Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families

Abstract

Background: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease.

Objective: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype.

Methods: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families.

Results: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15).

Conclusions: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.

Fig. 1

Patient 1, homozygous for c.472insC (p.His158ProfsTer8). (a) Neurological examination of the patient shows bilateral optic atrophy, upper extremity amyotrophy, proximal and distal weakness and spastic tetraparesis. Pedigree of the family and Sanger sequencing show segregation of the TACO1 variant in family members. The proband is homozygous and his mother, father and unaffected siblings are heterozygous for the TACO1; c.472insC variant. (b) Cranial MR imaging demonstrate progressive cerebral atrophy and T2 hyperintense periventricular white matter lesions (arrows).

Fig. 2

Patient 2, homozygous for c.252_253delCT (p.Cys85PhefsTer15). (a) Pedigree of family and Sanger sequencing show that the prob and is homozygous and her mother and father are heterozygous for the TACO1c.252_253delCT variant. (b) Baseline MRI image at the age of 25 years (i + iv on the left) and follow-up 14 years later (ii/iii+v/vi) show white matter degeneration with white matter atrophy and sulcal widening (arrows in i and ii) as well as cystic lesions that demonstrate CSF like signal behavior in the FLAIR (iii). The infratentorial T2-weighted image (vi)demonstrates hyperintensities within the middle cerebellar peduncle (asterix) and within the cerbellar white matter (arrow). (c) Color fundus photography (i) shows severe paleness of the optic nerve head. OCT (ii+iii) reveals atrophy of the peripapillary retinal nerve fiber layer (RNFL) (ii). The foveal depression is flattened due to atrophy of the ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) (see * in (iii)). All other retinal layers are intact; in particular, there are no signs or chorioretinal atrophy. Best corrected visual acuity was 20/400 (right eye) and 20/250 (left eye), the subject was legally blind (according to WHO definition). Images for the left eye are shown; all changes were present in both eyes.

Fig. 3

Schematic representation of exon-intron structure of TACO1 and the mutations detected in our patients. (a) Schematic representation of exon-intron structure of the TACO1 gene and the reported mutations c.472insC (p.His158ProfsTer8) andc.252_253delCT (p.Cys85PhefsTer15). (b) Haplotype analysis of the SNPs in the proximity of the c.472insC (p.His158ProfsTer8) mutation suggesting a founder effect for this variant.