DCX – Lissencephaly Spectrum Disorders

Lissencephaly spectrum disorders encompass a range of cortical malformations, from classical lissencephaly to subcortical band heterotopia, caused by defective neuronal migration. The X-linked gene DCX encodes doublecortin, a microtubule-associated protein vital for neuronal migration, and is causally implicated in these disorders (Lissencephaly Spectrum Disorders). Initial mutation screening in 11 unrelated females with subcortical laminar heterotopia identified DCX mutations in 10/11 cases, including nonsense, splice-site and missense variants, providing strong loss-of-function evidence ([PMID:9618162]).

Genetic evidence spans de novo and familial cases. Whole-exome sequencing in a sporadic 5-year-old girl with subcortical band heterotopia uncovered a heterozygous de novo DCX mutation c.665C>T (p.Thr222Ile), absent in both parents ([PMID:23583063]). Familial segregation has been demonstrated in an X-linked pedigree where a hemizygous boy presented with classical lissencephaly and his heterozygous mother with mild heterotopia, linked to a truncating p.Arg272Ter allele ([PMID:25868952]). Large cohorts now report over 153 distinct DCX mutations in ~188 patients, spanning missense, nonsense, frameshift and splice variants across affected males and females ([PMID:38045215]).

DCX mutations display an X-linked dominant inheritance pattern with hemizygous males developing severe lissencephaly and heterozygous females exhibiting subcortical band heterotopia. Segregation analysis confirms transmission from mosaic or affected carrier mothers, with at least one additional affected relative documented. The variant spectrum includes missense changes clustering in the conserved DC domains and truncating alleles leading to loss of microtubule binding, exemplified by c.665C>T (p.Thr222Ile).

Functional studies have elucidated DCX’s mechanism of pathogenicity. Patient-derived missense mutations and frameshifts within the tandem DC domains impair tubulin binding and microtubule polymerization in vitro and in vivo ([PMID:10946000], [PMID:10749977]). Mouse Dcx knockouts recapitulate migration defects and neuromuscular junction abnormalities, while rescue experiments with wild-type DCX restore neuronal migration in Lis1+/- neurons, confirming haploinsufficiency as the primary mechanism ([PMID:25817838]).

No conflicting reports have challenged the DCX–lissencephaly spectrum association; all studies consistently support loss of DCX function leading to neuronal migration failure. Additional evidence from large gene panels and exome sequencing reiterates DCX’s major contribution to X-linked cortical malformations beyond classical imaging patterns.

Integration of genetic and functional data yields a definitive gene-disease classification: DCX mutations reliably predict lissencephaly spectrum phenotypes, guiding molecular diagnosis, genetic counseling, and reproductive decision-making. Key take-home: DCX testing should be prioritized in males with lissencephaly and females with subcortical band heterotopia for accurate diagnosis and management.

References

• Pediatric neurology • 2013 • Identification of DCX gene mutation in lissencephaly spectrum with subcortical band heterotopia using whole exome sequencing. PMID:23583063
• Human Molecular Genetics • 1998 • doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). PMID:9618162
• The Journal of Biological Chemistry • 2000 • Patient mutations in doublecortin define a repeated tubulin-binding domain. PMID:10946000
• Human Molecular Genetics • 2000 • Doublecortin mutations cluster in evolutionarily conserved functional domains. PMID:10749977
• Heliyon • 2023 • DCX variants in two unrelated Chinese families with subcortical band heterotopia: Two case reports and review of literature. PMID:38045215
• Epilepsia • 2022 • Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics. PMID:35213059

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