Autosomal Dominant Lower Extremity-Predominant Spinal Muscular Atrophy Type 2 via the BICD2 Gene

Spinal Muscular Atrophies (SMAs) are a diverse group of genetic disorders characterized by neurodegeneration and muscle weakness. SMAs are clinically and genetically heterogeneous disorders that are categorized into different forms based on onset, severity of symptoms, and inheritance pattern (Neveling et al. 2013. PubMed ID: 23664116). The most common form of SMA is due to homozygous deletions or pathogenic variants of the survival of motor neuron 1 (SMN1) gene localized to 5q13.2. This type of SMA accounts for up to 95% of cases of SMA (Oates et al. 2013. PubMed ID: 23664120; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). The functional loss of SMN1 leads to this autosomal recessive form of SMA that is divided into different types based on the age of onset and severity of the symptoms. Other forms of SMA have been identified that are not linked to the SMN1 gene and include autosomal dominant lower extremity-predominant spinal muscular atrophy 1, caused by pathogenic variants in the DYNC1H1 gene, and autosomal dominant lower-extremity predominant spinal muscular atrophy 2A, Childhood Onset and 2B, Prenatal Onset, caused by pathogenic variants in the BICD2 gene.

Autosomal dominant lower extremity-predominant spinal muscular atrophy 2 (SMALED2) is a rare condition with unknown prevalence. It is caused by heterozygous pathogenic variants in the BICD cargo adaptor 2 (BICD2) gene. Overall, patients with SMALED2 experience nonprogressive muscle weakness and atrophy of the proximal lower limbs (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). About 5-29% of patients with BICD2 pathogenic variants experience fasciculations, hip contractures, hip dysplasia, hyperlordosis, hyperreflexia, knee flexion contracture, scapular winging, and spasticity. Additional symptoms may include Achilles tendon contracture, areflexia, axial muscle weakness, difficulty running, gowers sign, hyporeflexia, motor delay, spinal muscular atrophy, talipes equinovarus, toe walking, and waddling gait (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138; Rudnik-Schoneborn et al. 2016. PubMed ID: 26998597). Molecular genetic testing is advantageous to establish a diagnosis for individuals with muscular weakness lacking deletions or pathogenic variants in SMN1. Current treatment is supportive care.

There are two forms of SMALED2, both caused by variants in BICD2, which differ only in the age of onset and the severity of the symptoms. SMALED2 type A is characterized by early childhood onset of muscle weakness and atrophy, however adult onset has also been reported (Neveling et al. 2013. PubMed ID: 23664116; Oates et al. 2013. PubMed ID: 23664120; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). There is very limited to no disease progression observed in this disorder (Neveling et al. 2013. PubMed ID: 23664116). SMALED2 type B is a severe neuromuscular disorder with onset in utero and death occurring in early childhood. Symptoms at birth may include congenital contractures, severe hypotonia, muscle atrophy, and respiratory insufficiency due to muscle weakness (Storbeck et al. 2017. PubMed ID: 28635954).

SMALED2 is an autosomal dominant disorder that results from heterozygous pathogenic variants in BICD2. To date, about fifteen missense variants have been reported in patients with SMALED2 (Neveling et al. 2013. PubMed ID: 23664116; Peeters et al. 2013. PubMed ID: 23664119; Oates et al. 2013. PubMed ID: 23664120; Synofzik et al. 2013. PubMed ID: 24336790; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138; Rossor et al. 2015. PubMed ID: 25497877; Rudnik-Schoneborn et al. 2016. PubMed ID: 26998597; Fiorillo et al. 2016. PubMed ID: 27000979). These variants have not been reported in population databases or have been reported at very low frequencies.

BICD2 (9q22.31) encodes the Bicaudal D Homolog 2 protein. This protein is considered to be a golgin and is a resident protein of the Golgi apparatus where it works to help maintain the structure of the Golgi and is involved in regulation of vesicle transport via interaction with the dynein complex (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). All of the reported BICD2 missense variants in SMALED2 patients have been determined to exert a gain of function effect (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). Increased activity of the BICD2 protein leads to aberrant function as the protein is unable to properly bind with the dynein complex and regulate vesicle transport. In addition, the altered protein is unable to properly maintain the structure of the Golgi apparatus, leading to its destruction. The exact mechanism of the cause of disease remains to be elucidated as variants have been found throughout the gene and lack a strong correlation with disease onset or severity (Storbeck et al. 2017. PubMed ID: 28635954).

The BICD2 gene is highly conserved and is homologous to the Drosophila Bicaudal D (BicD) gene and to the murine Bicaudal D 2 (Bicd2) gene. Flies with mutant BicD showed reduced larvae locomotion, and the complete absence of BicD resulted in lethality during early development (Ran et al. 1994. PubMed ID: 8026332; Li et al. 2010. PubMed ID: 20111007; Neveling et al. 2013. PubMed ID: 23664116; Jaarsma et al. 2014. PubMed ID: 24614806; Martinez-Carerra et al. 2018. PubMed ID: 29528393). Mouse models with heterozygous loss of Bicd2 did not have pathological effects; however the complete absence resulted in lethality early in post-natal life (Ran et al. 1994. PubMed ID: 8026332; Jaarsma et al. 2014. PubMed ID: 24614806; Martinez-Carerra et al. 2018. PubMed ID: 29528393). No motor neuron abnormalities were observed in mice such as seen in patients with SMALED2, suggesting that missense pathogenic variants with a gain of function effect lead to disease in humans (Jaarsma et al. 2014. PubMed ID: 24614806). In vitro studies of BICD2 variants in HeLa cells and primary fibroblasts from SMALED2 patients showed increased fragmentation of the Golgi apparatus as a result of aberrant BICD2 protein function (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138).

The great majority of cases of SMA (~95%) are due homozygous deletions/variants of SMN1 localized to 5q13.2 (aka 5q SMA). The remaining ~5% of cases of SMA are non-5q SMA and are very rare. These disorders are clinically and genetically heterogeneous and are usually classified based on their inheritance pattern (AD, AR, or X-linked). Of the non-5q SMA disorders, a small percentage is inherited in an autosomal dominant manner. Of these autosomal dominantly inherited SMAs, SMALED1 and SMALED2, only ~30% have detectable pathogenic variants (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the BICD2 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 coverage as ≥20X NGS reads or Sanger reads.

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).