Dataset Information

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

ABSTRACT: Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

SUBMITTER: Reijnders MRF

PROVIDER: S-EPMC5992133 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Reijnders Margot R F MRF Miller Kerry A KA Alvi Mohsan M Goos Jacqueline A C JAC Lees Melissa M MM de Burca Anna A Henderson Alex A Kraus Alison A Mikat Barbara B de Vries Bert B A BBA Isidor Bertrand B Kerr Bronwyn B Marcelis Carlo C Schluth-Bolard Caroline C Deshpande Charu C Ruivenkamp Claudia A L CAL Wieczorek Dagmar D Baralle Diana D Blair Edward M EM Engels Hartmut H Lüdecke Hermann-Josef HJ Eason Jacqueline J Santen Gijs W E GWE Clayton-Smith Jill J Chandler Kate K Tatton-Brown Katrina K Payne Katelyn K Helbig Katherine K Radtke Kelly K Nugent Kimberly M KM Cremer Kirsten K Strom Tim M TM Bird Lynne M LM Sinnema Margje M Bitner-Glindzicz Maria M van Dooren Marieke F MF Alders Marielle M Koopmans Marije M Brick Lauren L Kozenko Mariya M Harline Megan L ML Klaassens Merel M Steinraths Michelle M Cooper Nicola S NS Edery Patrick P Yap Patrick P Terhal Paulien A PA van der Spek Peter J PJ Lakeman Phillis P Taylor Rachel L RL Littlejohn Rebecca O RO Pfundt Rolph R Mercimek-Andrews Saadet S Stegmann Alexander P A APA Kant Sarina G SG McLean Scott S Joss Shelagh S Swagemakers Sigrid M A SMA Douzgou Sofia S Wall Steven A SA Küry Sébastien S Calpena Eduardo E Koelling Nils N McGowan Simon J SJ Twigg Stephen R F SRF Mathijssen Irene M J IMJ Nellaker Christoffer C Brunner Han G HG Wilkie Andrew O M AOM

American journal of human genetics 20180531 6

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mi ...[more]

PMID: 29861108

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Project description:Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

Dataset Information

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Publications

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

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