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Condition report · Neurological

Lissencephaly Spectrum Disorders

Whole genome sequencing reads several genes, including DCX, ACTB, ACTG1, CEP85L and RELN, for changes that cause lissencephaly, a condition in which the brain's surface does not form its usual folds.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A group of conditions in which the brain's surface does not develop its usual folds, causing developmental delay, intellectual disability and seizures. This report covers several genes, including DCX, TUBG1, ACTB, ACTG1, CEP85L and RELN.

Lissencephaly means smooth brain. In these conditions the surface of the brain does not develop its usual folds, which causes developmental delay, intellectual disability and seizures that can be hard to control. Low muscle tone, later stiffness and feeding difficulties are also common. The severity varies a great deal between people and between genes.

Several genes can cause these conditions, and each plays a part in how nerve cells move into place in the developing brain. DCX is on the X chromosome and mainly affects males with classic lissencephaly, while females with a DCX change often have a milder form called subcortical band heterotopia. Changes in ACTB or ACTG1 cause Baraitser-Winter cerebrofrontofacial syndrome, which includes brain malformations, distinctive facial features, and eye and hearing problems.

Genetic counselling depends on the gene. Dominant changes often arise new in the affected person, DCX can be inherited from a carrier mother, and recessive forms such as RELN-related disease are passed on by two carrier parents. Care focuses on seizure control, feeding, physiotherapy and developmental support. Some other causes, such as PAFAH1B1 (LIS1) changes, are not part of this report.

The 5 conditions we analyse

Caused by changes in genes that control how nerve cells move into place in the developing brain. This report includes DCX on the X chromosome and APC2 (recessive).

Signs and symptoms

Developmental delay and intellectual disability, often severe, with seizures that can be hard to control. Low muscle tone, later stiffness and feeding difficulties are common. Females with a DCX change often have a milder form called subcortical band heterotopia, with seizures and variable learning difficulties.

What a diagnosis changes

Care focuses on seizure control, feeding and nutrition, physiotherapy and developmental support. Genetic counselling depends on the gene: dominant changes are often de novo, DCX can be inherited from a carrier mother, and recessive forms are passed on by two carrier parents.

Genes analysed

Also known as

Broad gyri of cerebrum; large gyri of cerebrum; Lissencephaly; lissencephaly (disease); macrogyria; pachygyria

Specific forms also covered

  • Baraitser-Winter Syndrome 2

    Autosomal dominant

    Caused by a change in one copy of ACTG1, which makes a form of actin, a key structural protein inside cells. The changes are missense variants that usually arise de novo.

    ACTG1

  • Lissencephaly 10

    Autosomal dominant

    Caused by a change in one copy of CEP85L, a protein involved in nerve cell migration. Changes may arise de novo or be inherited, and severity varies.

    CEP85L

  • Baraitser-Winter Cerebrofrontofacial Syndrome

    Autosomal dominant

    Caused by a change in one copy of ACTB (or ACTG1), the genes for the two cytoplasmic forms of actin. The changes are missense variants that usually arise de novo.

    ACTB, ACTG1

  • Lissencephaly with Cerebellar Hypoplasia

    Autosomal recessive

    Caused by changes in both copies of RELN, which guides the positioning of nerve cells in the developing cerebral cortex and cerebellum.

