BCL11B – Intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities

Intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities is a congenital, autosomal dominant syndrome (MONDO:0060763) characterized by global developmental delay (HP:0001263), speech impairment, craniofacial dysmorphism, and T-cell lymphopenia. Pathogenic variants in BCL11B disrupt its critical role in neurodevelopment and immune cell differentiation.

Heterozygous truncating variants in BCL11B have been identified in multiple unrelated probands. A novel de novo duplication, c.2439_2452dup (p.His818ArgfsTer31), was reported in a Japanese male with developmental delay, distinctive facial features, and early craniosynostosis (PMID:36470856). In a separate cohort, 13 additional patients harbored heterozygous frameshift, nonsense, missense, or chromosomal rearrangement variants, all presenting with global delay and variable immunophenotypes (PMID:29985992).

Inheritance is autosomal dominant with de novo occurrence in most cases. Segregation analysis in one pedigree demonstrated maternal transmission of a frameshift allele to two affected children, supporting co-segregation with disease in a multi-generational family (PMID:29985992).

Functional studies in a mouse hippocampal slice culture model revealed that C-terminal truncation variants fail to rescue neuronal progenitor proliferation defects seen in Bcl11b-deficient tissue, consistent with haploinsufficiency (PMID:29985992). Patient immunophenotyping further recapitulated the lack of peripheral type 2 innate lymphoid cells and altered T-cell subpopulations observed in knockout mice.

No conflicting reports have challenged the association between BCL11B haploinsufficiency and this neurodevelopmental-immunological syndrome. The combination of multiple independent probands, familial segregation, and concordant in vivo functional assays fulfills criteria for a Strong ClinGen gene-disease association.

Key Take-home: Heterozygous loss-of-function variants in BCL11B cause a distinct autosomal dominant syndrome of intellectual disability, dysmorphic facies, and T-cell abnormalities, supporting routine sequencing of BCL11B in undiagnosed developmental delay with immunodeficiency.

References

• Human genome variation • 2022 • Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis PMID:36470856
• Brain : a journal of neurology • 2018 • BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells PMID:29985992

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