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    Characterization and Engineered U1 snRNA Rescue of Splicing Variants in a Turkish Neurodevelopmental Disease Cohort
    (Wiley-Hindawi, 2024) Sonmezler, Ece; Stuani, Cristiana; Hiz Kurul, Semra; Gungor, Serdal; Buratti, Emanuele; Oktay, Yavuz
    Although they are rare in the population, rare neurodevelopmental disorders (RNDDs) constitute a significant portion of all rare diseases. While advancements in sequencing technologies led to improvements in diagnosing and managing rare neurodevelopmental diseases, accurate pathogenicity classification of the identified variants is still challenging. Sequence variants altering pre-mRNA splicing make up a significant part of pathogenic variants. Despite advances in the in silico prediction tools, noncanonical splice site variants are one of the groups of variants that pose a challenge in their clinical interpretation. In this study, we analyzed the effects of seven splicing variants we had previously proposed as disease-causing and demonstrated that all but one of the seven variants had a strong or moderate effect on splicing, as assessed by a minigene assay. Next, applying U1 snRNAs engineered for different splicing variants in the corresponding genes and expressed with minigene plasmids in HeLa cells provided a partial correction in four of the studied genes to varying degrees. Findings from our study highlight the importance of in vitro minigene-based assays for the reclassification of putative splice-altering variants of uncertain significance and the therapeutic potential of modified U1 snRNAs in RNDDs.
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    Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families
    (Ios Press, 2020) Oktay, Yavuz; Gungor, Serdal; Zeltner, Lena; Wiethoff, Sarah; Schoels, Ludger; Sonmezler, Ece; Yilmaz, Elmasnur
    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.
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    High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases
    (Oxford Univ Press, 2022) Kurul, Semra Hiz; Oktay, Yavuz; Topf, Ana; Szabo, Nora Zs; Gungor, Serdal; Yaramis, Ahmet; Sonmezler, Ece
    Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.
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    Severe neurodevelopmental disease caused by a homozygous TLK2 variant
    (Nature Publishing Group, 2020) Topf, Ana; Oktay, Yavuz; Balaraju, Sunitha; Yilmaz, Elmasnur; Sonmezler, Ece; Yis, Uluc; Laurie, Steven
    A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.
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    Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study
    (Georg Thieme Verlag Kg, 2023) Gunay, Cagatay; Aykol, Duygu; Ozsoy, Ozlem; Sonmezler, Ece; Hanci, Yaren Sena; Kara, Bulent; Sunnetci, Deniz Akkoyunlu
    Background Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. Method In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Results Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage- gated ion channel activity/voltage-gated channel activity, respectively. Conclusion Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.
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    y COL4A1-related autosomal recessive encephalopathy in 2 Turkish children
    (Lippincott Williams & Wilkins, 2020) Yaramis, Ahmet; Lochmueller, Hanns; Topf, Ana; Sonmezler, Ece; Yilmaz, Elmasnur; Hiz, Semra; Yis, Uluc
    Objective This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. Methods Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. Results We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_ 001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. Conclusions COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotypephenotype correlations remain to be established.