    CDK5, RELN

Includes 44 related subtypes ↓
  • Baraitser-Winter cerebrofrontofacial syndrome
  • Baraitser-Winter syndrome 1
  • Baraitser-winter syndrome 2
  • classic lissencephaly
  • cobblestone lissencephaly
  • cobblestone lissencephaly without muscular or ocular involvement
  • cortical dysplasia, complex, with other brain malformations 9
  • craniotelencephalic dysplasia
  • isolated lissencephaly type 1 without known genetic defects
  • lissencephaly 10
  • lissencephaly 4
  • lissencephaly 6 with microcephaly
  • lissencephaly 7 with cerebellar hypoplasia
  • lissencephaly 8
  • lissencephaly 9 with complex brainstem malformation
  • lissencephaly due to LIS1 mutation
  • lissencephaly due to TUBA1A mutation
  • lissencephaly spectrum disorder with complex brainstem malformation
  • lissencephaly type 1 due to doublecortin gene mutation
  • lissencephaly type 3
  • lissencephaly type 3-familial fetal akinesia sequence syndrome
  • lissencephaly type 3-metacarpal bone dysplasia syndrome
  • lissencephaly with cerebellar hypoplasia
  • lissencephaly with cerebellar hypoplasia type A
  • lissencephaly with cerebellar hypoplasia type B
  • lissencephaly with cerebellar hypoplasia type C
  • lissencephaly with cerebellar hypoplasia type D
  • lissencephaly with cerebellar hypoplasia type E
  • lissencephaly with cerebellar hypoplasia type F
  • massa casaer ceulemans syndrome
  • microlissencephaly
  • Miller-Dieker lissencephaly syndrome
  • muscle-eye-brain disease with bilateral multicystic leucodystrophy
  • Neu-Laxova syndrome
  • Neu-Laxova syndrome 1
  • Neu-Laxova syndrome 2
  • neu-laxova syndrome due to 3-phosphoserine phosphatase deficiency
  • Norman-Roberts syndrome
  • Warburg micro syndrome
  • Warburg micro syndrome 1
  • Warburg micro syndrome 2
  • Warburg micro syndrome 3
  • Warburg micro syndrome 4
  • X-linked lissencephaly with abnormal genitalia
MONDO:0018838Orphanet 48471MedGen 78604Sources: [2][1]

Why whole genome sequencing

Lissencephaly can have several genetic causes, and the right advice for a family depends on which gene is involved.

Several genes in one test

Changes in several genes can produce a smooth brain, with different patterns of inheritance. Whole genome sequencing reads the genes covered by this report in the same test rather than one gene at a time. Causes outside this report, such as PAFAH1B1 changes, are not covered.

Advice depends on the gene

For DCX, a carrier mother can pass the change to her sons, so relatives may be offered testing. For ACTB and ACTG1, most changes arise new, but genetic counselling and parental testing still guide the risk. For RELN, the recessive form is passed on by two carrier parents.

Limitations

  • Causes of lissencephaly such as changes or deletions in PAFAH1B1 (LIS1), including 17p13.3 deletions, and TUBA1A changes are not part of this report.
  • Some lissencephaly is caused by changes present in only some of a person's cells (mosaicism).

References

  1. Lambert de Rouvroit C, Goffinet AM, 2001. Neuronal migration. Mechanisms of development
  2. Geis T, Uyanik G, Aigner L, Couillard-Despres S, Winkler J, Hehr U, 2007. DCX-Related Disorders. GeneReviews
  3. Verloes A, Drunat S, Pilz D, Di Donato N, 2015. Baraitser-Winter Cerebrofrontofacial Syndrome. GeneReviews
  4. Schumann I, Abou Jamra R, Jauss RT, Karnstedt M, Specht U, Zacher P et al., 2025. Overview and expansion of CEP85L-associated lissencephaly. European journal of medical genetics
  5. Baraitser-Winter syndrome. MedlinePlus Genetics
  6. Yates TM, Turner CL, Firth HV, Berg J, Pilz DT, 2018. Baraitser-Winter cerebrofrontofacial syndrome. Clinical genetics
  7. Tsai MH, Muir AM, Wang WJ, Kang YN, Yang KC, Chao NH et al., 2020. Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly. Neuron
  8. Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B et al., 2015. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European journal of human genetics : EJHG
  9. Biglari S, Rezaei H, Asadollahzadeh E, Asl MS, Galehdari H, Garshasbi M et al., 2026. Zygosity-Dependent Phenotypic Spectrum of RELN-Related Disorders: 10 New Patients and Genotype-Phenotype Correlations Across 48 Kindreds. Human mutation

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