De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Maria João Nabais Sá ,Marieke F Van Dooren,Amélie Piton,Christiane Zweier,David J Amor,Somayeh Bakhtiari,Didier Lacombe,David A Koolen,Renzo Guerrini,Arjan P.M De Brouwer,Emilia K Bijlsma,Hanka Venselaar,Rolph Pfundt,Christian Gilissen,Anna Ruiz,Laurens Wiel,Regina Trollmann,Bert B.A De Vries,Tahsin Stefan Barakat,Michael C Kruer,Sophie Naudion,Aurélien Trimouille,Eulalie Lasseaux,Marjon Van Slegtenhorst,Annalisa Vetro,Elisabeth Gabau,M.a.a.p Willemsen ,Catherine Vincent‐Delorme

doi:10.1038/s41436-019-0703-y

Abstract

PurposeTo delineate the genotype–phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. MethodsWe describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. ResultsAll de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. ConclusionsThe wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Highlights

Three nonsense, two frameshift, three in-frame deletions, two missense and three splice site variants were identified in CLTC (Figure 1.a; Table S1) in seven males and six females
All missense variants had a CADD (Combined Annotation Dependent Depletion) score above 25.15 CLTC is depleted from truncating and missense variants in healthy individuals[12] suggestive for such variants being under strong purifying selection
Differences did not reach significance, severe intellectual disability (ID), epilepsy, microcephaly and hypoplasia of the corpus callosum were more frequent in the group of individuals with in-frame variants than in individuals with nonsense and frameshift variants (3/6 versus 0/10, 4/6 versus 1/9, 2/6 versus 0/9, 2/6 versus 0/9, respectively; Fisher’s exact p-values >0.05; Tables S1 and S4)

Summary

Introduction

Fisher’s Exact Test, using a two-sided p-value, was carried out to compare proportions of clinical features between groups of individuals with missense variants and in-frame deletions with nonsense and frameshift CLTC variants. Results Three nonsense, two frameshift, three in-frame deletions, two missense and three splice site variants were identified in CLTC (Figure 1.a; Table S1) in seven males and six females (median age: 14 years; range: 8 months – 41 years) .

Results

Conclusion