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Comprehensive pulmonary disease panel

January 16, 2019

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 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.

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ABCA3 601615 surfactant metabolism dysfunction-3 AR
ABCC8 600509 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; leucine-sensitive hypoglycemia of infancy; familial hyperinsulinemic hypoglycemia type 1; transient neonatal diabetes mellitus type 2 AD, AR
ACVRL1 601284 Telangiectasia, hereditary hemorrhagic, type 2 AD
AP3B1 603401 Hermansky-Pudlak syndrome type 2 AR
ASCL1 100790 congenital central hypoventilation syndrome AD
BLOC1S3 609762 Hermansky-Pudlak syndrome 8 AR
BLOC1S6 604310 Hermansky-pudlak syndrome 9 AR
BMPR1B 603248 Brachydactyly type A2; Chondrodysplasia, Acromesomelic, With Genital Anomalies AD, AR
BMPR2 600799 Pulmonary hypertension, familial primary, 1, with or without HHT AD
CAV1 601047 AD, AR
CCDC39 613798 Ciliary dyskinesia, primary, 14
CCDC40 613799 Ciliary dyskinesia, primary, 15
CFTR 602421 hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens AD, AR
CHAT 118490 Presynaptic congenital myasthenic syndrome type 6 AR
CHRNA1 100690 Multiple pterygium syndrome, lethal type; Myasthenic syndrome, slow-channel congenital; Myasthenic syndrome, fast-channel congenital AD, AR
CHRNB1 100710 Myasthenic syndrome, congenital, 2A, slow-channel; Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency AD, AR
CHRND 100720 Multiple pterygium syndrome, lethal type; slow-channel congenital myasthenic syndrome type 3A; Congenital fast-channel myasthenic syndrome type 3B; ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency AD, AR
CHRNE 100725 slow-channel congenital myasthenic syndrome type 4A; congenital myasthenic syndrome type 4C, associated with acetylcholine receptor deficiency; fast-channel congenital myasthenic syndrome type 4B AD, AR
COLQ 603033 congenital myasthenic syndrome type 5 AR
CSF2RA 306250 Surfactant metabolism dysfunction, pulmonary, 4
CSF2RB 138981 Surfactant metabolism dysfunction, pulmonary, 5 AR
DKC1 300126 X-linked dyskeratosis congenita XLR
DNAAF1 613190 Ciliary dyskinesia, primary, 13 AR
DNAAF2 612517 Ciliary dyskinesia, primary, 10
DNAH11 603339 primary ciliary dyskinesia type 7, with or without situs inversus AR
DNAH5 603335 primary ciliary dyskinesia type 3, with or without situs inversus
DNAH9 603330 AR
DNAI1 604366 primary ciliary dyskinesia type 1, with or without situs inversus AR
DNAI2 605483 primary ciliary dyskinesia type 9, with or without situs inversus
DNAL1 610062 Ciliary dyskinesia, primary, 16 AR
DOCK8 611432 Hyper-IgE recurrent infection syndrome, autosomal recessive AR
DTNBP1 607145 Hermansky-Pudlak syndrome 7 AR
ECE1 600423 Hirschsprung disease, cardiac defects, and autonomic dysfunction AD
EDN3 131242 congenital central hypoventilation syndrome; Waardenburg syndrome type 4B; Hirschsprung disease 4 AD, AR
EFEMP2 604633 Cutis laxa, autosomal recessive, type IB AR
EIF2AK4 609280 Pulmonary venoocclusive disease 2 AR
ELN 130160 Cutis laxa, autosomal dominant 1, ADCL1; Supravalvar aortic stenosis AD
ENG 131195 hereditary hemorrhagic telangiectasia type 1 AD
FBLN5 604580 Cutis laxa, autosomal recessive, type IA; hereditary neuropathy with or without age-related macular degeneration AD, AR
FBN1 134797 Marfan syndrome; stiff skin syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2; Marfan lipodystrophy syndrome AD
FLCN 607273 colorectal cancer; Birt-Hogg-Dube syndrome; Renal carcinoma, chromophobe, somatic; primary spontaneous pneumothorax AD
FOXF1 601089 Pulmonary hypertension, familial persistent, of the newborn AD
GDF2 605120 Telangiectasia, hereditary, hemorragic, type 5 AD
