Comprehensive pulmonary disease panel
Disease summary:
Abnormal lung development and function is a factor in a wide range of genetic disorders, often causing severe symptoms within the first few weeks of life.
Manifestations of pulmonary disease include abnormal development and functioning of the lungs, lung vasculature or connective tissue, lung cysts, pulmonary fibrosis, pneumothorax, surfactant metabolism dysfunction, bronchiectasis, pulmonary hypertension, central hypoventilation syndrome and lymphangioleiomyomatosis.
The severity of clinical presentation is variable, ranging from neonatal respiratory distress to recurrent lung infections or a persistent cough. Pulmonary disease can present as the main symptom of, for example, primary ciliary dyskinesia (PCD), a genetically heterogeneous disease characterized by chronic upper and lower respiratory tract disease due to abnormalities in ciliary structure/function.1 Pulmonary disease may also present as part of a wider spectrum of symptoms, typically evident from birth, such as Hermansky-Pudlak syndrome2 and Dyskeratosis congenita3.
- Autosomal dominant
- Autosomal recessive
- X-Linked (X-linked dyskeratosis congenita).
- 2/1,000,000 pulmonary hypertension4
- 1/10,000 primary ciliary dyskinesia5
- 1/1,000,000 dyskeratosis congenita
- 1/12,000-14,000 children aged <10 or in 1/6,000 live births6,7
- 1/500,000 – 1/1,000,000 (higher incidence in Puerto Rican population due to founder effect)
- <1/1 000 000 cutis laxa.
- Respiratory distress in early infancy
- Respiratory failure, neonatal
- Shortness of breath, difficulty breathing
- A persistent cough, with or without mucus
- Recurrent pulmonary infections
- Emphysema
- Pneumothorax
- Lung cysts.
Diagnostic criteria will differ widely depending on the origin and type of lung disease but are likely to require:
- Clinical classification
- Histological studies from tissue biopsies, for example, Transmission electron microscopy of ciliary ultrastructure (primary ciliary dyskinesia)
- Identification of a pathogenetic variant in one of the genes listed in the table below.
Treatment will differ depending on the nature of the lung disease. A precise diagnosis must be made to guide treatment options and disease management. Treatment may include:
- Airway clearance therapy
- Antibiotic therapy
- Prophylactic medication e.g. bronchodilator
- Surgery.
- Other forms of lung disease and related syndromes
- Immunodeficiency Syndromes
- Emphysema
- Pneumonia
- Other connective tissue disorders.
To confirm/establish the diagnosis, CENTOGENE offers the following tests:
- NGS Panel
- NGS Panel + CNV
- NGS Panel Genomic
- Deletion/Duplication testing (MLPA/qPCR).
The following individuals are candidates for pulmonary disease testing:
- Individuals with a family history of pulmonary disease and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling pulmonary disease.
- Individuals with a suspected family history, to perform proper genetic counselling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of comprehensive pulmonary disease panel genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with other forms of pulmonary could also be analysed for the presence of mutations, due to the overlap in many clinical features caused by those genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counselling and may direct medical management. Genetic counselling can provide a patient and/or family with the natural history of focal epilepsy, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.
Table 1. Overview of the genes in CENTOGENE´s Comprehensive pulmonary disease panel
| Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance | CentoMD® exclusive variant numbers (++) |
|---|---|---|---|---|
| ABCA3 | 601615 | surfactant metabolism dysfunction-3 | AR | 19 |
| ACVRL1 | 601284 | Telangiectasia, hereditary hemorrhagic, type 2 | AD | 3 |
| AP3B1 | 603401 | Hermansky-Pudlak syndrome type 2 | AR | 18 |
| ASCL1 | 100790 | congenital central hypoventilation syndrome | AD | 4 |
| BDNF | 113505 | 2 | ||
| BLOC1S3 | 609762 | Hermansky-Pudlak syndrome 8 | AR | 2 |
| BLOC1S6 | 604310 | Hermansky-pudlak syndrome 9 | AR | 0 |
| BMPR2 | 600799 | Pulmonary hypertension, familial primary, 1, with or without HHT | AD | 2 |
| CCDC39 | 613798 | Ciliary dyskinesia, primary, 14 | 5 | |
| CCDC40 | 613799 | Ciliary dyskinesia, primary, 15 | 25 | |
| CFTR | 602421 | hereditary pancreatitis; protection against chronic Pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens | AD, AR | 105 |
| CSF2RA | 306250 | Surfactant metabolism dysfunction, pulmonary, 4 | 32 | |
