Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.

Sébastien Lebon,Andrea Superti-Furga,Carlo Rivolta,Virginie G Peter,Mathieu Quinodoz,Carole Gengler,Gaëlle Blanchard,Viviane Cina,Belinda Campos-Xavier

doi:10.3390/genes12091397

Abstract

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

Highlights

Agenesis of the corpus callosum (ACC) is one of the brain anomalies most frequently detected on prenatal imaging
We report on the molecular workup of a family with two sibs affected by agenesis of the corpus callosum (ACC) that led us to identify compound heterozygous variants in KDM5B leading to a syndromic phenotype with facial dysmorphism and intellectual disability, adding KDM5B to the list of genes associated with callosal abnormalities
There is evidence that KDM5B haploinsufficiency may be associated with a phenotype of developmental delay, its penetrance is incomplete [10]

Summary

Introduction

Agenesis of the corpus callosum (ACC) is one of the brain anomalies most frequently detected on prenatal imaging. In isolated ACC, intellectual disability is observed in approximatively 25% of cases only [2]. Because of this wide clinical spectrum, an extensive workup is necessary to provide accurate counseling in a prenatal setting. 30–45% of callosal abnormalities are estimated to occur in a syndromic context and to have an identifiable genetic origin, most commonly single gene variants. We report on the molecular workup of a family with two sibs affected by ACC that led us to identify compound heterozygous variants in KDM5B leading to a syndromic phenotype with facial dysmorphism and intellectual disability, adding KDM5B to the list of genes associated with callosal abnormalities

Case Reports

Findings

Discussion