be a rare cause of pulmonary hypoplasia. ACDMPV is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intra-acinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Babies with ACD may appear normal at birth but within minutes or hours they develop respiratory distress with persistent pulmonary hypertension. ACD does not respond to standard therapies that resolve simple pulmonary hypertension, and this lack of response is an essential diagnostic clue.

Availability

Results in 3-4 weeks.

Genes in the Neonatal Respiratory Distress – Surfactant Dysfunction Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ABCA3Interstitial lung disease, Surfactant metabolism dysfunction, pulmonaryAD/AR11181
FOXF1Alveolar capillary dysplasia with misalignment of pulmonary veinsAD795
NKX2-1Thyroid cancer, nonmedullary, Choreoathetosis, hypothyroidism, and neonatal respiratory distressAD13123
SFTPBSurfactant metabolism dysfunction, pulmonaryAR530
SFTPCSurfactant metabolism dysfunction, pulmonaryAD781

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive neonatal respiratory distress - surfactant dysfunction panel that covers classical genes associated with alveolar capillary with vein misalignment, chronic respiratory distress with surfactant metabolism deficiency, congenital alveolar capillary dysplasia and infant acute respiratory distress syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ81479


ICD codes

Commonly used ICD-10 codes when ordering the Neonatal Respiratory Distress – Surfactant Dysfunction Panel

ICD-10Disease
P22.0Infant acute respiratory distress syndrome
J84.8Chronic respiratory distress with surfactant metabolism deficiency
Q33Congenital alveolar capillary dysplasia
J84.843Alveolar capillary with vein misalignment

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.