Invitae Asphyxiating Thoracic Dystrophy Panel


Test description

The Invitae Asphyxiating Thoracic Dystrophy Panel analyzes three genes that are associated with asphyxiating thoracic dystrophy (ATD). The protein products of these genes are involved in the formation and proper function of cilia, which are the hairlike projections extending from the surface of the cell. Cilia are necessary for proper cellular motility, for the movement of material around a cell, and for chemical signaling pathways. Pathogenic variants in these genes impair the function of cilia and are described as a class of pediatric developmental disorders known as ciliopathies.

Molecular genetic testing for ATD can provide patients with a definitive diagnosis when skeletal dysplasias such as Sensenbrenner syndrome or Mainzer-Saldino syndrome are being considered as differential diagnoses. There is also overlap between ATD and other ciliopathies, such as Joubert syndrome. With the molecular determination of the patient’s phenotype, precise clinical care and monitoring can be administered. Identification of the molecular basis of the disorder in an affected individual may confirm diagnosis and encourage testing of additional family members to inform reproductive risk.

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Primary panel (3 genes)


Alternative tests to consider

Asphyxiating thoracic dystrophy is a member of a class of disorders called ciliopathies. Ciliopathies are caused by pathogenic variants in genes that affect the function of cilia—the hair-like structures on the surface of cells. Ciliopathies share many overlapping symptoms, often making it difficult to distinguish between them based on clinical presentation alone.

The Invitae Sensory Ciliopathies Panel has been designed to provide a broad genetic analysis of this class of disorders and may be considered as an alternative to testing for a specific disorder. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional charge.

Asphyxiating thoracic dystrophy (ATD)

Asphyxiating thoracic dystrophy is a skeletal ciliopathy characterized by shortened ribs and long bones, polydactyly, and brachydactyly. Additional, extraskeletal clinical features may include retinal dystrophy, renal disease, hepatic fibrosis, heart defects, and subglottic stenosis. Asphyxiating thoracic dystrophy can potentially be lethal in the neonatal period due to diminished respiratory capacity from a constricted thoracic cage.

Asphyxiating thoracic dystrophy is a rare, genetically heterogeneous disorder. Consequently, definitive gene-attribution proportions for the genes represented on this panel have yet to be determined. It is estimated that a causative mutation can be found in one of the genes implicated in asphyxiating thoracic dystrophy in approximately 70% of cases, and that variants in DYNC2H1 are responsible for 50% of disease-causing variants.

Asphyxiating thoracic dystrophy is inherited in an autosomal recessive manner.

Asphyxiating thoracic dystrophy has been reported to have variable expressivity. Variability ranges from mild breathing difficulties to more severe respiratory difficulties that could result in neonatal lethality. Intrafamilial variability has also been reported among family members who have the same pathogenic variant but who exhibit phenotypes with varying degrees of severity. The degree of severity may also depend on the gene in which a pathogenic variant is found. For example, it has been reported that patients with variants found in DYNC2H1 may have a lower incidence of extraskeletal complications.

The prevalence of ATD is estimated at1 in 100,000 to 1 in 130,000 people.

This test should be considered for patients who have shortened ribs and long bones, with or without polydactyly and extraskeletal findings. Variants in the genes on this panel have been implicated in the severe, lethal form of this disorder (known as short rib polydactyly syndrome) and in phenotypes that are compatible with life, such as Jeune thoracic dystrophy. There is considerable phenotypic variation associated with this disorder, as well as phenotypic overlap between these symptoms and those found associated with other ciliopathies. These symptoms include retinal dystrophy, polydactyly, renal cystic disease, and situs inversus.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
DYNC2H1 NM_001080463.1
IFT80 NM_020800.2
TTC21B NM_024753.4