GDNF 600837 pheochromocytoma; congenital central hypoventilation syndrome; Hirschsprung Disease, Susceptibility To, 3 AD
GLRA1 138491 Hyperekplexia, hereditary 1, autosomal dominant or recessive AD, AR
HPS1 604982 Hermansky-Pudlak syndrome type 1 AR
HPS3 606118 Hermansky-Pudlak syndrome type 3 AR
HPS4 606682 Hermansky-Pudlak syndrome type 4 AR
HPS5 607521 Hermansky-Pudlak syndrome type 5 AR
HPS6 607522 Hermansky-Pudlak syndrome type 6 AR
ITGA3 605025 Congenital interstitial lung disease with nephrotic syndrome and epidermolysis bullosa AR
KCNA5 176267 Atrial fibrillation, familial, 7 AD
KCNK3 603220 primary pulmonary hypertension AD
MECP2 300005 MENTAL RETARDATION, X-LINKED 13; X-linked syndromic mental retardation, Lubs type; Autism susceptibility, X-linked 3; severe neonatal encephalopathy; Rett syndrome XL, XLD, XLR
NF1 613113 neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Leukemia, juvenile myelomonocytic AD
NFU1 608100 Multiple mitochondrial dysfunctions syndrome 1 AR
NKX2-1 600635 Chorea, Benign Hereditary; Thyroid Carcinoma, Papillary; Choreoathetosis, hypothyroidism, and neonatal respiratory distress AD
NME8 607421 Ciliary dyskinesia, primary, 6 AR
NOP10 606471 Dyskeratosis Congenita, Autosomal Recessive, 1 AR
NOTCH3 600276 CADASIL; Lateral meningocele syndrome AD
PARN 604212 Dyskeratosis congenita, autosomal recessive 6; telomere-related pulmonary fibrosis and/or bone marrow failure type 4 AD, AR
PHOX2A 602753 Fibrosis of extraocular muscles, congenital, 2 AR
PHOX2B 603851 congenital central hypoventilation syndrome AD
RAPSN 601592 congenital myasthenic syndrome, type 11, associated with acetylcholine receptor deficiency AR
RASA1 139150 Capillary malformation-arteriovenous malformation AD
RET 164761 Hirschsprung disease; familial medullary thyroid carcinoma; multiple endocrine neoplasia 2B; pheochromocytoma; multiple endocrine neoplasia 2A; congenital central hypoventilation syndrome AD
RSPH1 609314 primary ciliary dyskinesia, 24 AR
RSPH4A 612647 Ciliary dyskinesia, primary, 11
RSPH9 612648 Ciliary dyskinesia, primary, 12
RTEL1 608833 dyskeratosis congenita; that telomere-related pulmonary fibrosis and/or bone marrow failure type 3 AD, AR
SARS2 612804 Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis AR
SCN4A 603967 Paramyotonia congenita; Hyperkalemic periodic paralysis, type 2; Atypical myotonia congenita, acetazolamide-responsive; Hypokalemic periodic paralysis, type 2; Myasthenic syndrome, acetazolamide-responsive AD, AR
SCNN1A 600228 Pseudohypoaldosteronism, type I AD, AR
SCNN1B 600760 Liddle syndrome; Bronchiectasis with or without elevated sweat chloride type 1; Pseudohypoaldosteronism, type I AD, AR
SCNN1G 600761 Pseudohypoaldosteronism, type I; Bronchiectasis with or without elevated sweat chloride 3 AD, AR
SERPINA1 107400 alpha-1 antitrypsin deficiency AR
SFTPA2 178642 Pulmonary fibrosis, idiopathic, susceptibility to AD
SFTPB 178640 Surfactant metabolism dysfunction, pulmonary, 1 AR
SFTPC 178620 Surfactant metabolism dysfunction, pulmonary, 2 AD
SLC6A5 604159 Hyperekplexia 3 AD, AR
SLC7A7 603593 Lysinuric protein intolerance AR
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome, infantile form; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD
SMAD9 603295 Pulmonary hypertension, primary, 2 AD
SMPD1 607608 Niemann-Pick disease type A; Niemann-Pick disease type A/B AR
STAT3 102582 Hyper-IgE recurrent infection syndrome; infantile-onset multisystem autoimmune disease, 1 AD
STRA6 610745 Microphthalmia, isolated, with coloboma 8 AR
TERT 187270 acute myeloid leukemia; Dyskeratosis congenita 4; Bone marrow failure, telomere-related, 1 AD, AR
TINF2 604319 Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 AD
TSC1 605284 tuberous sclerosis type 1 AD
TSC2 191092 tuberous sclerosis-2 AD
ZEB2 605802 Mowat-Wilson syndrome AD