Research Article: Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

Date Published: March 31, 2017

Publisher: Public Library of Science

Author(s): Zafar Iqbal, Siri L. Rydning, Iselin M. Wedding, Jeanette Koht, Lasse Pihlstrøm, Aina H. Rengmark, Sandra P. Henriksen, Chantal M. E. Tallaksen, Mathias Toft, Klaus Brusgaard.


Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

Partial Text

The spinocerebellar degenerative disorders; hereditary ataxias (HA) and hereditary spastic paraplegias (HSP) are heterogeneous disorders causing progressive gait difficulties due to degeneration of the cerebellum, corticospinal tracts, brainstem, and/or spinal cord [1]. These disorders are relatively rare with an estimated total prevalence of 13.9/100,000 in southeast Norway [2]. HA is characterized by progressive limb and gait ataxia, loss of coordination and disturbances of speech and oculomotor control. HSP is characterized by progressive spasticity and weakness of the lower limbs, the weakness often being mild relative to the spasticity [1, 2]. Onset is reported at all ages, and all monogenic modes of inheritances—autosomal dominant, autosomal recessive, and X-linked—have been identified [3]. To date, pathogenic variants in more than 100 genes have been identified in spinocerebellar degenerative disorders [4–7]. Identifying molecular diagnoses in such genetically heterogeneous disorders is challenging. Usually multitier, expensive and time-consuming investigations are performed. Nevertheless, a large number of affected individuals remain without a molecular diagnosis.

The brain is the most complex and sophisticated organ in our body. 84% of the human genes are expressed in the brain [25]. A small perturbation in the expression of genes in the brain could lead to serious consequences and a number of neurological disorders including HA and HSP. Today, routine investigation of these disorders often involves a large number of serial independent molecular tests after the clinical diagnosis has been made. Certain mutations are very common in some populations, thus narrowing down the required number of tests. Other populations show high numbers of rare genotypes, as so far seen in the Norwegian ataxia population [2]. A correct molecular diagnosis is important for affected individuals, providing certainty, preventing unnecessary diagnostic tests and giving access to relevant supportive therapies and genetic counseling.




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