Rare respiratory diseases

Carried by: RespiFIL

References:

Clinician(s): David MONTANI

Biologist(s): Alix DE BECDELIEVRE, Florence COULET

Presentation

Many rare respiratory diseases remain unexplained by targeted gene panel analysis. Thus, a genetic cause is identified in nearly 90% of cases of central hypoventilation (CH), 80% of primary ciliary dyskinesia (PCD), 30% of diffuse interstitial lung disease (ILD), 25% of sporadic forms of venous occlusive disease in young people, 15% of isolated forms of pulmonary arterial hypertension (PAH), and less than 10% of syndromic pulmonary development abnormalities (SPD) or idiopathic bronchiectasis (IBE). Unexplained forms may benefit from Genome Sequencing.

Criteria before considering a discussion in MDM-FMG

Criteria for pulmonary arterial hypertension (PAH) or pulmonary veno-occlusive disease (PVOD)

Pulmonary arterial hypertension (PAH) or pulmonary veno-occlusive disease (PVOD) in children or young adults not associated with pathologies explaining these diseases. Samples from parents should ideally be available for trio STHD analysis.
Familial PAH or PVOD (at least 2 cases up to the 3rd degree). Samples from at least 2 affected patients must be available for STHD analysis.
Negative genetic panel analysis.

Criteria for diffuse interstitial lung disease (ILD)

Diffuse interstitial lung disease (ILD) in children with no known aetiology. Samples from parents should ideally be available for trio STHD analysis.
Familial ILD (at least 2 cases up to the 3rd degree). Samples from at least 2 affected patients must be available for STHD analysis.
Pulmonary or extrapulmonary phenotype suggesting a genetic cause (e.g. suspected telomeropathy with DIP and familial or sporadic haematological or hepatic involvement). Samples from at least 2 relatives must be available for STHD analysis
AND negative targeted genetic panel analysis

Criteria for primary ciliary dyskinesia (PCD)

Negative study of PCD-related genes (NGS panel and/or exome) in a patient with respiratory signs suggestive of PCD with nasal NO <diagnostic threshold on two occasions with at least one of the following:
- Situs inversus
- Ciliary ultrastructure abnormalities typical of PCD in EM
Moderate clinical suspicion of PCD but personal or familial (siblings) extrarespiratory clinical manifestations suggestive of ciliopathies (retinitis pigmentosa, congenital heart disease, hydrocephalus, polysplenia, morphological abnormalities of the sperm flagellum, etc.)

Criteria for central hypoventilation (CH)

Central hypoventilation (= persistent alveolar hypoventilation not explained by neurological, neuromuscular or pulmonary parenchymal involvement). Samples from parents must be available for GS analysis in trios.
Familial central hypoventilation (at least 2 cases up to the 3rd degree). Samples from at least 2 affected patients must be available for GS analysis.
Negative genetic analysis of the PHOX 2B gene.

Criteria for abnormal pulmonary development (APD)

Abnormal pulmonary development in children with pulmonary or extrapulmonary phenotype suggesting a genetic cause (at least 1 criterion):
- Syndromic malformation
- Clinical severity that may warrant genetic counselling for future pregnancies
- Documented risk of recurrence

Familial pulmonary development anomaly in children (at least 2 cases up to the 3rd degree). Samples from at least 2 affected patients must be available for GS analysis
AND negative genetic panel analysis for known genes

Criteria for idiopathic bronchiectasis (IBE)

Idiopathic bronchiectasis in children with a phenotype suggesting a genetic cause (at least 1 criterion):
- Syndromic malformation
- Clinical severity that may justify genetic counselling for future pregnancies
- Documented risk of recurrence

Familial idiopathic bronchiectasis (at least 2 cases up to the 3rd degree). Samples from at least 2 affected patients must be available for GS analysis
AND negative genetic panel analysis for known genes