BCL11A – Dias-Logan syndrome

Dias-Logan syndrome (MONDO:0014914), or BCL11A-related intellectual developmental disorder, is an autosomal dominant neurodevelopmental condition characterised by intellectual disability, global developmental delay, postnatal microcephaly, hypotonia, strabismus, dysmorphic facial features, autism spectrum behaviours and persistence of fetal hemoglobin (HbF). Haploinsufficiency of the B cell leukemia/lymphoma 11A gene (BCL11A) underlies the disorder through loss-of-function variants that disrupt its role as a transcriptional repressor in neural and hematopoietic development.

Genetic evidence: To date, 77 unrelated individuals with de novo heterozygous variants in BCL11A have been reported, including 30 frameshifts, 17 nonsense, 7 missense, 6 splice-site variants and 8 microdeletions, all consistent with autosomal dominant inheritance and de novo occurrence (77 probands (PMID:39448799)). Case reports describe novel truncating variants such as c.271delG (p.Glu91ArgfsTer2) in a boy with intellectual disability, language delay, strabismus and controlled epilepsy (1 proband (PMID:32903878)).

Functional evidence: In vitro studies demonstrate that BCL11A loss-of-function variants impair nuclear localization, dimerization and transcriptional repression activity, while mouse Bcl11a haploinsufficiency recapitulates cognitive impairment, social deficits and microcephaly observed in patients (PMID:27453576). Neuroimaging of affected individuals reveals hindbrain structural anomalies correlating with genotype, and persistence of HbF serves as a reliable biomarker of BCL11A dysfunction.

Diagnostic and clinical utility: Monitoring of HbF levels facilitates diagnosis, distinguishing Dias-Logan syndrome from phenocopies such as fetal alcohol spectrum disorders. Given the frequent co-occurrence of epilepsy, BCL11A should be included in developmental and epilepsy gene panels. Knowledge of variant spectrum and biomarker status informs genetic counselling and management, including anticipatory guidance for neurological and hematological features.

Key take-home: Heterozygous loss-of-function variants in BCL11A cause a consistent neurodevelopmental syndrome with persistent HbF, supporting its diagnostic inclusion in intellectual disability and epilepsy testing panels.

References

• Molecular syndromology • 2020 • A Novel de novo Frameshift Mutation in the BCL11A Gene in a Patient with Intellectual Disability Syndrome and Epilepsy. PMID:32903878
• SAGE open medical case reports • 2025 • Dias-Logan syndrome with a de novo p.Leu360Profs*212 heterozygous pathogenic variant of BCL11A in a Chinese patient: A case report. PMID:39835253
• European journal of human genetics : EJHG • 2025 • BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. PMID:39448799
• American journal of human genetics • 2016 • BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. PMID:27453576

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