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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.

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% 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 specialised bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity. The project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. YO is supported by the Turkish Academy of Sciences’ Young Investigator award, TÜBA-GEBİP (2017). PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Data was analysed using the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement nº 305444) and funding from EJP-RD and INB/ELIXIR-ES. The study was further supported by the Horizon 2020 research and innovation program via grant 779257 “Solve-RD” (RH, SB, AT and HL). RH, PFC and YO were supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1

Background Congenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far. Case Here, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions. Results We studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C > T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet. Conclusion Although prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.

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. The project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. RH is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). The Broad Centre for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) programme and the National Eye Institute. Data were analysed using the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement no. 305444)

Dihydropyridine receptor congenital myopathy is a recently described congenital myopathy caused by dominant or recessive mutations in the CACNA1S gene. To date, only 11 cases from 7 families were described in a single report. Here, we describe a consanguineous family with three affected children, presenting congenital hypotonia, contractures, ophthalmoplegia and respiratory insufficiency, with a novel homozygous mutation in the CACNA1S gene. They also showed cognitive delay, pes equinovarus deformity and neurogenic changes that have not been associated with this myopathy in the previous reports. This report expands the phenotypic spectrum of dihydropyridine receptor congenital myopathy and underscores the importance of whole exome sequencing in early onset neuromuscular disorders.