The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice

Abstract

A BS TRACT: Background: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. Objective: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. Methods: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype.Results: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. Conclusion:With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey.

Phenotypical spectrum of SACS variants: Neuromuscular perspective of a complex neurodegenerative disorder

“…We identified three novel pathogenic variants [c.11274_11276delAAC (p. Ile3758_Thr3759delinsMet), c.7732_7734delGAT (p. Asp2578del), and c.3767A>G, (p. Tyr1256Cys)] in the SACS gene, which were validated by Sanger sequencing (4/IV, 6/VI) (Figure S3). 8 Of those, c.7732_7734delGAT (p. Asp2578del), and c.3767A>G, (p. Tyr1256Cys) homozygous variants were present in the same patient (4/IV) (Table 1). In silico analysis of these variants was shown in Figure S2.…”

“…Asp2578del), and c.3767A>G, (p. Tyr1256Cys)] in the SACS gene, which were validated by Sanger sequencing (4/IV, 6/VI) (Figure S3). 8 Of those, c.7732_7734delGAT (p. Asp2578del), and c.3767A>G, (p.…”

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

“…The variant has been previously reported in Portuguese and Brazilian patients, and it is characterized as causing a classical phenotype [ 25 , 27 ]; in our cohort this was the most frequent variant detected in patients from Latin America. The p.S954L variant (Top3, 3.5%) has been described in patients with adult onset of neurological symptoms (ataxia, supranuclear palsy, psychiatric manifestations) [ 4 , 13 , 28 , 29 ]. The p.R1186H variant (Top4) has been reported as the most frequent variant in patients from Greece, and it is associated with the classical filipin staining form [ 26 ].…”

Milestones in genetics of cerebellar ataxias

“…More information on the utility of NGS in early-onset cerebellar ataxias (EOCAs) comes from studies on larger series of adults, whose symptoms started appearing before the age of 40. Overall, they showed a diagnostic yield of NGS ranging from 21% to over 50%, with higher percentages of molecular diagnoses in patients with a positive family history compatible with Mendelian inheritance [20,[32][33][34][35][36][37][38][39]. The results of NGS studies outlined the most common etiologies of EOCAs in different populations.…”