KIF1A-Related Disorders via the KIF1A Gene

The KIF1A gene has been associated with a spectrum of disorders which include: mental retardation autosomal dominant 9 (MRD9), spastic paraplegia 30 (SPG30) and hereditary sensory neuropathy IIC (HSNIIC).

MRD9 is a disorder characterized by intellectual disability associated with adaptive behavior impairments. The variable features include delayed speech development, microcephaly, ataxia, hypotonia, progressive spastic paraparesis and peripheral neuropathy. MRD9 patients typically have onset of disease in the first years of life (Hamdan et al. 2011. PubMed ID: 21376300; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038).

SPG30 is a neurodegenerative disorder with onset of a progressive weakness and stiffness in the lower limbs in the first or second decades. The severity of symptoms and rate of progression are quite variable. The weakness and spasticity may spread to arms and some patients may have bladder symptoms (Klebe et al. 2006. PubMed ID: 16434418; Erlich et al. 2011; Klebe et al. 2012. PubMed ID: 22258533; Ylikallio et al. 2015. PubMed ID: 25585697).

HSNIIC is a type of sensory neuropathy characterized by distal sensory loss leading to ulceration and amputation of the digits. The onset of the disease is usually in the first decade. Some HSNIIC patients may also develop distal muscle weakness primarily in the lower limbs (Rivière et al. 2011. PubMed ID: 21820098).

KIF1A encodes kinesin family member 1A, which functions as an anterograde motor protein to transport dense core vesicle (DCVs) along microtubules to the pre- and post-synaptic regions. KIF1A dysfunction results in a reduction of DCVs at synapses and its accumulation in the cell body, leading to neuronal death (Lo et al. 2011. PubMed ID: 21256924).

To date, in the KIF1A gene only missense and frameshift variants have been reported to cause disease (Human Gene Mutation Database). Missense pathogenic variants predominate in cases of MRD9 and SPG30; all the reported pathogenic variants for HSANIIC are small deletions or insertions that cause a frameshift (Rivière et al. 2011. PubMed ID: 21820098). Pathogenic variants identified so far for MRD9 are de novo (Hamdan et al. 2011. PubMed ID: 21376300; Lee et al. 2015. PubMed ID: 25265257; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038; Ohba et al. 2015. PubMed ID: 26354034). For HSNIIC, the inheritance mode in the reported families is consistent with autosomal recessive inheritance (Rivière et al. 2011. PubMed ID: 21820098). SPG30 is typically inherited in an autosomal recessive manner, however, autosomal dominant cases have been reported recently (Iqbal et al. 2017. PubMed ID: 28362824).

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the KIF1A gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the KIF1A 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).