Central Hypoventilation Syndrome Panel (6 Genes) Test Details
The Central Hypoventilation Syndrome Panel sequences 6 genes associated with congenital central hypoventilation syndrome (CCHS). CCHS is a rare, autosomal dominant condition that classically can present in newborns with hypoventilation, shallow breathing, and autonomic nervous system dysregulation. CCHS also is associated with defects in the development of neural crest structures and/or tumors of neural crest origin. CCHS also has a late-onset presentation in toddlers, children, and adults.
|ASCL1||Achaete-Scute Complex Homolog 1 (Drosophila)||100790||12q23.2|
|BDNF||BDNF Antisense RNA||611468||11p14.1|
|GDNF||Glial Cell Derived Neurotrophic Factor||600837||5p13.1-p12|
|PHOX2B||Paired-Like Homeobox 2B||603851||4p12|
The Central Hypoventilation Syndrome Panel should be ordered for individuals with a diagnosis or suspected diagnosis of central hypoventilation syndrome, including congenital or later-onset forms. This panel will provide comprehensive coverage of the implicated genes and minimize the incidence of variants of unknown significance compared with the PulmoGene panel.
We recommend careful consideration when deciding whether to order the full panel or the disease-specific sub-panels. For clinically complex cases where the diagnosis is not clear, the complete multi-disease panel may shorten the “testing odyssey.” However, it should be noted that large multi-disease panels typically come with an increased risk of an inconclusive result. as many genes have not yet been sufficiently interrogated for all included diseases. Disease-specific sub-panels may, therefore, be the better first line test for individuals with clear clinical diagnoses.
This test is performed by next-generation sequencing, using Agilent SureSelect capture, followed by sequencing of the coding regions and splice sites, using Illumina sequencing technologies. Variant calls are generated using the Burrows-Wheeler Aligner, followed by Genomic Analysis Tool Kit (GATK) analysis. Detection of copy number variants (CNVs) encompassing 1 or more exons is performed, using VisCap™ analysis. Sanger sequencing is used to fill in regions with insufficient coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR. Variants classified as likely benign or benign are not confirmed. This test does not detect variants in non-coding regions that could affect gene expression, aside from the splice junctions, and a few exons have been excluded due to technical difficulties. CNV analysis is performed only when data meets necessary quality standards and may not be available for all cases.
Analytical and Clinical Sensitivity
This test is 100.00% sensitive (525/525 variants tested; 95% CI = 99.27-100.00% ) to detect variants changing a single base and 100.00% sensitive to detect insertion/deletions 1-21 bp in size (17/17 variants tested; 95% CI = 81.57-100.00%). Regions with high sequence homology are included in this test if a unique Sanger sequencing assay can be designed to rule out false positive calls. Analytical sensitivity in these regions may be reduced.
Given the recent launch of this disease area, the detection rate for the Central Hypoventilation Syndrome Panel remains unknown at this point.
Amato F, Bellia C, Cardillo G, Castaldo G, Ciaccio M, Elce A, Lembo F, Tomaiuolo R. 2012. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 14(1):81-9.
Armanios M. 2012. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730(1-2):52-8.
Boon M, Jorissen M, Proesmans M, De Boeck K. 2013. Primary ciliary dyskinesia, an orphan disease. Eur. J. Pediatr. 172(2):151-62.
Borie R, Kannengiesser C, Crestani B. 2012. Familial forms of nonspecific interstitial pneumonia/idiopathic pulmonary fibrosis: clinical course and genetic background. Curr Opin Pulm Med. 18(5):455-61.
De Pontual L, Trochet D, Caillat-Zucman S, Abou Shenab OA, Bougneres P, Crow Y, Cunningham S, Esteva B, Heberle LC, Leger J, Pinto G, Polak M, Shafik MH, Straus C, Trang H, Munnich A, Lyonnet S, Desguerre I, Amiel J. 2008. Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr. Res. 64(6):689-94.
Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halbower AC, Planer B, Stephan MJ, Uchida DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, Nogee LM. 2013. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 144(3):794-804.
Hu Q, Shifren A, Sens C, Choi J, Szabo Z, Starcher BC, Knutsen RH, Shipley JM, Davis EC, Mecham RP, Urban Z. 2010. Mechanisms of emphysema in autosomal dominant cutis laxa. Matrix Biol. 29(7):621-8.
Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, Soubrier F, Trembath RC, Chung WK. 2009. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54(1 Suppl):S32-42.
Muzykewicz DA, Sharma A, Muse V, Numis AL, Rajagopal J, Thiele EA. 2009. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J. Med. Genet. 46(7):465-8.
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. 2002. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2(2):157-64.
Nogee LM. 2010. Genetic Basis of Children's Interstitial Lung Disease. Pediatr Allergy Immunol Pulmonol. 23(1):15-24.
Pulkkinen V, Bruce S, Rintahaka J, Hodgson U, Laitinen T, Alenius H, Kinnula VL, Myllärniemi M, Matikainen S, Kere J. 2010. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB J. 24(4):1167-77.
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, sous-commission « syndrome d’hypoventilation alvéolaire centrale congénitale » de l’American Thoracic Society. 2013. [ATS clinical policy statement: Congenital central hypoventilation syndrome. Genetic basis, diagnosis and management]. Rev Mal Respir. 30(8):706-33.
Wei ML. 2006. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. 19(1):19-42.Less