| CSF2RB | 138981 | Surfactant metabolism dysfunction, pulmonary, 5 | AR | 19 |
| DKC1 | 300126 | X-linked dyskeratosis congenita | XLR | 2 |
| DNAAF1 | 613190 | Ciliary dyskinesia, primary, 13 | AR | 9 |
| DNAAF2 | 612517 | Ciliary dyskinesia, primary, 10 | 5 | |
| DNAH11 | 603339 | primary ciliary dyskinesia type 7, with or without situs inversus | AR | 54 |
| DNAH5 | 603335 | primary ciliary dyskinesia type 3, with or without situs inversus | 36 | |
| DNAI1 | 604366 | primary ciliary dyskinesia type 1, with or without situs inversus | AR | 3 |
| DNAI2 | 605483 | primary ciliary dyskinesia type 9, with or without situs inversus | 6 | |
| DNAL1 | 610062 | Ciliary dyskinesia, primary, 16 | AR | 2 |
| DOCK8 | 611432 | Hyper-IgE recurrent infection syndrome, autosomal recessive | AR | 26 |
| DTNBP1 | 607145 | Hermansky-Pudlak syndrome 7 | AR | 6 |
| EDN3 | 131242 | congenital central hypoventilation syndrome; Waardenburg syndrome type 4B; Hirschsprung disease 4 | AD, AR | 8 |
| EFEMP2 | 604633 | Cutis laxa, autosomal recessive, type IB | AR | 2 |
| ELMOD2 | 610196 | 0 | ||
| ELN | 130160 | Cutis laxa, autosomal dominant 1, ADCL1; Supravalvar aortic stenosis | AD | 3 |
| ENG | 131195 | hereditary hemorrhagic telangiectasia type 1 | AD | 6 |
| FBLN5 | 604580 | Cutis laxa, autosomal recessive, type IA | AD, AR | 0 |
| FBN1 | 134797 | Marfan syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2 | AD | 73 |
| FLCN | 607273 | colorectal cancer; Birt-Hogg-Dube syndrome; Renal carcinoma, chromophobe, somatic; primary spontaneous pneumothorax | AD | 7 |
| FOXF1 | 601089 | Pulmonary hypertension, familial persistent, of the newborn | AD | 2 |
| GDNF | 600837 | pheochromocytoma; congenital central hypoventilation syndrome; Hirschsprung Disease, Susceptibility To, 3 | AD | 0 |
| HPS1 | 604982 | Hermansky-Pudlak syndrome type 1 | AR | 13 |
| HPS3 | 606118 | Hermansky-Pudlak syndrome type 3 | AR | 10 |
| HPS4 | 606682 | Hermansky-Pudlak syndrome type 4 | AR | 6 |
| HPS5 | 607521 | Hermansky-Pudlak syndrome type 5 | AR | 8 |
| HPS6 | 607522 | Hermansky-Pudlak syndrome type 6 | AR | 3 |
| LTBP4 | 604710 | Cutis laxa, autosomal recessive, type IC | AR | 7 |
| NKX2-1 | 600635 | Chorea, Benign Hereditary; Thyroid Carcinoma, Papillary; Choreoathetosis, hypothyroidism, and neonatal respiratory distress | AD | 11 |
| NME8 | 607421 | Ciliary dyskinesia, primary, 6 | AR | 10 |
| NOP10 | 606471 | Dyskeratosis Congenita, Autosomal Recessive, 1 | AR | 0 |
| PARN | 604212 | Dyskeratosis congenita, autosomal recessive 6; telomere-related pulmonary fibrosis and/or bone marrow failure type 4 | AD, AR | 2 |
| PHOX2B | 603851 | congenital central hypoventilation syndrome | AD | 10 |
| RET | 164761 | Hirschsprung disease; familial medullary thyroid carcinoma; multiple endocrine neoplasia 2B; pheochromocytoma; multiple endocrine neoplasia 2A; congenital central hypoventilation syndrome | AD | 16 |
| RSPH1 | 609314 | primary ciliary dyskinesia, 24 | AR | 0 |
| RSPH4A | 612647 | Ciliary dyskinesia, primary, 11 | 4 | |
| RSPH9 | 612648 | Ciliary dyskinesia, primary, 12 | 2 | |
| RTEL1 | 608833 | dyskeratosis congenita; that telomere-related pulmonary fibrosis and/or bone marrow failure type 3 | AD, AR | 6 |
| SCNN1A | 600228 | Pseudohypoaldosteronism, type I | AD, AR | 13 |
| SCNN1B | 600760 | Liddle syndrome; Bronchiectasis with or without elevated sweat chloride type 1; Pseudohypoaldosteronism, type I | AD, AR | 18 |
| SCNN1G | 600761 | Pseudohypoaldosteronism, type I; Bronchiectasis with or without elevated sweat chloride 3 | AD, AR | 16 |
| SERPINA1 | 107400 | severe early-onset chronic obstructive pulmonary disease; alpha-1 antitrypsin deficiency | AR | 4 |
| SFTPA1 | 178630 | 11 | ||
| SFTPA2 | 178642 | Pulmonary fibrosis, idiopathic, susceptibility to | AD | 4 |
| SFTPB | 178640 | Surfactant metabolism dysfunction, pulmonary, 1 | AR | 6 |
| SFTPC | 178620 | Surfactant metabolism dysfunction, pulmonary, 2 | AD | 9 |
| SFTPD | 178635 | 4 | ||
| SMAD9 | 603295 | AD | 0 | |
| STAT3 | 102582 | Hyper-IgE recurrent infection syndrome; infantile-onset multisystem autoimmune disease, 1 | AD | 2 |
| TERC | 602322 | Dyskeratosis congenita, autosomal dominant 1; Aplastic anemia | AD | 1 |
| TERT | 187270 | acute myeloid leukemia; Dyskeratosis congenita, autosomal recessive 4; Bone marrow failure, telomere-related, 1 | AD, AR | 4 |
| TINF2 | 604319 | Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 | AD | 1 |
| TSC1 | 605284 | tuberous sclerosis type 1 | AD | 71 |
| TSC2 | 191092 | tuberous sclerosis-2 | AD | 149 |
Abbreviations:
AD autosomal dominant; AR autosomal recessive; XLD X-linked;