Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders

Joanne Trinh,Gabriela Oprea,Martin Werber,Maximilian E R Weiss,Katja Lohmann,Shivendra Kishore,Krishna Kumar Kandaswamy,Arndt Rolfs

doi:10.1186/s11689-019-9270-4

Abstract

BackgroundRare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID).MethodsExome sequencing was performed on 4351 patients with global developmental delay, seizures, microcephaly, macrocephaly, motor delay, delayed speech and language development, or ID according to Human Phenotype Ontology (HPO) terms. All patients had previously undergone whole exome sequencing as part of diagnostic genetic testing with a focus on variants in genes implicated in neurodevelopmental disorders up to January 2017. This resulted in a genetic diagnosis in 1336 of the patients. In this study, we specifically searched for variants in 14 recently implicated novel neurodevelopmental disorder (NDD) genes.ResultsWe identified 65 rare, protein-changing variants in 11 of these 14 novel candidate genes. Fourteen variants in CDK13, CHD4, KCNQ3, KMT5B, TCF20, and ZBTB18 were scored pathogenic or likely pathogenic. Of note, two of these patients had a previously identified cause of their disease, and thus, multiple molecular diagnoses were made including pathogenic/likely pathogenic variants in FOXG1 and CDK13 or in TMEM237 and KMT5B.ConclusionsLooking for pathogenic variants in newly identified NDD genes enabled us to provide a molecular diagnosis to 14 patients and their close relatives and caregivers. This underlines the relevance of re-evaluation of existing exome data on a regular basis to improve the diagnostic yield and serve the needs of our patients.

Highlights

Rare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID)
* Correspondence: joanne.trinh@neuro.uni-luebeck.de †Katja Lohmann and Arndt Rolfs contributed to this work. 1Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany Full list of author information is available at the end of the article we find novel pathogenic or likely pathogenic variants in six recently identified neurodevelopmental disorder (NDD) genes, namely Cyclin-dependent kinase 13 (CDK13), Chromodomain-helicase-DNAbinding protein 4 (CHD4), Potassium voltage-gated channel subfamily Q member 3 (KCNQ3), Lysine methyltransferase 5B (KMT5B), Transcription factor 20 (TCF20), and Zinc finger and BTB domain containing 18 (ZBTB18)
Among all 4351 NDD patients, we identified 65 heterozygous variant carriers (1.5%), for 65 different rare, protein sequence-changing variants in 11 out of 14 genes recently nominated by the Deciphering Developmental Disorders (DDD) study [9] (Additional file 1: Figure S1 and Table S2)

Summary

Introduction

Rare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID). Major congenital malformations, which include neurodevelopmental disorders (NDDs), are present in ~ 2–5% of children [1]. Children with NDD have variable severity of phenotypic features and different behavioral abnormalities. NDD arises from de-novo variants in genes important for central nervous system (CNS) development [2]. Whole exome sequencing has been critical and effective in diagnosing patients with NDD. Treatment for NDD has become more refined through molecular genetic diagnosis rather than phenotype-driven management of symptoms [3].

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Conclusion