SREBF1 – Hirschsprung Disease

SREBF1 has been implicated as a novel candidate in Hirschsprung disease (HSCR) based on whole-exome sequencing (WES) of two unrelated HSCR trios, where rare heterozygous SREBF1 variants were identified in each proband ([PMID:33151932]). Additional rare SREBF1 variants were detected in an expanded cohort of HSCR patients, although no affected relatives with segregating variants were reported. Given the low number of unrelated probands and absence of segregation data, the genetic support remains limited and warrants further case-level and familial studies.

Transcriptomic profiling confirmed SREBF1 expression in embryonic and fetal gastrointestinal neural crest–derived tissues. CRISPR-based knockout of SREBF1 in genome-edited neuronal cell clones led to markedly impaired enteric neuronal cell differentiation, reduced proliferation, and decreased survival, consistent with HSCR pathobiology ([PMID:33151932]). These functional data provide moderate experimental support, suggesting a loss-of-function mechanism in enteric nervous system development.

Key Take-home: SREBF1 represents a novel candidate gene for Hirschsprung disease with limited clinical validity but moderate functional evidence, highlighting the need for additional genetic and segregation studies to establish diagnostic utility and inform future research.

References

• PLoS Genetics • 2020 • A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PMID:33151932

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