P-15

Phenotypic spectrum of DCX pathogenic mutations in females: from childhood to adulthood clinical onset

Maria João Sá^I,II; Rui Chorão^III; Manuela Santos^III; Ana Maria Fortuna^I,II; Gabriela Soares^I

^IUnit of Medical Genetics, Centro Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto - EPE, Porto, Portugal
^IIMultidisciplinary Unit for Biomedical Research, UMIB, Porto, Portugal;
^IIIDepartment of Neuropediatrics, Hospital de Santo António/Centro Hospitalar do Porto - EPE, Porto, Portugal

Introduction: DCX-related disorders  (MIM#300067) are caused by pathogenic mutations in the DCX gene (MIM*300121; Xq23) that result in abnormal neuronal migration patterns, including isolated lissencephaly sequence (ILS) and subcortical band heterotopia (SBH; also called double cortex). Often occurring in males, ILS causes intellectual disability (ID) and childhood-onset epilepsy. More common in females, SBH is associated with a broad spectrum of clinical features, from ID and epilepsy to normal intelligence without epilepsy. We report two families that illustrate the phenotypic spectrum of DCX pathogenic mutations in females, from childhood to adulthood onset.

Patients and methods: Family 1: A 3 years old boy, born to non-consanguineous parents, presented with global developmental delay, seizures and microcephaly. Brain MRI diagnosed fronto-parietal classic lissencephaly. Sequence analysis of DCX detected a novel likely pathogenic variant, c.806G>T, p.(Gly269Val), in hemizygosity. Segregation analysis confirmed that his mother, who has mild ID and a frontal simplified gyration pattern shown by brain MRI, carries this variant in heterozygosity. Family 2: A 15 years-old girl, born to non-consanguineous parents, had epilepsy since 4 years old and global developmental delay. Brain MRI showed SBH and the previously reported pathogenic variant c.1150C>T, p.(Arg384*) was identified in DCX gene, in heterozygosity. Her mother, who carried the same mutation, had epilepsy with onset at 19 years old, an unremarkable brain MRI and normal intelligence.

Discussion: Pathogenic DCX  mutations  are  identified in approximately 40% of males with classic lissencephaly (more severe anteriorly than posteriorly), as well as in 85% of patients with SBH. Given the well-known genotype- phenotype correlation in DCX-related disorders, the decision of testing this gene was made based on the clinical and cerebral imaging features of the probands.

A novel likely pathogenic variant was identified in DCX, increasing the genotypic spectrum of mutations in this gene. DCX mutations were also detected in the probands’ mothers, who had previously non-investigated mild ID (family 1) and adult-onset epilepsy (family 2).

DCX-related disorders may not be clinically recognizable in females due to its clinical heterogeneity. Consequently, molecular testing of DCX is warranted in the mothers of affected children, allowing genetic counselling to at-risk family members, including prenatal diagnosis and preimplantation genetic diagnosis. Massive parallel sequencing, either whole exome or gene panels, of females with ID with or without epilepsy will likely increase detection of mutations in the DCX gene.