Beyond Neurodevelopmental Delay: BICRA-Related Coffin–Siris Syndrome 12 with Severe Intestinal Dysmotility and Recurrent Pneumothorax

TL;DR

This case report expands the known features of a rare genetic disorder, showing that it can cause serious intestinal and lung problems in addition to developmental delays.

Contribution

The paper reports new systemic complications in BICRA-related Coffin–Siris Syndrome 12, highlighting visceral and vascular involvement.

Findings

Severe intestinal dysmotility and colectomy were observed in a patient with BICRA-related CSS12.

Recurrent pneumothoraces and apical bullous lung disease were identified as new complications.

The BICRA variant disrupts a domain critical for protein interactions, supporting a loss-of-function mechanism.

Abstract

Background: Coffin–Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. Case Description: We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient’s systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. Conclusions: This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development.

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