Exome sequencing in undiagnosed inherited and sporadic ataxias

Abstract

Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision.

Keywords: ataxia; whole exome sequencing.

Figure 1

De novo TUBB4A mutation in Patients P11, 12 and 13. Top: Segregation of TUBB4A c.900C>A (p.Met300Ile) mutation in Patient P13 (mother), and her two daughters. Confirmatory Sanger sequencing and pyrosequencing in different tissues from the mother showing tissue mosaicism in the mother for the presumed de novo dominant allele. Middle: Pyrosequencing results of this mutation in different tissues. Bottom: Brain MRI from Patient P13, the mother (A and B) and daughter Patient P12 (C and D). (A and B) T₂ and T₁ images showing generalized atrophy and periventricular high signal. (C and D) T₂ images showing marked cerebellar atrophy and diffuse hypomyelination.

Figure 2

T₁ axial (A) and T₂ sagittal (B) MRI in Patient P19. The MRI shows global cerebral atrophy with relative sparing of the occipital lobes and cerebellum, and marked atrophy of the corpus callosum previously described in patients with mutations in ZFYVE26 (SPG15) (Goizet et al., 2009).