Achondrogenesis Type 1A via the TRIP11 Gene

Achondrogenesis is a group of disorders related to incomplete ossification of bones in the skull, spine and pelvis. Radiographic features include extremely shortened limbs, short ribs and severe pulmonary hypoplasia. Most patients are stillborn or die soon after birth due to respiratory failure (Borochowitz, Z. et al. J Pediatr 112(1):23-31, 1988). Clinically, it is divided into three subtypes: 1A (OMIM# 200600, also called Houston-Harris Type), 1B (OMIM# 600972, also called Fraccaro Type), and 2 (OMIM#200610), which are caused by mutations in TRIP11, SLC26A2 and COL2A1, respectively.

Achondrogenesis Type 1A caused by mutations in TRIP11 (Thyroid hormone receptor interactor 11) is inherited in an autosomal recessive manner. GMAP210 protein (Golgi –microtubule-associated protein, GMAP210) coded by the TRIP11 gene is a Golgi apparatus associated protein containing three domains: a N-terminal Golgi binding domain (exons 1 to 7), a central coiled-coil domain (exons 7 to 17) and a C-terminal microtubule-binding domain (exons 18 to 21). Studies suggested that it plays a role in assembly and maintenance of the Golgi ribbon structure around the centrosome and Golgi network, and is also required for the glycosylation and cellular transport of multiple proteins (Ramos-Morales, F. et al. Biochem J 357(Pt 3): 699-708, 2001; Rios, R. M et al. Cell 118(3): 323-335, 2004; Smits, P. et al. N Engl J Med 362(3):206-16, 2010). To date, only six unique causative mutations have been identified in achondrogenesis patients. These mutations are four nonsense and two splicing site mutations (Smits, P. et al., 2010).

Clinical sensitivity is unknown due to the limited number of patients. Analytical sensitivity may be high because all the reported mutations are point mutations which are expected to be detected by sequencing method. No large deletions/insertions have been reported (Smits, P. et al. N Engl J Med 362(3):206-16, 2010).

This test provides full coverage of all coding exons of the TRIP11 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).