Phenotypic Variability in Novel Doublecortin Gene Variants Associated with Subcortical Band Heterotopia

Abstract

Doublecortin, encoded by the DCX gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the DCX gene are the major causes of the "lissencephaly (LIS) spectrum", which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother-daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic-phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.

Keywords: DCX; Subcortical Band Heterotopia (SBH); doublecortin.

Figure 1

Brain MRI changes of Family 1, 2 and 3. Coronal (A-1) and axial (A-2) T1-weighted images of the proband (F1-III-1) of Family 1 showed a fronto-central SBH with mixed pachygyria (red arrows). Coronal (B-1), axial (B-2) and sagittal (B-3) T1 images of the F1-III-2 also showed a fronto-central SBH with mixed pachygyria together with a hypoplastic aspect of corpus callosum and cavum vergae (red arrows). Brain MRI (C-1–C-3) of the (F1-II-1) showed the same findings of the proband. Notice the dysmorphic aspect of corpus callosum (C-3, red arrow). MRI findings of the F1-I-1 with fronto-central SBH with mixed pachygyria and a dysmorphic aspect of corpus callosum as well (D-1,D-2). Coronal T1-weighted images of the proband (F2-II-1) of Family 2 show a bi-hemispheric fronto-parietal pachygyria with a thick SBH (E-1,E-2). Also notice the thick band of SBH of the proband (F3-II-1) of Family 3 (F-1, red arrow).

Figure 2

Pedigree of the families recruited and DCX sequence variants. (A) The fully filled symbols represent the affected individuals; unfilled symbols, unaffected; arrow, proband; plus, individuals undergoing genetic analysis. (B-1) Electropherogram shows the wildtype sequence (at the top), the c.601A>G variant in proband F1-III-1 and her affected family members (sister F1-III-2, mother F1-II-1, and grandmother F1-I-1) (middle), and the wildtype sequence in her unaffected father F1-II-2 (at the bottom). (B-2) The wildtype sequence (at the top), the c.210C>G variant in heterozygous proband F2-II-1 (middle), and the wildtype sequence in her unaffected mother F2-I-1 (at the bottom). (B-3) The wildtype sequence (above) and c.907C>T variant in heterozygous proband F3-II-1 (below).