Brain malformations

The spectrum of brain malformations (also termed structural brain anomalies or malformations of cortical development, MCD, when restricted to cortical forms) encompasses holoprosencephaly, primary microcephaly, megalencephaly, classic lissencephaly and subcortical band heterotopia,
polymicrogyria, periventricular and subcortical heterotopia, schizencephaly, and corpus callosum anomalies. Most cases are first identified on prenatal ultrasound or foetal MRI, or postnatally during evaluation for developmental delay, abnormal head circumference, seizures, or characteristic dysmorphic features. Onset spans the prenatal period through early infancy, reflecting a structural anomaly that is present from foetal life and manifests clinically depending on severity. Both syndromic and nonsyndromic presentations are clinically relevant: many entities occur as isolated brain malformations, while others form part of multisystem syndromes with extracerebral findings such as craniofacial anomalies, somatic overgrowth, or organ-specific manifestations.

Due to insufficient data, no reliable statement on prevalence can currently be made. A genetic cause is identifiable in a substantial proportion of individuals presenting with brain malformations; exome sequencing yields a molecular diagnosis in approximately 30-40% of paediatric brain-malformation cohorts, with higher yields after trio reanalysis.

More than 100 genes and loci have been associated with brain malformations, and submicroscopic microdeletions and microduplications represent a further important mechanistic class. The genetic forms can be grouped into disorders of forebrain patterning and midline development and malformations of cortical development. The most common genetic cause varies by malformation subtype: trisomy 13 is the most frequent cause of holoprosencephaly, deletions and germline pathogenic variants involving PAFAH1B1 predominate in classic lissencephaly, and somatic mTOR-pathway variants underlie a large proportion of focal cortical dysplasia and hemimegalencephaly.3 Disorders of forebrain patterning and midline development include nonsyndromic holoprosencephaly (SHH, ZIC2, SIX3, TGIF1; incomplete cleavage of the forebrain with HPE-spectrum craniofacial findings) and aneuploidy-associated holoprosencephaly (trisomy 13, trisomy 18, triploidy; most common chromosomal cause of holoprosencephaly). Malformations of cortical development include classic lissencephaly and subcortical band heterotopia (PAFAH1B1, DCX, TUBA1A; smooth cortex with
severe developmental delay and epilepsy) and mTOR-pathway megalencephaly and focal cortical dysplasia (MTOR, PIK3CA, AKT3, DEPDC5, TSC1, TSC2; somatic or germline mTOR-pathway activation causing focal or hemispheric overgrowth).

The genetic conditions associated with brain malformations follow heterogeneous inheritance patterns. Autosomal dominant, autosomal recessive, X-linked, and chromosomal (aneuploidy and structural rearrangements) mechanisms are all represented across the spectrum, with chromosomal
abnormalities identified in approximately 25-50% of individuals with holoprosencephaly. De novo variants account for a substantial share of severe cortical malformations such as classic lissencephaly and tubulinopathies.

• Where a brain malformation is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Tekendo-Ngongang C, Muenke M, Kruszka P. Holoprosencephaly overview. 2000 Dec 27 [Updated 2026 Jun 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301702.
• Kooshavar D, Amor DJ, Boggs K, Baker N, Barnett C, de Silva MG, et al. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Commun. 2024;6(2). doi:10.1093/braincomms/fcae056. PMID:; PMCID: PMC10914449. 
• Russ JB, Agarwal S, Venkatesan C, Scelsa B, Vollmer B, Tarui T, et al. Fetal malformations of cortical development: review and clinical guidance. Brain. 2025;148(6):1888-903. doi:10.1093/brain/awaf094. PMID:; PMCID: PMC12129737. 
• Hoeberigs MC, Tousseyn S, ACE Study Group. Malformations of cortical development: embryology and epilepsy. Epilepsia. 2025;66(10):3642-55. doi:10.1111/epi.18501. PMID:; PMCID: PMC12605774.