Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

Arslan, Elif Acar; Öncel, İbrahim; Ceylan, Ahmet Cevdet; Topçu, Meral; Topaloǧlu, Haluk

doi:10.1016/j.braindev.2019.08.004

Cited by 13 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there is great variation in predominance of distinctive ataxic disorders in different ethnicities and geographical regions because founder effects and consanguinity can greatly influence the population prevalence. 13,[27][28][29][30] This study aims to unravel the genetic epidemiology of HCA in a representative Turkish cohort. It further aims to raise awareness among young Turkish clinicians to facilitate the choice of genetic tests in clinical practice and to shorten the long diagnostic odyssey of patients with ataxia.…”

Section: Discussionmentioning

confidence: 99%

“…Population data for ataxias are primarily limited to the populations of Europe and North America. However, there is great variation in predominance of distinctive ataxic disorders in different ethnicities and geographical regions because founder effects and consanguinity can greatly influence the population prevalence 13,27‐30 . This study aims to unravel the genetic epidemiology of HCA in a representative Turkish cohort.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Studies show that AD has a significant polygenic component, which may be used in calculating genetic risk of developing the disease. The sum of risk alleles carried by an individual, where each single nucleotide polymorphism (SNP) is weighted by the effect [20,21,24,[32][33][34][35][36] size from the prior GWAS, is called a polygenic risk score (PRS) and may have a predictive value for multiple common diseases. Promising results that point to potential clinical utility of PRS in the future have been published for AD and epilepsy [63,64].…”

Section: Cerebellar Ataxias-beyond Monogenic Diseasesmentioning

confidence: 99%

“…Similar result was published by Ohba et al [ 23 ], who evaluated children with cerebellar atrophy and reported a 39% success rate (9 of 28 families). Application of targeted ataxia gene panel in a group of 84 pediatric patients resulted in genetic diagnosis in 25% [ 24 ]. In consanguineous families, exome sequencing can provide a molecular diagnosis in up to 80% of cases [ 25 , 26 ].…”

Section: Utility Of Next-generation Sequencing In Childhood-onset Cerebellar Ataxiasmentioning

confidence: 99%

Milestones in genetics of cerebellar ataxias

Krygier

Mazurkiewicz-Bełdzińska

2021

Neurogenetics

View full text Add to dashboard Cite

Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the cerebellar syndrome, which is often accompanied by other neurological or non-neurological signs. In the last 30 years, our understanding of the CA etiology has increased significantly, and numerous ataxia-associated genes have been discovered. Conventional variants or tandem repeat expansions, localized in the coding or non-coding DNA sequences, lead to hereditary ataxia, which can display different patterns of inheritance. Advances in molecular techniques have enabled a rapid and cost-effective detection of causative variants in a significant number of CA patients. However, despite performing extensive investigations, a definite diagnosis is still unknown in the majority of affected individuals. In this review, we discuss the major advances in the genetics of CAs over the last 30 years, focusing on the impact of next-generation sequencing on the genetic landscape of childhood- and adult-onset CAs. Additionally, we outline possible directions for further genetic research in hereditary and sporadic CAs in the era of increasing application of whole-genome sequencing and genome-wide association studies in various neurological disorders.

show abstract

“…[9][10][11] Ataxia and Oculomotor Apraxia type 1 (AOA1) is a speci c type of hereditary ataxia found in patients with mutations in the APTX gene and a clinical presentation accompanied by oculomotor apraxia. 1,[12][13][14][15][16] The APTX gene encodes for a protein called Aprataxin, composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3′-phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-nger proteins. 14,15,[17][18][19][20][21][22] Given the role of PNKP in DNA single-strand break reparation, Aprataxin has been involved in the repair of DNA in cells of various tissues, including the brain, spinal cord, and muscles.…”

Section: Introductionmentioning

confidence: 99%

Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings

Aguillón

Vásquez

Madrigal

et al. 2021

Preprint

View full text Add to dashboard Cite

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

show abstract

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

Cited by 13 publications

References 18 publications

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

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

Milestones in genetics of cerebellar ataxias

Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings

Contact Info

Product

Resources

About