Seipin-Related Disorders via the BSCL2 Gene

Seipin-related neurologic disorders include distal hereditary motor neuronopathy type V (HMNV; OMIM 600794) and spastic paraplegia 17 (SPG17, Silver syndrome; OMIM 270685). The distal hereditary motor neuronopathies represent a phenotypic continuum of distal neuropathy with weakness and wasting starting in the distal limbs, predominately the hands. Onset of the BSCL2 related neuronopathies is between the first and seventh decades of life and progression is slow. Motor neuron involvement includes amyotrophy of the peroneal and hand muscles, gait disturbances, and mild to severe spasticity (Wagner and Auer-Grumbach. GeneReviews, 2005). Remarkable variability of phenotypic expression, even within families, has been described (Auer-Grumbach et al. Ann Neurol 57:415-424, 2005). Variants in the seipin gene are also the cause of congenital generalized lipodystrophy (CGL2, Berardinelli-Seip congential lipodystrophy; OMIM 269700), a congenital or early infancy onset disorder characterized by near absence of adipose tissue and insulin resistance (Magré et al. Nature Genetics 28:365-370, 2001). Patients affected with CGL2 exhibit accelerated growth and maturation in early childhood, muscle hypertrophy, hyperpigmented and coarse skin, hirsutism, hepatomegaly, hyperlipidemia, and insulin resistant diabetes mellitus.

Distal hereditary motor neuronopathy type V and Silver syndrome are inherited as autosomal dominant disorders. Missense variants in the gene encoding seipin (BSCL2; OMIM 606158) are the cause of both neuropathies (Windpassinger et al. Nature Genetics 36:271-276, 2004). Variants in the GARS gene are another cause of HMNV (Antonellis et al. Am J Hum Genet 72:1293-1299, 2003). Congenital generalized lipodystrophy type 2 is inherited as an autosomal recessive disorder and almost all reported causative BSCL2 variants for this disorder predict null alleles.

Among a cohort of 45 congenital generalized lipodystrophy patients Agarwal et al. (J Clin Endocrin Metab 88:4840-4847, 2003) found 11 with BSCL2 variants and 26 with AGPAT2 gene variants. Two BSCL2 variants (p.Asn88Ser and p.Ser90Leu) have been found in a small number of patients with neurological disorders. Analytical sensitivity should be high because all BSCL2 variants reported to date are of the type expected to be detected by DNA sequencing of genomic DNA.

This test provides full coverage of all coding exons of the BSCL2 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).