Limb Girdle Muscular Dystrophy Type 2Y via the TOR1AIP1 Gene

Limb girdle muscular dystrophy (LGMD) is a descriptive term for a group of disorders with atrophy and weakness of proximal girdle muscles and typical sparing of the heart and bulbar muscles. Clinical severity, age of onset, and disease progression are highly variable among the subtypes (Sáenz et al. 2005). Serum creatine kinase levels are typically elevated, and muscle biopsies demonstrate a dystrophic process. For comprehensive reviews, see Pegoraro and Hoffman (2012) and Nigro and Savarese (2014).

Two different families thus far have had pathogenic TOR1AIP1 variants identified. In a consanguineous Turkish family with three affected individuals, homozygosity mapping was used to identify the TOR1AIP1 gene as a candidate for sequencing. These individuals presented with proximal limb-girdle weakness during childhood which later progressed to distal weakness with atrophy, rigid spine, and contractures of proximal and distal hand joints. Cardiomyopathy and respiratory involvement were also noted in adulthood. In a second family with one affected individual, TOR1AIP1 variants were detected via whole exome sequencing (WES). This patient presented with LGMD-like weakness and severe dilated cardiomyopathy at 12 years of age. The muscle biopsy from this patient was consistent with a dystrophic process.

Limb girdle muscular dystrophy type 2Y is inherited as an autosomal recessive disorder. So far, only missense and small deletion variants have been observed (Ghaoui et al. 2015; Kayman-Kurekci et al. 2014). The TOR1AIP1 gene encodes the lamina-associated polypeptide 1B (LAP1B) protein which is a type-2 integral membrane protein located in the inner nuclear membrane and shown to bind both A- and B-type lamins (Kayman-Kurekci et al 2014). The full function of this protein is not completely understood; however, the LAP1B protein is widely expressed in a variety of tissues, including skeletal muscle.

Too few cases of LGMD2Y have been reported to provide a numeric estimate of clinical or analytical sensitivity. However, pathogenic variants in TOR1AIP1 appear to be a rare cause of LGMD. Analytical sensitivity could be high as the reported pathogenic variants are detectable by sequencing.

Thus far, no large deletions or duplications involving the TOR1AIP1 gene have been reported.

This test provides full coverage of all coding exons of the TOR1AIP1 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).