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

Margot R.F Reijnders,Mariya Kozenko,Jacqueline A.C Goos,Alexander P.A Stegmann,Peter J Van Der Spek,Merel Klaassens,Rolph Pfundt,Steven A Wall,Katelyn Payne,Andrew O.M Wilkie,Lynne M Bird,Kerry A Miller,Mohsan Alvi,Sarina G Kant,Diana Baralle,Nils Koelling,Patrick Yap,Bertrand Isidor,Scott Mclean,Lauren Brick,Dagmar Wieczorek,Phillis Lakeman,Michelle Steinraths,Kirsten Cremer,Eduardo Calpena,Rebecca O Littlejohn,Jacqueline Eason,Han G Brunner,Marieke F Van Dooren,Charu Deshpande,Simon J Mcgowan,Stephen R.F Twigg,Kate Chandler,Patrick Edery,Tim M Strom,Sébastien Küry,Bert B.A De Vries,Marije Koopmans,Carlo Marcelis,Alex Henderson,Hartmut Engels,Gijs W.E Santen,Rachel L Taylor,Megan L Harline,Alison Kraus,Shelagh Joss,Anna De Burca,Bronwyn Kerr,Irene M.J Mathijssen,Barbara Mikat,Sofia Douzgou,Margje Sinnema,Caroline Schluth-Bolard,Kelly Radtke,Saadet Mercimek‐Andrews ,Jill Clayton‐Smith ,Hermann‐Josef Lüdecke ,Ingo Helbig ,Sigrid Swagemakers ,Paulien A Terhal ,Claudia Ruivenkamp ,Mariëlle Alders ,Edward Blair ,Christoffer Nellåker ,N Cooper ,Kimberly Nugent ,Melissa Lees ,Katrina Tatton‐Brown ,Maria Bitner‐Glindzicz

doi:10.1016/j.ajhg.2018.04.014

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.

Highlights

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs)
By including Tousled-like kinase 2 (TLK2) in a Deciphering Developmental Disorders11 Complementary Analysis Project, by using of GeneMatcher,12 and by sharing data with international collaborators, we identified a total of 38 unrelated individuals and two affected mothers with heterozygous variants in TLK2
Two additional individuals with de novo TLK2 variants c.1514T>A (p.Val505Asp) and c.2171G>A (p.Arg724Gln), each of whom had a second likely pathogenic mutation in another gene, were excluded from further consideration to avoid confounding in the phenotypic analysis (Supplemental Subjects and Methods)

Summary

Introduction

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Two additional individuals with de novo TLK2 variants c.1514T>A (p.Val505Asp) and c.2171G>A (p.Arg724Gln), each of whom had a second likely pathogenic mutation in another gene, were excluded from further consideration to avoid confounding in the phenotypic analysis (Supplemental Subjects and Methods).

Results

Conclusion