Implementing Genetic Testing and Counseling in a Rare Lung Diseases Clinic at a Pediatric Tertiary Care Center
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Rare lung diseases encompass over 200 heterogeneous disorders that present diagnostic and therapeutic challenges. The Rare Lung Diseases Frontier program at the Children’s Hospital of Philadelphia (CHOP) was created as an umbrella program to advance knowledge and improve care for children with a broad spectrum of complex and rare pulmonary conditions. Among the types of disorders included are interstitial lung disease (ILD), developmental lung diseases, and pulmonary manifestations and complications of connective tissue/rheumatologic disorders, immune dysregulation disorders, oncologic predisposition conditions, and inborn errors of metabolism. Our objective was to describe the implementation of genetic testing and genetic counseling within this diverse patient population to inform strategies to improve diagnostic accuracy and guide targeted therapies.
Methods:
This is a single-center retrospective cohort study of patients who received clinical care as part of the Rare Lung Diseases Frontier program at CHOP. Of the more than 600 patients evaluated since program inception, 100 cases were randomly selected for the initial phase of review to evaluate criteria for genetic test selection, the role of genetic counseling, the types of genetic tests utilized, and outcomes of testing.
Results:
Of the initial 100 cases reviewed, a pulmonary diagnosis was established for 56 without genetic testing, while others underwent testing including targeted single-gene sequencing, pulmonary panel testing, or exome and genome sequencing. We identified several cases in which targeted single-gene sequencing was informative, such as ATM for the diagnosis of ataxia-telangiectasia. In these cases, genetic counseling played a key role in counseling parents – who may be carriers of ATM – about their increased risk of adult-onset cancers and in identifying at-risk siblings at pre-symptomatic or symptomatic ages. Historically, pulmonary panel testing was often utilized as the first-tier test in our center. Several cases of ABCA3-associated surfactant metabolism dysfunction were diagnosed through panel testing.
Comprehensive genetic testing, including exome and genome sequencing, identified multiple genetic etiologies associated with pulmonary disease. These include primary immunodeficiency disorders resulting from pathogenic variants detected in STAT1, FERMT3 and ADA2 (CECR1), which are associated with recurrent respiratory infections that could lead to complications such as bronchiolitis obliterans. Other notable genetic findings include NOTCH1-associated Adams-Oliver syndrome, which can involve pulmonary vascular anomalies, and CEP135-associated primary ciliary dyskinesia (PCD). Of note, CEP135 is a gene not usually included in PCD panels but has been shown to be associated with severe pulmonary manifestations such as recurrent infections and bronchiectasis. Lastly, cytogenetic testing also detected pathogenic copy number variants (CNVs), such as chromosome 2 deletions and duplications, highlighting the significance of structural genomic changes in children with complex phenotypes which may also include lung disease.
Conclusion:
Incorporation of genetic testing into our rare lung diseases program highlights the value in diagnostic precision in individuals whose lung disease is not explained by environmental exposures or systemic diseases. Genetic counselors play a pivotal role in communicating the genetic testing process and interpreting results. Genetic diagnoses can obviate the need for invasive procedures like lung biopsy and can influence management decisions, such as using immunomodulatory treatments for immune-related pulmonary diseases. Identifying pathogenic CNVs can also inform disease mechanisms involving critical pulmonary genes. Processes are needed to ensure that periodic reanalysis of genetic testing is undertaken in patients with suggestive clinical phenotypes but prior negative genetic testing. Further case review is underway as we also refine referral processes within the clinic to identify patients most likely to benefit from genetic testing and counseling.
Rare lung diseases encompass over 200 heterogeneous disorders that present diagnostic and therapeutic challenges. The Rare Lung Diseases Frontier program at the Children’s Hospital of Philadelphia (CHOP) was created as an umbrella program to advance knowledge and improve care for children with a broad spectrum of complex and rare pulmonary conditions. Among the types of disorders included are interstitial lung disease (ILD), developmental lung diseases, and pulmonary manifestations and complications of connective tissue/rheumatologic disorders, immune dysregulation disorders, oncologic predisposition conditions, and inborn errors of metabolism. Our objective was to describe the implementation of genetic testing and genetic counseling within this diverse patient population to inform strategies to improve diagnostic accuracy and guide targeted therapies.
Methods:
This is a single-center retrospective cohort study of patients who received clinical care as part of the Rare Lung Diseases Frontier program at CHOP. Of the more than 600 patients evaluated since program inception, 100 cases were randomly selected for the initial phase of review to evaluate criteria for genetic test selection, the role of genetic counseling, the types of genetic tests utilized, and outcomes of testing.
Results:
Of the initial 100 cases reviewed, a pulmonary diagnosis was established for 56 without genetic testing, while others underwent testing including targeted single-gene sequencing, pulmonary panel testing, or exome and genome sequencing. We identified several cases in which targeted single-gene sequencing was informative, such as ATM for the diagnosis of ataxia-telangiectasia. In these cases, genetic counseling played a key role in counseling parents – who may be carriers of ATM – about their increased risk of adult-onset cancers and in identifying at-risk siblings at pre-symptomatic or symptomatic ages. Historically, pulmonary panel testing was often utilized as the first-tier test in our center. Several cases of ABCA3-associated surfactant metabolism dysfunction were diagnosed through panel testing.
Comprehensive genetic testing, including exome and genome sequencing, identified multiple genetic etiologies associated with pulmonary disease. These include primary immunodeficiency disorders resulting from pathogenic variants detected in STAT1, FERMT3 and ADA2 (CECR1), which are associated with recurrent respiratory infections that could lead to complications such as bronchiolitis obliterans. Other notable genetic findings include NOTCH1-associated Adams-Oliver syndrome, which can involve pulmonary vascular anomalies, and CEP135-associated primary ciliary dyskinesia (PCD). Of note, CEP135 is a gene not usually included in PCD panels but has been shown to be associated with severe pulmonary manifestations such as recurrent infections and bronchiectasis. Lastly, cytogenetic testing also detected pathogenic copy number variants (CNVs), such as chromosome 2 deletions and duplications, highlighting the significance of structural genomic changes in children with complex phenotypes which may also include lung disease.
Conclusion:
Incorporation of genetic testing into our rare lung diseases program highlights the value in diagnostic precision in individuals whose lung disease is not explained by environmental exposures or systemic diseases. Genetic counselors play a pivotal role in communicating the genetic testing process and interpreting results. Genetic diagnoses can obviate the need for invasive procedures like lung biopsy and can influence management decisions, such as using immunomodulatory treatments for immune-related pulmonary diseases. Identifying pathogenic CNVs can also inform disease mechanisms involving critical pulmonary genes. Processes are needed to ensure that periodic reanalysis of genetic testing is undertaken in patients with suggestive clinical phenotypes but prior negative genetic testing. Further case review is underway as we also refine referral processes within the clinic to identify patients most likely to benefit from genetic testing and counseling.